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Phase I study of samalizumab in chronic lymphocytic leukemia and multiple myeloma: blockade of the immune checkpoint CD200

Phase I study of samalizumab in chronic lymphocytic leukemia and multiple myeloma: blockade of... Purpose: Samalizumab is a novel recombinant humanized monoclonal antibody that targets CD200, an immunoregulatory cell surface member of the immunoglobulin superfamily that dampens excessive immune responses and maintains self-tolerance. This first-in-human study investigated the therapeutic use of samalizumab as a CD200 immune checkpoint inhibitor in chronic lymphocytic leukemia (CLL) and multiple myeloma (MM). Experimental design: Twenty-three patients with advanced CLL and 3 patients with MM were enrolled in an open- label phase 1 study (NCT00648739). Patients were assigned sequentially to one of 7 dose level cohorts (50 to 600 mg/m ) in a 3 + 3 study design, receiving a single dose of samalizumab intravenously once every 28 days. Primary endpoints were safety, identification of the maximum tolerated dose (MTD), and pharmacokinetics. Secondary endpoints were samalizumab binding to CD200, pharmacodynamic effects on circulating tumor cells and leukocyte subsets, and clinical responses. Results: Twenty-one patients received > 1 treatment cycle. Adverse events (AEs) were generally mild to moderate in severity. Samalizumab produced dose-dependent decreases in CD200 expression on CLL cells and decreased frequencies of circulating CD200 + CD4+ T cells that were sustained at higher doses. The MTD was not reached. Decreased tumor burden was observed in 14 CLL patients. One CLL patient achieved a durable partial response and 16 patients had stable disease. All MM patients had disease progression. Conclusions: Samalizumab had a good safety profile and treatment was associated with reduced tumor burden in a majority of patients with advanced CLL. These preliminary positive results support further development of samalizumab as an immune checkpoint inhibitor. Trial registration: ClinicalTrials.gov, NCT00648739 registered April 1, 2008. Keywords: CLL, Multiple myeloma, CD200, Immune checkpoint inhibitor, Samalizumab * Correspondence: DMahadevan@uacc.arizona.edu Department of Medicine Division of Hematology/Oncology, University of Arizona Cancer Center, 1515. N. Campbell Avenue, Room 1905, Tucson, AZ 85724, USA Full list of author information is available at the end of the article © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Mahadevan et al. Journal for ImmunoTherapy of Cancer (2019) 7:227 Page 2 of 13 Introduction tumor immunity such as activated T cells and dendritic CD200 and CD200 receptor (CD200R) are highly con- cells [26]. Blockade of various immune checkpoints, served type I paired membrane glycoproteins, consisting alone or in combination, to reverse T-cell mediated im- of two immunoglobulin (Ig)-like domains (V and C) that mune suppression and activate anti-tumor immunity is a belong to the Ig protein superfamily [1–3]. CD200 is promising approach to treating cancers [19–21, 27]. widely expressed on a variety of cell types, including B Durable clinical responses, including enhanced survival, cells, a subset of T cells, dendritic cells, endothelial, neur- have been reported with therapeutic blockade of CTLA-4 onal and other cells, while CD200R expression is largely with ipilimumab, and of PD-1 with pembrolizumab and limited to subsets of T cells and myeloid lineage cells [3–7]. nivolumab in patients with melanoma, non-small cell lung The ligation of CD200 with its receptor, CD200R, im- cancer, renal cancer and head and neck squamous cell car- parts a multipronged immunosuppressive signal, po- cinoma, leading to FDA approvals [28–35]. Combination tently inhibiting T-cell immune responses and natural therapy blocking both CTLA-4 and PD-1 is now approved killer (NK) cytotoxic activity, promoting macrophage for melanoma. Other combinations of targeted therapies, secretion of indoleamine-2,3 dioxygenase (IDO), an immune checkpoint inhibitors and activators that enhance immunosuppressive tryptophan-catabolizing enzyme, and innate immunity are also being evaluated [36–40]. triggering regulatory T cell (T )expansion [8–12]. The Samalizumab is a novel recombinant, humanized mono- reg immune checkpoint function of CD200 on dendritic cells clonal antibody (mAb) that specifically binds to CD200 and lymphoid effector cells modulates the activation and blocks its ligation to the CD200 receptor (CD200R). threshold of inflammatory immune responses and con- Samalizumab was rationally engineered with an Ig G2/G4 tributes to the maintenance of self-tolerance [13]. constant region to minimize effector function and pre- CD200 is overexpressed in a wide variety of solid and serve immune cell subsets [26]. hematological tumor cell types, including chronic lympho- This is a first-in-human phase I trial to evaluate the cytic leukemia (CLL) multiple myeloma (MM), acute mye- safety, pharmacokinetics (PK), pharmacodynamic (PD), loid leukemia (AML) and others, and is also expressed at and anti-tumor activity of CD200 blockade with samali- elevated levels on cancer stem cells [14–18]. McWhirter zumab in patients with CLL and MM, and to identify et al. first showed that primary tumor cells from CLL the maximum tolerated dose (MTD) and dose-limiting patients overexpress CD200 compared with expression on toxicity (DLT) of samalizumab. normal B cells [14]. Dampened anti-tumor cytotoxic T cell (CTL) responses Methods are associated with the overexpression of immune check- Eligibility and study schema points including CD200, cytotoxic T lymphocyte antigen- This was an open-label, multi-center, sequential cohort 4 (CTLA-4) and programmed death-1 (PD-1) on tumor, dose escalation study (June 2008 - Dec. 2010). The pri- immune and stromal cells within the tumor microenvir- mary endpoints were safety, identification of MTD, and onment, and the consequent immunoregulatory signaling characterization of PK. Secondary endpoints were sama- events following binding to their respective ligands or lizumab binding to CD200, PD effects on circulating receptors [19–21]. Down-regulation of allogeneic Type 1 tumor cells and leukocyte subsets, and clinical responses T helper (Th1) responses, as measured by decreases in to treatment. The study was conducted in accordance interleukin-2 (IL-2) and interferon-gamma (IFN-γ), was with the Declaration of Helsinki and principles of the noted following the addition of primary CLL cells to an in International Conference on Harmonisation guidelines vitro mixed lymphocyte reaction, and anti-CD200 anti- on Good Clinical Practice. bodies reversed this effect, restoring Th1 responses and Patients with relapsed or refractory CLL or MM, de- suppressing T [14, 16, 22, 23]. In syngeneic and fined as either having failed or refractory to at least one regs xenograft murine models, treatment with anti-CD200 approved therapeutic agent, or who declined standard antibodies restored lymphocyte mediated anti-tumor treatment options, were eligible. Additional inclusion responses in vivo [23, 24]. criteria included an Eastern Cooperative Oncology Group In addition to immunosuppression, overexpression of performance status score of 0–2 and anticipated survival CD200 on tumor cells has been correlated with aggres- of > 6 months. Patients were excluded from the study if sive tumor progression, greater metastatic potential, and they met any of the following criteria: absolute neutrophil 9 9 reduced patient survival, which suggests that CD200 is a count < 1000 × 10 /L, platelet count < 50,000 × 10 /L; promising target for cancer immunotherapy [15, 25]. Ac- pregnant or lactating; prior history of autoimmune cumulated evidence supports the rationale for develop- hemolysis; immune thrombocytopenia; active autoimmune ing therapeutic anti-CD200 antibodies lacking effector disease requiring immunosuppressive therapy; positive function to block CD200-CD200R-mediated signaling Coombs’ test; chronic infection with HBV, HCV or HIV; while preserving immune components critical for anti- ongoing corticosteroid treatment equivalent to ≥10 mg/day Mahadevan et al. Journal for ImmunoTherapy of Cancer (2019) 7:227 Page 3 of 13 of prednisone; prior stem cell transplantation or prior vital signs, ECG, and physical and ophthalmology slit chemotherapy within 4 weeks or 30 days of enrollment, lamp examinations. respectively; neurosurgery or cranial radiotherapy within one year of enrollment; serum creatinine > 1.5 times upper Pharmacokinetic assessment limit of normal, alanine amino transferase or aspartate Blood samples for PK analyses in cycle 1 were collected amino transferase > 2.5 times upper limit of normal, cardio- at pre-dose on day 0 (0 h) and at 0.5 h, end of infusion, pulmonary disease (New York Heart Association Func- and 8, 24, 48, 72, 168, 240, 336, 672, and 1008 h after tional Class III or IV); active systemic bacterial or fungal the start of the infusion. Estimated PK parameters for infection; prior therapy with another investigational prod- samalizumab, derived from serum concentration-time uct within 30 days of screening; or any condition that could curves, were total clearance (CL), maximum concentra- increase the patient’sriskor confoundoutcome,at the tion (C ), time to reach C (T ), terminal elimin- max max max investigators’ discretion. ation half-life (T ), volume of distribution based on 1/2 Patients were assigned sequentially to one of 7 dose terminal elimination phase (V ) and area under the z , level cohorts following a 3 + 3 study design: 50 mg/m , serum concentration-time curve from time zero extrapo- 2 2 2 2 2 100 mg/m , 200 mg/m , 300 mg/m , 400 mg/m , 500 mg/m lated to infinity (AUC ). PK parameters were estimated or 600 mg/m . Each patient only received the dose to which using non-compartmental methods with WinNonlin® they were assigned. The first dose day was considered (Version 6.4, Pharsight Corporation, Menlo Park, CA). as cycle 1, day 0. Patients who tolerated the study drug See Additional file 1 for methodologic details. and had at least stable disease at six weeks following the first dose were permitted to continue therapy until Pharmacodynamic assessment they experienced disease progression, toxicity, or if the Blood samples for the measurement of PD markers in investigator or patient wished to discontinue therapy. cycle 1 were collected pre-dose on day 0, and post-dose Additional dosing cycles at the same dose were added on days 1, 7, 14, 24, and 42; during cycles 2 to 4, PD as one dose per 28-day cycle, beginning no sooner than assessments were evaluated pre-dose and on day 14. six weeks after the initial dose. Samalizumab binding to CD200 on circulating CLL cells At least three patients were assigned per cohort; if none was evaluated by multi-parametric flow cytometry using experienced a DLT, escalation to the next dose level a fluorescently-labeled mAb specific for samalizumab occurred with a new cohort. A DLT was defined as any together with a second anti-CD200 mAb specific for an grade 3 or greater toxicity, according to the NCI Common epitope of CD200 distinct from the binding site of sama- Terminology Criteria for Adverse Events (CTCAE) ver- lizumab. CD200 and CD200R expression on peripheral sion 3.0, (NCI 2006) occurring in the first 28 days after T-cell subsets (CD3+, CD4+, CD8+, activated T cells, dosing in cycle 1. Patients were followed for 10 weeks after T ) collected from CLL and MM patients were evalu- regs their last dose with safety, PK, PD, anti-tumor and clinical ated by immunofluorescence and flow cytometry. Data response evaluations. were analyzed as percent of CD200+ cells within the in- Baseline evaluations for all patients included medical dicated population as well as by mean channel fluores- history, physical examination, ophthalmologic slit lamp cence intensity (MFI) of bound antibody to reflect the examination, CBC and differential, chemistry and thy- CD200 density on CD200+ cells. See Additional file 1 roid panels, electrocardiogram (ECG), hepatitis and HIV for methodologic details. serology, Coombs’ test, anti-drug antibody (ADA), co- agulation panel, and bone marrow biopsy (optional). CT Cytokine assessment scans were performed in all CLL patients, while MM Serum from patients was evaluated for interleukin (IL)- patients were evaluated for beta-2 microglobulin, serum 1β (IL-1β), IL-2, IL-4, IL-6, IL-10, IL-12p70, IFN-γ and protein electrophoresis, serum free light chain and ratio, tumor necrosis factor alpha (TNF-α) pre-dose and at 24 h urine for total protein and urine protein electrophor- various times post-dose through week 10 (See Additional esis, serum viscosity, and skeletal survey. See Additional file 1 for methodologic details). file 1 for further information on dosing and clinical laboratory assays. Anti-tumor assessment Clinical responses were based on the Modified NCI Working Group Response Criteria for CLL [41]and on Safety and tolerability the International Myeloma Working Group Uniform The safety and tolerability of samalizumab in the study Response Criteria for MM [42]. For CLL, the overall re- patient population were assessed by treatment-emergent sponse rate (ORR) was defined as the percentage of pa- adverse events (TEAEs), treatment-emergent serious tients who maintained their best response for at least adverse events (SAEs), clinical laboratory evaluations, one month after achieving that best response and having Mahadevan et al. Journal for ImmunoTherapy of Cancer (2019) 7:227 Page 4 of 13 either a complete response (CR), partial response (PR), not complete the study and died of progressive disease nodular partial response (nPR), or stable disease (SD). shortly after two weeks of follow-up. A total of 256 Progressive disease (PD) was defined by one of the fol- TEAEs were reported by 25 (96%) patients; the most lowing: > 50% increase in the sum of the products of at commonly reported TEAEs are listed in Table 2. Five least two lymph nodes (at least one lymph node must be patients experienced TEAEs that were deemed possibly, > 2 cm), appearance of new lymph nodes, > 50% increase probably, or definitely related to study drug that were in the size of the liver and/or spleen, > 50% increase in grade 3–4 in severity. The most common drug-related the absolute number of circulating lymphocytes to at grade 3–4 TEAEs were blood and lymphatic system dis- least 5000/uL, or transformation to a more aggressive orders (anemia, neutropenia, and thrombocytopenia) re- histology (Richter’s Syndrome). For MM, ORR was de- ported in three patients (12%). The other drug-related fined as the percentage of patients who had sCR (strin- grade 3–4 TEAEs were reduced visual acuity and mus- gent CR), CR, very good partial response (VGPR), or PR cular weakness (both in the same patient, 4%), respira- on two consecutive assessments made at any time before tory syncytial virus infection (1 patient, 4%), and rash (1 the administration of any new therapy. PD was defined patient, 4%) (Table S1). TEAEs that were considered def- as > 25% increase of urine M-protein. initely related to the study drug occurred in two of three Computed tomography (CT) scans of the neck, chest, patients with elevated ADA at the time of samalizumab abdomen, and pelvis in CLL patients were evaluated administration: hypersensitivity (grade 1 allergic reac- using sum of the products of bi-dimensional measure- tion) and urticaria (grade 2 hives). ments of all target lesions [41], Additional cycles of Of the 26 study participants, six (23%) experienced at treatment were continued if there was evidence of re- least one SAE; four (15%) had SAEs considered unre- sponse by blood counts or physical exam at weeks 4 and lated to study drug and two (8%) had SAEs considered 8. Anti-tumor responses were evaluated as the percent possibly related to study drug. One fatal SAE, due to change from baseline in lymphadenopathy. complications post-elective cholecystectomy and ensuing renal failure, occurred 23 days after the fourth dose of Statistical analyses 100 mg/m . The investigators determined that the event was Patients who received at least one dose of samalizumab unrelated to samalizumab. No SAEs led to discontinuation. were included in safety, PK, PD, and clinical response- In some patients, ECGs revealed heart rate, PR interval, analyses. Data collected at all sites were pooled for ana- QRS duration and QTc intervals outside normal ranges lysis, and descriptive statistics were used to summarize the on occasion, but these were not clinically significant data. All tables and listings were generated using SAS® events. In aggregate, no QT interval changes were ob- Version 9.2 or higher (SAS Institute, Inc., Cary, NC). served. No significant ophthalmologic findings were at- tributed to samalizumab treatment. Results Patient disposition and treatment exposure Pharmacokinetics Twenty-six patients, 23 with CLL (4 were treatment Following a single intravenous dose of samalizumab naïve) and 3 with MM, were enrolled from June 2008 to (100–600 mg/m ), the mean T values across all dose max December 2010 across four study sites. Patient charac- levels ranged from 1.23 to 8.93 h, the mean T for 1/2 teristics are given in Table 1. All 26 patients received at samalizumab increased from 85.1 h to 537.9 h (3.5 to least one samalizumab dose. The clinical study was 22.4 days), and mean systemic CL showed a decreasing amended to allow multiple doses of samalizumab to be trend in the three highest dose cohorts (Table 3). The administered. Twenty-one patients (81%) received mul- mean V did not appear to be dose related. C in- z max tiple dosing cycles and five patients (19%), including two creased in a dose-proportional manner and AUC MM patients, received one dose. Thirteen patients (50%) increased in a more than dose-proportional manner. For received ≥4 cycles of samalizumab. The maximum number C the β value was 1.01 (95% CI: 0.85–1.17) and for max, of cycles received by any patient was 18 (300 mg/m dose AUC , the β value was 2.01 (95% CI: 1.59–2.42). The cohort). The study was terminated prematurely by the serum concentration-time profiles of samalizumab are sponsor for administrative reasons. Data from all 26 pa- graphed as the mean serum concentration of samalizumab tients were analyzed except where noted. after the first intravenous administration at the indicated doses. Error bars represent the standard deviation Safety and adverse events (Additional file 1:FigureS1). The MTD was not reached, and administration of sama- lizumab from 50 to 600 mg/m was well-tolerated in pa- Pharmacodynamics tients with CLL or MM. Only one patient was treated The binding of samalizumab to CD200 on peripheral with the 600 mg/m dose; this patient (with MM) did CLL cells was evaluated in 21 of 23 (91%) CLL patients. Mahadevan et al. Journal for ImmunoTherapy of Cancer (2019) 7:227 Page 5 of 13 Table 1 Patient characteristics 2 2 2 2 2 2 2 Parameter 50 mg/m (N = 4) 100 mg/m (N = 5) 200 mg/m (N = 3) 300 mg/m (N = 3) 400 mg/m (N = 3) 500 mg/m (N = 7) 600 mg/m (N = 1) Total (N = 26) % Gender Male 3 3 2 1 3 6 0 18 69 Female 1 2 1 2 0 1 1 8 31 Race Caucasian 3 4 3 3 2 6 1 23 89 Black 0 1 0 0 1 1 0 3 11 Age (years, at screening) Mean (SD) 64.645 (11.7737) 60.716 (13.5373) 62.387 (20.6538) 68.227 (15.4956) 74.25 (11.0807) 67.104 (9.5240) 65.92 (NA) 65.9 (12.14) Median 66.92 59.43 61.370 70.500 69.00 66.98 65.92 66.9 Range 49.84–74.9 41.0–77.3 42.26–83.53 51.72–82.76 66.77–86.98 53.65–79.69 65.92 41–87 Type of malignancy CLL 4 4 43 35 023 89 Multiple Myeloma 0 0 0 0 0 2 1 3 11 Time from diagnosis to first samalizumab dose (days) Mean (SD) 3672.3 (3323.28) 1556.6 (1571.86) 3017.0 (912.22) 1577.3 (1010.13) 3371.0 (2045.69) 1850.4 (1190.99) 1451.0 (NA) 233 (1817.1) Median 2510.5 813.0 2922.0 1264.0 3061.0 1649.0 1451.0 1887 Range 1148–8520 43–4200 2156–3973 761–2707 1498–5554 154–3123 1451–1451 154–8520 Patients with previous chemotherapy 3 3 3 3 2 7 1 22 85 Patients with previous radiation 0 0 0 0 0 1 1 2 8 Patients without prior chemotherapy1 2 00 10 04 15 or radiation treatments Study completion Yes 2 3 0 1 1 2 0 9 34.6 No 2 2 3 2 2 5 1 17 65.4 Reason for non-completion Treatment-emergent adverse event 1 0 1 2 1 0 0 5 19.2 Patient requested to withdraw 1 0 1 0 0 2 0 4 15.4 Lack of efficacy 0 0 0 0 1 2 0 3 11.5 Investigator considered it advisable/in0 0 00 01 12 7.7 the patient’s best interest Patient did not complete follow up 0 1 0 0 0 0 0 1 3.8 Death (not related to study drug) 0 1 0 0 0 0 0 1 3.8 Positive antidrug antibody serology 0 0 1 0 0 0 0 1 3.8 Mahadevan et al. Journal for ImmunoTherapy of Cancer (2019) 7:227 Page 6 of 13 Table 2 Treatment-emergent adverse events (TEAEs) reported in ≥5% patients by organ system System Organ Class Samalizumab Treatment Group 2 2 2 2 2 2 50 mg/m 100 mg/m 200 mg/m 300 mg/m 400 mg/m 500 mg/m 600 mg/m Overall N =4 N =5 N =3 N =3 N =3 N =7 N =1 N =26 General Disorders and 11 (42) Administration Sites Fatigue 1 (25) – 1 (33) 3 (100) – 1 (14) – Peripheral coldness 1 (25) –– – – –– Pyrexia –– – – – 1 (14) – Chills –– – – – 1 (14) – Edema –– – 2 (67) –– – Skin and Subcutaneous Tissue 9 (35) Erythema –– – 1 (33) –– – Night sweats –– – – – 1 (14) – Pruritus 1 (25) 1 (20) –– –– – Rash 1 (25) 1 (20) 1 (33) 1 (33) –– – Urticaria 1 (25) –– – – –– Gastrointestinal 5 (19) Abdominal distension –– – 1 (33) –– – Abdominal Pain –– – 2 (67) –– – Diarrhea 1 (25) 1 (20) –– –– – Infections and Infestations 4 (15) Upper Respiratory Tract Infection – 1 (20) –– 1 (33) 1 (14) – Abscess –– – 1 (33) –– – Musculoskeletal and Connective 4 (15) Tissue Arthralgia –– – 1 (33) –– – Muscular weakness 1 (25) –– – – –– Myalgia 1 (25) –– – – –– Stiffness – 1 (20) –– –– – Nervous System 3 (12) Dizziness –– – 1 (33) –– – Headache –– – – – 1 (14) – Paraesthesia –– – 1 (33) –– – Blood and Lymphatic System 7 (27) Anemia –– – 1 (33) 1 (33) –– Neutropenia 2 (50) –– 1 (33) 1 (33) –– Thrombocytopenia –– – – 1 (33) –– Eye 6 (23) Eye pain 1 (25) –– – – 1 (14) – Night blindness 1 (25) –– – – –– Photophobia 1 (25) –– – – 1 (14) – Reduced visual acuity 1 (25) –– – – –– Laboratory –– – – – 2 (8) Increased blood viscosity – 1 (33) – Decreased platelets 1 (20) – Mahadevan et al. Journal for ImmunoTherapy of Cancer (2019) 7:227 Page 7 of 13 Table 2 Treatment-emergent adverse events (TEAEs) reported in ≥5% patients by organ system (Continued) System Organ Class Samalizumab Treatment Group 2 2 2 2 2 2 50 mg/m 100 mg/m 200 mg/m 300 mg/m 400 mg/m 500 mg/m 600 mg/m Overall N =4 N =5 N =3 N =3 N =3 N =7 N =1 N =26 Respiratory, Thoracic and Mediastinal 4 (15) Cough –– – – – 1 (14) – Dyspnea –– – 1 (33) – 1 (14) – Pulmonary edema –– – – – 1 (14) – Values in parentheses are the percentage of patients Only one occurrence per patient counted for each category “-” indicates zero Two patients were not evaluable because of insufficient By day 1 after samalizumab dosing, all evaluable patients circulating CLL cells and high background level staining showed a decrease in the frequency of peripheral CD200+ precluding reliable analysis. Despite considerable inter- CD4+ T cells (range of − 15.6% to − 85.3% from baseline). patient variability in baseline peripheral CLL counts Of 17 patients who received > 1 dose of samalizumab, 16 (range 0.8–90.7%), nearly all CLL cells (85 to 100%) were (94%) continued to show reductions in CD200+ CD4+ T CD200+, although there was wide interpatient variation cell frequencies in response to dosing. Similar to the reduc- in the intensity of CD200 expression on CLL cells. tion in CD200 expression observed on CLL cells, a dose- On day 1 after dosing, bound samalizumab was de- dependent reduction in the frequencies of peripheral tected on peripheral CD200+ CLL cells in 16 of 21 CD200+ CD4+ T cells was also observed, with transient (76%) evaluable patients. Increased binding was observed responses at low doses (50–200 mg/m ) and sustained 2 2 at higher doses (200–500 mg/m ). The range of frequen- responses at higher doses (300–500 mg/m ). cies of CLL cells with bound samalizumab on day 1, and With the exception of CD200+ CD4+ T cells, no ap- the density of bound samalizumab MFI by dose cohort parent dose-dependent effect of samalizumab on other are summarized in Table 4. Down-regulation of CD200 T-cell subsets was found. Changes in the frequencies of expression on CLL cells was observed in 18 of 21 pa- CD3+ cells or total CD4+ cells (regardless of CD200 ex- tients (86%) after samalizumab dosing (Fig. 1a). The pression) revealed considerable inter-patient variability density of CD200 expression (MFI) on day 1 was re- across and within cohorts, with no clear trends discern- duced from baseline by 6.8–74.3%. A dose-dependent re- able. Cell counts of CD8 + cells, activated T cells, and duction in CD200 expression on CLL cells was observed T , at baseline or during treatment, were too low to regs after multiple dosing: transient reductions in CD200 ex- provide reliable results. A notable exception is Patient pression were generally observed in patients treated with #102–502, treated at the 400 mg/m dose, who had suffi- lower doses (50–200 mg/m ), whereas sustained reduc- cient immune cells for analysis; this patient is discussed tions were seen in 18 of 21 evaluable patients (86%) pa- in the Additional file 1 (pages 8–10). Patients with MM tients receiving higher doses (300–500 mg/m ). received up to three doses of samalizumab and showed The percent change from baseline in peripheral CD200+ little change in T-cell subsets. CD4+ T cells for all evaluable CLL and MM patients is In one patient, a transient increase in peripheral B-CLL showninFig. 1b. Of the 26 enrolled patients, 21 (81%) were count, absolute lymphocyte count and white cell count evaluated; four patients with CLL and one with MM were was observed following initial samalizumab treatment not evaluable due to insufficient circulating immune cells. (Additional file 1: Figure S2). The observed binding to Table 3 Summary of samalizumab PK parameters Dose No. of patients T C AUC T CL V max max ∞ 1/2 z (h) (μg/mL) (μg·h/mL) (h) (mL/h) (mL) 100 mg/m 5 2.21 ± 3.25 38.9 ± 4.75 2792 ± 2227 85.1 ± 60.9 101 ± 67.5 8246 ± 1499 200 mg/m 3 1.23 ± 0.09 90.2 ± 10.6 11,957 ± 6599 107 ± 45.2 36.3 ± 14.9 4943 ± 469 300 mg/m 3 4.71 ± 4.65 109 ± 42.7 36,636 ± 11,540 371 ± 48.9 16.9 ± 4.15 9186 ± 3215 400 mg/m 3 8.93 ± 11.1 135 ± 37.8 37,679 ± 7219 245 ± 33.9 21.3 ± 4.61 7391 ± 897 500 mg/m 7 3.87 ± 1.85 211 ± 44.9 62,898 ± 24,222 365 ± 172 19.5 ± 10.4 8490 ± 1715 600 mg/m 1 3.08 288 134,629 538 7.58 5880 Values are presented as Mean ± SD. The samalizumab serum concentration assay had a lower limit of quantification of 3.70 μg/mL and the standard curve ranged from 3.7 to 100 μg/mL Assay precision was 1 to 18% and accuracy was 93.2 to 127.8% (Mean % of recovery) Mahadevan et al. Journal for ImmunoTherapy of Cancer (2019) 7:227 Page 8 of 13 Table 4 Samalizumab bound to CD200+ CLL cells by cohort Samalizumab Cohort CLL cells bound by samalizumab (%) Density of bound samalizumab (MFI) Pre-dose Day 1 Pre-dose Day 1 50 mg/m (n = 4) 0.3–0.7 1.1–3.3 1.9–3.1 3.3–4.1 100 mg/m (n = 5) 0.2–2.4 0.2–9.5 3.5–5.6 5.0–11.1 200 mg/m (n = 2) 0.3–0.7 27.8–29.6 3.2–3.3 16.6–19.3 300 mg/m (n = 2) 0.5–0.7 5–28.6 1.7–3.0 5.6–16.8 400 mg/m (n = 3) 1.1–5.7 1.7–71.3 1.7–3.4 4.6–26.6 500 mg/m (n = 5) 0.5–2.1 1–47.0 1–3.7 1.9–17.6 Binding of samalizumab to CD200 on circulating CLL cells was evaluated by multi-parametric flow cytometry using a fluorescently-labeled monoclonal antibody specific for samalizumab (7B8) together with a second anti-CD200 antibody (IB2) specific for an epitope of CD200 distinct from the binding site of samalizumab CD200+ B-CLL cells and the reduction in CD200 ex- subsequent scan after dosing with samalizumab, 14 (64%) pression indicates that samalizumab is binding to and had a decrease in tumor burden post-dosing. Twelve of blocking its intended target, the immunoregulatory these patients were from all dose level cohorts and had a molecule CD200. However, even at doses of 500 mg/m , maximum decrease in lymphadenopathy ranging from 3.3 neither maximal saturation of CD200 binding nor maximal to 28.7%. Two patients had a > 50% reduction in the total sustained decreases in CD200 expression on the B-CLL tar- amount of lymphadenopathy: these patients were from get cells was achieved. Changes from Baseline in absolute the two highest dose cohorts (400 and 500 mg/m )and lymphocyte count and circulating B-CLL cells were found had maximum decreases in lymphadenopathy of 63.4 and to trend similarly: an overall reduction in peripheral B-CLL 73.7%, respectively. A 30% decrease in total lymphadenop- cells after samalizumab dosing paralleled the reduction in athy was the cut-off below which lymph node regression absolute lymphocyte count. In 14/23 (56.5%) patients, this was considered a clinically significant improvement. The increase was followed by a reduction in both peripheral maximum change in lymphadenopathy in individual pa- CLL cells and absolute lymphocyte count with multiple tients is shown in Fig. 2. samalizumab doses (% decrease 0.5 to 50%). Eight patients from all dose level cohorts had a max- Detectable levels of Th1 and Th2 cytokines (IFN-γ, IL- imum increase in lymphadenopathy (range: 2.8 to 118%). 2, IL-10, IL-12p70 and TNF-α) were observed following Two of these patients had a > 50% maximum increase in the first dose, but levels were neither sustained nor asso- lymphadenopathy, a cut-off above which lymph node en- ciated with clinical symptoms (data not shown). largement represents progressive disease. Twenty of the 22 patients (91%) showed a decrease in Response to therapy thesizeofatleast asinglelesion. Ten(45%)had amax- The ORR for CLL patients was 4% (1 of 23) with this imum reduction > 40% and five (23%) had > 50% reduc- conservative dosing schedule. Sixteen CLL patients tion. The reductions in individual lesions did not (70%) achieved SD, and five patients (22%) had PD. One always correlate with a similar reduction in the sum of patient was not evaluable and one patient had a PR that the bi-dimensional products of target lesions at the same was confirmed at cycle 12 (Patient #102–502; see case time point. Eight patients (36%) had an increase in the study in Additional file 1 – pages 3–5and 8–10). Patient sum of products of bi-dimensional target lesions at the #102–502 was a newly diagnosed with Rai stage IV and time they experienced a maximum reduction in a single was treated at the 400 mg/m dose. A reduction in CD200 lesion (Table 5). expression on CLL cells was associated with a transient in- crease in peripheral CLL cells followed by a progressive Discussion reduction peripheral CLL cells (Fig. S2), CD200+ CD4+ T Although promising novel therapies have recently become cells and T s. In contrast, CD8+ T-cells increased indi- available, the majority of patients with CLL and MM will REG cating an anti-tumor immune response (Additional file 1: ultimately relapse or become refractory to currently avail- Figure S3). Reduced CD200 expression on CLL cells paral- able therapeutic regimens, and the only known curative leled a reduction in bulky lymphadenopathy (Additional therapy for CLL and MM is stem cell transplantation, with file 1: Figure S4). One patient, maintained SD through its associated high morbidity and mortality [43, 44]. Block- cycle 18 (300 mg/m ) and two patients maintained a SD ade of the CD200-CD200R immune checkpoint using a through cycle 6 (500 mg/m ) when the study was termi- therapeutic anti-CD200 mAb was hypothesized to restore nated. All 3 MM patients had PD. and/or enhance tumor cell recognition and CTL mediated Of the 22 patients whose primary target lesions were anti-tumor responses in advanced CLL and MM patients measured by CT scans at baseline and at least one with limited therapeutic options. Samalizumab is a novel, Mahadevan et al. Journal for ImmunoTherapy of Cancer (2019) 7:227 Page 9 of 13 Fig. 1 Each panel displays data for a single patient (indicated at the top of each graph) at baseline (Day 0) and after samalizumab dosing at the indicated time points. For simplicity, no more than the first 4 dosing cycles are shown. a. Percent change from baseline in CLL CD200 expression (mean channel fluorescence (MFI)) in CLL patients. b. Percent change from baseline in CD200+ CD4+ T cells (%) in CLL and MM patients Mahadevan et al. Journal for ImmunoTherapy of Cancer (2019) 7:227 Page 10 of 13 Fig. 2 Each vertical bar represents the maximum change obtained for a single patient, identified by the six digit code at the bottom of the graph, that had a baseline CT scan and at least one subsequent scan. The horizontal dotted line at 50% represents a cut-off above which lymph node enlargement represents progressive disease whereas the horizontal dotted line at − 30% represent a cut-off below which lymph node regression represents clinically significant improvement. Patient 107–602 (500 mg/m cohort) did not have a post-dose CT scan and was not evaluable first-in-class, recombinant humanized anti-CD200 mAb, observed. TEAEs were generally mild or moderate in se- engineered to ablate effector function, that specifically verity and, overall, were considered manageable. None of binds to the immune checkpoint CD200, blocks receptor the patients discontinued samalizumab treatment due to engagement and signaling and antagonizes CD200-driven SAEs and the frequency of SAEs appears not to be dose- immune suppression, thereby allowing the patient’sim- related. However, two patients discontinued participa- mune surveillance to detect tumor cells and mount an tion in the post-dose follow-up period due to SAEs that anti-tumor immune response. were unrelated to study drug. Samalizumab dosing was Samalizumab at doses of 50 to 600 mg/m was well not associated with clinically significant cytokine re- tolerated, MTD was not determined and no DLTs were sponses at any time (data not shown). ADA frequency Mahadevan et al. Journal for ImmunoTherapy of Cancer (2019) 7:227 Page 11 of 13 Table 5 Maximum reduction in the sum of lesions and a single lesion after samalizumab dosing b b Samalizumab Patient ID Single Lesion Sum of Lesions Treatment Group % Change Cycle Day % Change Cycle Day 50 mg/m (N = 4) 101–103 −3.45 C1 D28 2.77 C1 D28 101–104 −45.29 C1 D77 −9.8 C1 D35 102–101 −19.75 C4 D16 4.32 C4 D16 102–102 −9.77 C1 D35 −9.46 C1 D35 2 a 100 mg/m (N =4) 101–202 −37.78 C4 D0 −6.83 C4 D0 101–203 −11.54 C4 D0 7.0 C1 D28 102–201 −95.31 C4 D0 −20.7 C4 D0 102–205 −41.36 C3 D26 −18.7 C3 D26 2 a 200 mg/m (N =2) 101–301 − 48.67 C1 D28 −28.7 C1 D28 102–303 −42.05 C3 D21 −4.75 C3 D21 300 mg/m (N = 3) 101–402 −14.29 C4 D43 8.3 C4 D43 101–403 −23.81 C1 D29 −12.5 C1 D29 102–401 −58.73 C1 D35 −16.1 C16 D1 400 mg/m (N = 3) 102–502 −87.02 C13 D35 −63.4 C13 D35 107–503 −54.55 C4 D27 −3.34 C1 D42 107–504 −29.34 C1 D29 9.52 C1 D29 2 a 500 mg/m (N =4) 101–606 −48.15 C6 D0 −6.91 C6 D0 102–601 −86.36 C2 D28 −73.7 C2 D28 102–603 −5.13 C1 D25 1.84 C1 D25 102–607 −37.36 C1 D28 −19.4 C1 D28 a 2 2 2 Patient 107–602 (500 mg/m cohort) did not have a post-dose CT scan and was not evaluable; Patients 104–204 (100 mg/m cohort) and 104–302 (200 mg/m cohort) had no reduction in any of their target lesions and are not included Maximum reduction for a single lesion (product of bi-dimensional tumor measurement) and maximum reduction for sum of lesions (sum of the products of bi- dimensional tumor measurements) are presented as a % Change from baseline on the indicated Cycle and Day was consistent with that in literature reports of other T-cell subsets were consistently observed, although one therapeutic mAbs [45, 46]. patient with no prior chemotherapy demonstrated the The mean T for samalizumab increased with increas- predicted immunomodulatory changes following mul- 1/2 2 2 ing doses (100 mg/m –600 mg/m ). The high clearance of tiple doses of samalizumab: increases in frequencies of samalizumab at low doses likely represents saturation bind- activated T cells and CD8+ T cells during prolonged ing to membrane-associated CD200 surface antigen. At samalizumab treatment, with concomitant reduction of higher doses, antibody clearance is likely due to nonspecific T (Additional file 1 pages 3–5and 8–10). REGs elimination through the cells of the reticuloendothelial sys- The clinical responses reported support the study’s tem [47]. These findings are consistent with those of other central hypothesis that blockade of the immune inhibi- therapeutic mAbs reported in the literature [48]. tory ligand CD200 by samalizumab promotes anti-tumor Samalizumab binding dampens CD200 overexpression activity: serial CT scans revealed that more than half on CLL cells in a dose-dependent manner, and the re- (64%) of evaluable CLL patients had reductions in tumor duction in CD200 expression is sustained at higher doses burden, with two patients having > 50% reduction. Most (300–500 mg/m ). However, it is apparent from these CLL patients had a decrease in size of at least one lesion, early data that the concentrations of samalizumab achieved with 22.7% of CLL patients experiencing a reduction of in this phase I study were insufficient to completely saturate > 50% in at least one lesion. However, in 8 patients, 4 of cell-surface CD200 on the CLL cells. The PK and PD assays whom had SD, the maximum reductions in a single le- incorporated in this study may provide a strategy to guide sion did not always correlate with the maximum reduc- optimal dosing in future trials. Sustained decreases in tion in the sum of the products of all lesions at the same CD200 expression on peripheral CD200+ CD4+ T cells time point. This may represent an immune-modulated (reduction in the percentage of CD200+ CD4+ T cells) response consistent with pseudoprogression [49]. In is observed in CLL and MM patients at higher doses clinical trials of solid tumors, increases in tumor burden (300–600 mg/m ). No other dose-dependent changes in that can precede responses led to novel evaluation Mahadevan et al. Journal for ImmunoTherapy of Cancer (2019) 7:227 Page 12 of 13 criteria (immune-related response criteria (irRC)) [49]. Authors’ contributions DM, MCL, LTH, MP and CF were the principle investigators at each study site An increase in tumor burden prior to response evalu- and enrolled patients. All co-authors contributed to data collection, analysis ation may reflect either continued tumor growth until a and writing of the manuscript. All authors read and approved the final sufficient immune response develops or transient manuscript. immune-cell infiltrate. Similar patterns of stable disease Funding or improvement after an initial increase in tumor burden The authors express their appreciation to the patients and their families and have been observed with other immune checkpoint in- acknowledge the contributions of Alexion Pharmaceuticals, Inc. The study was sponsored by Alexion Pharmaceuticals, Inc. hibitors such as ipilimumab and anti-PD-1 mAbs [28, 32, 33]. Although the irRC have been implemented in Availability of data and materials solid tumors, mechanisms underlying these increases Supporting data is available at the journals request. may also apply to lymphadenopathy in B-cell Ethics approval and consent to participate malignancies. All sites consented patients per site IRB and WIRB. SD was achieved in sixteen CLL patients: one patient received 18 cycles of samalizumab and maintained SD Consent for publication All authors read the manuscript and agree to publication. through cycle 18 (300 mg/m ) and two patients main- tained SD through cycle 6 (500 mg/m ). All 3 patients Competing interests remained on samalizumab until the trial was concluded. Academic authors have nothing to disclose. MW, SJF, TU, AK, LL, CLB, and XP are employed by Alexion Pharmaceuticals, Inc. One treatment-naïve Rai Stage IV CLL patient (Patient# 102–502) who received 13 cycles of samalizumab achieved Author details a durable PR lasting for > 6 years with no further interven- Department of Medicine Division of Hematology/Oncology, University of Arizona Cancer Center, 1515. N. Campbell Avenue, Room 1905, Tucson, AZ tions and is reported to be healthy at the time of this 2 3 85724, USA. Duke University Medical Center, Durham, NC, USA. Summit manuscript. This patient may have had a superior clinical Medical Center, MD Anderson Cancer Center, Morristown, NJ, USA. The response to samalizumab because of his preserved im- West Cancer Center, University of Tennessee, Memphis, TN, USA. Alexion Pharmaceuticals, Inc., New Haven, CT, USA. Winship Cancer Institute of mune function prior to treatment. Emory University, Atlanta, GA, USA. Received: 20 May 2019 Accepted: 14 August 2019 Conclusions Advances in the understanding of the mechanisms of protective anti-tumor immunity has led to the develop- References ment of immune checkpoint therapy with mAbs target- 1. Barclay AN, Clark MJ, McCaughan GW. Neuronal/lymphoid membrane glycoprotein MRC OX-2 is a member of the immunoglobulin superfamily ing inhibitory pathways that normally suppress anti- with a light-chain-like structure. Bioch Soc Symp. 1986;51:149–57. tumor T-cell immunity and mediate immune tolerance. 2. Clark MJ, Gagnon J, Williams AF, Barclay AN. MRC OX-2 antigen: a The findings of this study provide proof-of-concept for lymphoid/neuronal membrane glycoprotein with a structure like a single immunoglobulin light chain. EMBO J. 1985;4(1):113–8. targeted inhibition of the immune checkpoint CD200, as 3. Wright GJ, Puklavec MJ, Willis AC, et al. 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Phase I study of samalizumab in chronic lymphocytic leukemia and multiple myeloma: blockade of the immune checkpoint CD200

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Medicine & Public Health; Oncology; Immunology
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Abstract

Purpose: Samalizumab is a novel recombinant humanized monoclonal antibody that targets CD200, an immunoregulatory cell surface member of the immunoglobulin superfamily that dampens excessive immune responses and maintains self-tolerance. This first-in-human study investigated the therapeutic use of samalizumab as a CD200 immune checkpoint inhibitor in chronic lymphocytic leukemia (CLL) and multiple myeloma (MM). Experimental design: Twenty-three patients with advanced CLL and 3 patients with MM were enrolled in an open- label phase 1 study (NCT00648739). Patients were assigned sequentially to one of 7 dose level cohorts (50 to 600 mg/m ) in a 3 + 3 study design, receiving a single dose of samalizumab intravenously once every 28 days. Primary endpoints were safety, identification of the maximum tolerated dose (MTD), and pharmacokinetics. Secondary endpoints were samalizumab binding to CD200, pharmacodynamic effects on circulating tumor cells and leukocyte subsets, and clinical responses. Results: Twenty-one patients received > 1 treatment cycle. Adverse events (AEs) were generally mild to moderate in severity. Samalizumab produced dose-dependent decreases in CD200 expression on CLL cells and decreased frequencies of circulating CD200 + CD4+ T cells that were sustained at higher doses. The MTD was not reached. Decreased tumor burden was observed in 14 CLL patients. One CLL patient achieved a durable partial response and 16 patients had stable disease. All MM patients had disease progression. Conclusions: Samalizumab had a good safety profile and treatment was associated with reduced tumor burden in a majority of patients with advanced CLL. These preliminary positive results support further development of samalizumab as an immune checkpoint inhibitor. Trial registration: ClinicalTrials.gov, NCT00648739 registered April 1, 2008. Keywords: CLL, Multiple myeloma, CD200, Immune checkpoint inhibitor, Samalizumab * Correspondence: DMahadevan@uacc.arizona.edu Department of Medicine Division of Hematology/Oncology, University of Arizona Cancer Center, 1515. N. Campbell Avenue, Room 1905, Tucson, AZ 85724, USA Full list of author information is available at the end of the article © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Mahadevan et al. Journal for ImmunoTherapy of Cancer (2019) 7:227 Page 2 of 13 Introduction tumor immunity such as activated T cells and dendritic CD200 and CD200 receptor (CD200R) are highly con- cells [26]. Blockade of various immune checkpoints, served type I paired membrane glycoproteins, consisting alone or in combination, to reverse T-cell mediated im- of two immunoglobulin (Ig)-like domains (V and C) that mune suppression and activate anti-tumor immunity is a belong to the Ig protein superfamily [1–3]. CD200 is promising approach to treating cancers [19–21, 27]. widely expressed on a variety of cell types, including B Durable clinical responses, including enhanced survival, cells, a subset of T cells, dendritic cells, endothelial, neur- have been reported with therapeutic blockade of CTLA-4 onal and other cells, while CD200R expression is largely with ipilimumab, and of PD-1 with pembrolizumab and limited to subsets of T cells and myeloid lineage cells [3–7]. nivolumab in patients with melanoma, non-small cell lung The ligation of CD200 with its receptor, CD200R, im- cancer, renal cancer and head and neck squamous cell car- parts a multipronged immunosuppressive signal, po- cinoma, leading to FDA approvals [28–35]. Combination tently inhibiting T-cell immune responses and natural therapy blocking both CTLA-4 and PD-1 is now approved killer (NK) cytotoxic activity, promoting macrophage for melanoma. Other combinations of targeted therapies, secretion of indoleamine-2,3 dioxygenase (IDO), an immune checkpoint inhibitors and activators that enhance immunosuppressive tryptophan-catabolizing enzyme, and innate immunity are also being evaluated [36–40]. triggering regulatory T cell (T )expansion [8–12]. The Samalizumab is a novel recombinant, humanized mono- reg immune checkpoint function of CD200 on dendritic cells clonal antibody (mAb) that specifically binds to CD200 and lymphoid effector cells modulates the activation and blocks its ligation to the CD200 receptor (CD200R). threshold of inflammatory immune responses and con- Samalizumab was rationally engineered with an Ig G2/G4 tributes to the maintenance of self-tolerance [13]. constant region to minimize effector function and pre- CD200 is overexpressed in a wide variety of solid and serve immune cell subsets [26]. hematological tumor cell types, including chronic lympho- This is a first-in-human phase I trial to evaluate the cytic leukemia (CLL) multiple myeloma (MM), acute mye- safety, pharmacokinetics (PK), pharmacodynamic (PD), loid leukemia (AML) and others, and is also expressed at and anti-tumor activity of CD200 blockade with samali- elevated levels on cancer stem cells [14–18]. McWhirter zumab in patients with CLL and MM, and to identify et al. first showed that primary tumor cells from CLL the maximum tolerated dose (MTD) and dose-limiting patients overexpress CD200 compared with expression on toxicity (DLT) of samalizumab. normal B cells [14]. Dampened anti-tumor cytotoxic T cell (CTL) responses Methods are associated with the overexpression of immune check- Eligibility and study schema points including CD200, cytotoxic T lymphocyte antigen- This was an open-label, multi-center, sequential cohort 4 (CTLA-4) and programmed death-1 (PD-1) on tumor, dose escalation study (June 2008 - Dec. 2010). The pri- immune and stromal cells within the tumor microenvir- mary endpoints were safety, identification of MTD, and onment, and the consequent immunoregulatory signaling characterization of PK. Secondary endpoints were sama- events following binding to their respective ligands or lizumab binding to CD200, PD effects on circulating receptors [19–21]. Down-regulation of allogeneic Type 1 tumor cells and leukocyte subsets, and clinical responses T helper (Th1) responses, as measured by decreases in to treatment. The study was conducted in accordance interleukin-2 (IL-2) and interferon-gamma (IFN-γ), was with the Declaration of Helsinki and principles of the noted following the addition of primary CLL cells to an in International Conference on Harmonisation guidelines vitro mixed lymphocyte reaction, and anti-CD200 anti- on Good Clinical Practice. bodies reversed this effect, restoring Th1 responses and Patients with relapsed or refractory CLL or MM, de- suppressing T [14, 16, 22, 23]. In syngeneic and fined as either having failed or refractory to at least one regs xenograft murine models, treatment with anti-CD200 approved therapeutic agent, or who declined standard antibodies restored lymphocyte mediated anti-tumor treatment options, were eligible. Additional inclusion responses in vivo [23, 24]. criteria included an Eastern Cooperative Oncology Group In addition to immunosuppression, overexpression of performance status score of 0–2 and anticipated survival CD200 on tumor cells has been correlated with aggres- of > 6 months. Patients were excluded from the study if sive tumor progression, greater metastatic potential, and they met any of the following criteria: absolute neutrophil 9 9 reduced patient survival, which suggests that CD200 is a count < 1000 × 10 /L, platelet count < 50,000 × 10 /L; promising target for cancer immunotherapy [15, 25]. Ac- pregnant or lactating; prior history of autoimmune cumulated evidence supports the rationale for develop- hemolysis; immune thrombocytopenia; active autoimmune ing therapeutic anti-CD200 antibodies lacking effector disease requiring immunosuppressive therapy; positive function to block CD200-CD200R-mediated signaling Coombs’ test; chronic infection with HBV, HCV or HIV; while preserving immune components critical for anti- ongoing corticosteroid treatment equivalent to ≥10 mg/day Mahadevan et al. Journal for ImmunoTherapy of Cancer (2019) 7:227 Page 3 of 13 of prednisone; prior stem cell transplantation or prior vital signs, ECG, and physical and ophthalmology slit chemotherapy within 4 weeks or 30 days of enrollment, lamp examinations. respectively; neurosurgery or cranial radiotherapy within one year of enrollment; serum creatinine > 1.5 times upper Pharmacokinetic assessment limit of normal, alanine amino transferase or aspartate Blood samples for PK analyses in cycle 1 were collected amino transferase > 2.5 times upper limit of normal, cardio- at pre-dose on day 0 (0 h) and at 0.5 h, end of infusion, pulmonary disease (New York Heart Association Func- and 8, 24, 48, 72, 168, 240, 336, 672, and 1008 h after tional Class III or IV); active systemic bacterial or fungal the start of the infusion. Estimated PK parameters for infection; prior therapy with another investigational prod- samalizumab, derived from serum concentration-time uct within 30 days of screening; or any condition that could curves, were total clearance (CL), maximum concentra- increase the patient’sriskor confoundoutcome,at the tion (C ), time to reach C (T ), terminal elimin- max max max investigators’ discretion. ation half-life (T ), volume of distribution based on 1/2 Patients were assigned sequentially to one of 7 dose terminal elimination phase (V ) and area under the z , level cohorts following a 3 + 3 study design: 50 mg/m , serum concentration-time curve from time zero extrapo- 2 2 2 2 2 100 mg/m , 200 mg/m , 300 mg/m , 400 mg/m , 500 mg/m lated to infinity (AUC ). PK parameters were estimated or 600 mg/m . Each patient only received the dose to which using non-compartmental methods with WinNonlin® they were assigned. The first dose day was considered (Version 6.4, Pharsight Corporation, Menlo Park, CA). as cycle 1, day 0. Patients who tolerated the study drug See Additional file 1 for methodologic details. and had at least stable disease at six weeks following the first dose were permitted to continue therapy until Pharmacodynamic assessment they experienced disease progression, toxicity, or if the Blood samples for the measurement of PD markers in investigator or patient wished to discontinue therapy. cycle 1 were collected pre-dose on day 0, and post-dose Additional dosing cycles at the same dose were added on days 1, 7, 14, 24, and 42; during cycles 2 to 4, PD as one dose per 28-day cycle, beginning no sooner than assessments were evaluated pre-dose and on day 14. six weeks after the initial dose. Samalizumab binding to CD200 on circulating CLL cells At least three patients were assigned per cohort; if none was evaluated by multi-parametric flow cytometry using experienced a DLT, escalation to the next dose level a fluorescently-labeled mAb specific for samalizumab occurred with a new cohort. A DLT was defined as any together with a second anti-CD200 mAb specific for an grade 3 or greater toxicity, according to the NCI Common epitope of CD200 distinct from the binding site of sama- Terminology Criteria for Adverse Events (CTCAE) ver- lizumab. CD200 and CD200R expression on peripheral sion 3.0, (NCI 2006) occurring in the first 28 days after T-cell subsets (CD3+, CD4+, CD8+, activated T cells, dosing in cycle 1. Patients were followed for 10 weeks after T ) collected from CLL and MM patients were evalu- regs their last dose with safety, PK, PD, anti-tumor and clinical ated by immunofluorescence and flow cytometry. Data response evaluations. were analyzed as percent of CD200+ cells within the in- Baseline evaluations for all patients included medical dicated population as well as by mean channel fluores- history, physical examination, ophthalmologic slit lamp cence intensity (MFI) of bound antibody to reflect the examination, CBC and differential, chemistry and thy- CD200 density on CD200+ cells. See Additional file 1 roid panels, electrocardiogram (ECG), hepatitis and HIV for methodologic details. serology, Coombs’ test, anti-drug antibody (ADA), co- agulation panel, and bone marrow biopsy (optional). CT Cytokine assessment scans were performed in all CLL patients, while MM Serum from patients was evaluated for interleukin (IL)- patients were evaluated for beta-2 microglobulin, serum 1β (IL-1β), IL-2, IL-4, IL-6, IL-10, IL-12p70, IFN-γ and protein electrophoresis, serum free light chain and ratio, tumor necrosis factor alpha (TNF-α) pre-dose and at 24 h urine for total protein and urine protein electrophor- various times post-dose through week 10 (See Additional esis, serum viscosity, and skeletal survey. See Additional file 1 for methodologic details). file 1 for further information on dosing and clinical laboratory assays. Anti-tumor assessment Clinical responses were based on the Modified NCI Working Group Response Criteria for CLL [41]and on Safety and tolerability the International Myeloma Working Group Uniform The safety and tolerability of samalizumab in the study Response Criteria for MM [42]. For CLL, the overall re- patient population were assessed by treatment-emergent sponse rate (ORR) was defined as the percentage of pa- adverse events (TEAEs), treatment-emergent serious tients who maintained their best response for at least adverse events (SAEs), clinical laboratory evaluations, one month after achieving that best response and having Mahadevan et al. Journal for ImmunoTherapy of Cancer (2019) 7:227 Page 4 of 13 either a complete response (CR), partial response (PR), not complete the study and died of progressive disease nodular partial response (nPR), or stable disease (SD). shortly after two weeks of follow-up. A total of 256 Progressive disease (PD) was defined by one of the fol- TEAEs were reported by 25 (96%) patients; the most lowing: > 50% increase in the sum of the products of at commonly reported TEAEs are listed in Table 2. Five least two lymph nodes (at least one lymph node must be patients experienced TEAEs that were deemed possibly, > 2 cm), appearance of new lymph nodes, > 50% increase probably, or definitely related to study drug that were in the size of the liver and/or spleen, > 50% increase in grade 3–4 in severity. The most common drug-related the absolute number of circulating lymphocytes to at grade 3–4 TEAEs were blood and lymphatic system dis- least 5000/uL, or transformation to a more aggressive orders (anemia, neutropenia, and thrombocytopenia) re- histology (Richter’s Syndrome). For MM, ORR was de- ported in three patients (12%). The other drug-related fined as the percentage of patients who had sCR (strin- grade 3–4 TEAEs were reduced visual acuity and mus- gent CR), CR, very good partial response (VGPR), or PR cular weakness (both in the same patient, 4%), respira- on two consecutive assessments made at any time before tory syncytial virus infection (1 patient, 4%), and rash (1 the administration of any new therapy. PD was defined patient, 4%) (Table S1). TEAEs that were considered def- as > 25% increase of urine M-protein. initely related to the study drug occurred in two of three Computed tomography (CT) scans of the neck, chest, patients with elevated ADA at the time of samalizumab abdomen, and pelvis in CLL patients were evaluated administration: hypersensitivity (grade 1 allergic reac- using sum of the products of bi-dimensional measure- tion) and urticaria (grade 2 hives). ments of all target lesions [41], Additional cycles of Of the 26 study participants, six (23%) experienced at treatment were continued if there was evidence of re- least one SAE; four (15%) had SAEs considered unre- sponse by blood counts or physical exam at weeks 4 and lated to study drug and two (8%) had SAEs considered 8. Anti-tumor responses were evaluated as the percent possibly related to study drug. One fatal SAE, due to change from baseline in lymphadenopathy. complications post-elective cholecystectomy and ensuing renal failure, occurred 23 days after the fourth dose of Statistical analyses 100 mg/m . The investigators determined that the event was Patients who received at least one dose of samalizumab unrelated to samalizumab. No SAEs led to discontinuation. were included in safety, PK, PD, and clinical response- In some patients, ECGs revealed heart rate, PR interval, analyses. Data collected at all sites were pooled for ana- QRS duration and QTc intervals outside normal ranges lysis, and descriptive statistics were used to summarize the on occasion, but these were not clinically significant data. All tables and listings were generated using SAS® events. In aggregate, no QT interval changes were ob- Version 9.2 or higher (SAS Institute, Inc., Cary, NC). served. No significant ophthalmologic findings were at- tributed to samalizumab treatment. Results Patient disposition and treatment exposure Pharmacokinetics Twenty-six patients, 23 with CLL (4 were treatment Following a single intravenous dose of samalizumab naïve) and 3 with MM, were enrolled from June 2008 to (100–600 mg/m ), the mean T values across all dose max December 2010 across four study sites. Patient charac- levels ranged from 1.23 to 8.93 h, the mean T for 1/2 teristics are given in Table 1. All 26 patients received at samalizumab increased from 85.1 h to 537.9 h (3.5 to least one samalizumab dose. The clinical study was 22.4 days), and mean systemic CL showed a decreasing amended to allow multiple doses of samalizumab to be trend in the three highest dose cohorts (Table 3). The administered. Twenty-one patients (81%) received mul- mean V did not appear to be dose related. C in- z max tiple dosing cycles and five patients (19%), including two creased in a dose-proportional manner and AUC MM patients, received one dose. Thirteen patients (50%) increased in a more than dose-proportional manner. For received ≥4 cycles of samalizumab. The maximum number C the β value was 1.01 (95% CI: 0.85–1.17) and for max, of cycles received by any patient was 18 (300 mg/m dose AUC , the β value was 2.01 (95% CI: 1.59–2.42). The cohort). The study was terminated prematurely by the serum concentration-time profiles of samalizumab are sponsor for administrative reasons. Data from all 26 pa- graphed as the mean serum concentration of samalizumab tients were analyzed except where noted. after the first intravenous administration at the indicated doses. Error bars represent the standard deviation Safety and adverse events (Additional file 1:FigureS1). The MTD was not reached, and administration of sama- lizumab from 50 to 600 mg/m was well-tolerated in pa- Pharmacodynamics tients with CLL or MM. Only one patient was treated The binding of samalizumab to CD200 on peripheral with the 600 mg/m dose; this patient (with MM) did CLL cells was evaluated in 21 of 23 (91%) CLL patients. Mahadevan et al. Journal for ImmunoTherapy of Cancer (2019) 7:227 Page 5 of 13 Table 1 Patient characteristics 2 2 2 2 2 2 2 Parameter 50 mg/m (N = 4) 100 mg/m (N = 5) 200 mg/m (N = 3) 300 mg/m (N = 3) 400 mg/m (N = 3) 500 mg/m (N = 7) 600 mg/m (N = 1) Total (N = 26) % Gender Male 3 3 2 1 3 6 0 18 69 Female 1 2 1 2 0 1 1 8 31 Race Caucasian 3 4 3 3 2 6 1 23 89 Black 0 1 0 0 1 1 0 3 11 Age (years, at screening) Mean (SD) 64.645 (11.7737) 60.716 (13.5373) 62.387 (20.6538) 68.227 (15.4956) 74.25 (11.0807) 67.104 (9.5240) 65.92 (NA) 65.9 (12.14) Median 66.92 59.43 61.370 70.500 69.00 66.98 65.92 66.9 Range 49.84–74.9 41.0–77.3 42.26–83.53 51.72–82.76 66.77–86.98 53.65–79.69 65.92 41–87 Type of malignancy CLL 4 4 43 35 023 89 Multiple Myeloma 0 0 0 0 0 2 1 3 11 Time from diagnosis to first samalizumab dose (days) Mean (SD) 3672.3 (3323.28) 1556.6 (1571.86) 3017.0 (912.22) 1577.3 (1010.13) 3371.0 (2045.69) 1850.4 (1190.99) 1451.0 (NA) 233 (1817.1) Median 2510.5 813.0 2922.0 1264.0 3061.0 1649.0 1451.0 1887 Range 1148–8520 43–4200 2156–3973 761–2707 1498–5554 154–3123 1451–1451 154–8520 Patients with previous chemotherapy 3 3 3 3 2 7 1 22 85 Patients with previous radiation 0 0 0 0 0 1 1 2 8 Patients without prior chemotherapy1 2 00 10 04 15 or radiation treatments Study completion Yes 2 3 0 1 1 2 0 9 34.6 No 2 2 3 2 2 5 1 17 65.4 Reason for non-completion Treatment-emergent adverse event 1 0 1 2 1 0 0 5 19.2 Patient requested to withdraw 1 0 1 0 0 2 0 4 15.4 Lack of efficacy 0 0 0 0 1 2 0 3 11.5 Investigator considered it advisable/in0 0 00 01 12 7.7 the patient’s best interest Patient did not complete follow up 0 1 0 0 0 0 0 1 3.8 Death (not related to study drug) 0 1 0 0 0 0 0 1 3.8 Positive antidrug antibody serology 0 0 1 0 0 0 0 1 3.8 Mahadevan et al. Journal for ImmunoTherapy of Cancer (2019) 7:227 Page 6 of 13 Table 2 Treatment-emergent adverse events (TEAEs) reported in ≥5% patients by organ system System Organ Class Samalizumab Treatment Group 2 2 2 2 2 2 50 mg/m 100 mg/m 200 mg/m 300 mg/m 400 mg/m 500 mg/m 600 mg/m Overall N =4 N =5 N =3 N =3 N =3 N =7 N =1 N =26 General Disorders and 11 (42) Administration Sites Fatigue 1 (25) – 1 (33) 3 (100) – 1 (14) – Peripheral coldness 1 (25) –– – – –– Pyrexia –– – – – 1 (14) – Chills –– – – – 1 (14) – Edema –– – 2 (67) –– – Skin and Subcutaneous Tissue 9 (35) Erythema –– – 1 (33) –– – Night sweats –– – – – 1 (14) – Pruritus 1 (25) 1 (20) –– –– – Rash 1 (25) 1 (20) 1 (33) 1 (33) –– – Urticaria 1 (25) –– – – –– Gastrointestinal 5 (19) Abdominal distension –– – 1 (33) –– – Abdominal Pain –– – 2 (67) –– – Diarrhea 1 (25) 1 (20) –– –– – Infections and Infestations 4 (15) Upper Respiratory Tract Infection – 1 (20) –– 1 (33) 1 (14) – Abscess –– – 1 (33) –– – Musculoskeletal and Connective 4 (15) Tissue Arthralgia –– – 1 (33) –– – Muscular weakness 1 (25) –– – – –– Myalgia 1 (25) –– – – –– Stiffness – 1 (20) –– –– – Nervous System 3 (12) Dizziness –– – 1 (33) –– – Headache –– – – – 1 (14) – Paraesthesia –– – 1 (33) –– – Blood and Lymphatic System 7 (27) Anemia –– – 1 (33) 1 (33) –– Neutropenia 2 (50) –– 1 (33) 1 (33) –– Thrombocytopenia –– – – 1 (33) –– Eye 6 (23) Eye pain 1 (25) –– – – 1 (14) – Night blindness 1 (25) –– – – –– Photophobia 1 (25) –– – – 1 (14) – Reduced visual acuity 1 (25) –– – – –– Laboratory –– – – – 2 (8) Increased blood viscosity – 1 (33) – Decreased platelets 1 (20) – Mahadevan et al. Journal for ImmunoTherapy of Cancer (2019) 7:227 Page 7 of 13 Table 2 Treatment-emergent adverse events (TEAEs) reported in ≥5% patients by organ system (Continued) System Organ Class Samalizumab Treatment Group 2 2 2 2 2 2 50 mg/m 100 mg/m 200 mg/m 300 mg/m 400 mg/m 500 mg/m 600 mg/m Overall N =4 N =5 N =3 N =3 N =3 N =7 N =1 N =26 Respiratory, Thoracic and Mediastinal 4 (15) Cough –– – – – 1 (14) – Dyspnea –– – 1 (33) – 1 (14) – Pulmonary edema –– – – – 1 (14) – Values in parentheses are the percentage of patients Only one occurrence per patient counted for each category “-” indicates zero Two patients were not evaluable because of insufficient By day 1 after samalizumab dosing, all evaluable patients circulating CLL cells and high background level staining showed a decrease in the frequency of peripheral CD200+ precluding reliable analysis. Despite considerable inter- CD4+ T cells (range of − 15.6% to − 85.3% from baseline). patient variability in baseline peripheral CLL counts Of 17 patients who received > 1 dose of samalizumab, 16 (range 0.8–90.7%), nearly all CLL cells (85 to 100%) were (94%) continued to show reductions in CD200+ CD4+ T CD200+, although there was wide interpatient variation cell frequencies in response to dosing. Similar to the reduc- in the intensity of CD200 expression on CLL cells. tion in CD200 expression observed on CLL cells, a dose- On day 1 after dosing, bound samalizumab was de- dependent reduction in the frequencies of peripheral tected on peripheral CD200+ CLL cells in 16 of 21 CD200+ CD4+ T cells was also observed, with transient (76%) evaluable patients. Increased binding was observed responses at low doses (50–200 mg/m ) and sustained 2 2 at higher doses (200–500 mg/m ). The range of frequen- responses at higher doses (300–500 mg/m ). cies of CLL cells with bound samalizumab on day 1, and With the exception of CD200+ CD4+ T cells, no ap- the density of bound samalizumab MFI by dose cohort parent dose-dependent effect of samalizumab on other are summarized in Table 4. Down-regulation of CD200 T-cell subsets was found. Changes in the frequencies of expression on CLL cells was observed in 18 of 21 pa- CD3+ cells or total CD4+ cells (regardless of CD200 ex- tients (86%) after samalizumab dosing (Fig. 1a). The pression) revealed considerable inter-patient variability density of CD200 expression (MFI) on day 1 was re- across and within cohorts, with no clear trends discern- duced from baseline by 6.8–74.3%. A dose-dependent re- able. Cell counts of CD8 + cells, activated T cells, and duction in CD200 expression on CLL cells was observed T , at baseline or during treatment, were too low to regs after multiple dosing: transient reductions in CD200 ex- provide reliable results. A notable exception is Patient pression were generally observed in patients treated with #102–502, treated at the 400 mg/m dose, who had suffi- lower doses (50–200 mg/m ), whereas sustained reduc- cient immune cells for analysis; this patient is discussed tions were seen in 18 of 21 evaluable patients (86%) pa- in the Additional file 1 (pages 8–10). Patients with MM tients receiving higher doses (300–500 mg/m ). received up to three doses of samalizumab and showed The percent change from baseline in peripheral CD200+ little change in T-cell subsets. CD4+ T cells for all evaluable CLL and MM patients is In one patient, a transient increase in peripheral B-CLL showninFig. 1b. Of the 26 enrolled patients, 21 (81%) were count, absolute lymphocyte count and white cell count evaluated; four patients with CLL and one with MM were was observed following initial samalizumab treatment not evaluable due to insufficient circulating immune cells. (Additional file 1: Figure S2). The observed binding to Table 3 Summary of samalizumab PK parameters Dose No. of patients T C AUC T CL V max max ∞ 1/2 z (h) (μg/mL) (μg·h/mL) (h) (mL/h) (mL) 100 mg/m 5 2.21 ± 3.25 38.9 ± 4.75 2792 ± 2227 85.1 ± 60.9 101 ± 67.5 8246 ± 1499 200 mg/m 3 1.23 ± 0.09 90.2 ± 10.6 11,957 ± 6599 107 ± 45.2 36.3 ± 14.9 4943 ± 469 300 mg/m 3 4.71 ± 4.65 109 ± 42.7 36,636 ± 11,540 371 ± 48.9 16.9 ± 4.15 9186 ± 3215 400 mg/m 3 8.93 ± 11.1 135 ± 37.8 37,679 ± 7219 245 ± 33.9 21.3 ± 4.61 7391 ± 897 500 mg/m 7 3.87 ± 1.85 211 ± 44.9 62,898 ± 24,222 365 ± 172 19.5 ± 10.4 8490 ± 1715 600 mg/m 1 3.08 288 134,629 538 7.58 5880 Values are presented as Mean ± SD. The samalizumab serum concentration assay had a lower limit of quantification of 3.70 μg/mL and the standard curve ranged from 3.7 to 100 μg/mL Assay precision was 1 to 18% and accuracy was 93.2 to 127.8% (Mean % of recovery) Mahadevan et al. Journal for ImmunoTherapy of Cancer (2019) 7:227 Page 8 of 13 Table 4 Samalizumab bound to CD200+ CLL cells by cohort Samalizumab Cohort CLL cells bound by samalizumab (%) Density of bound samalizumab (MFI) Pre-dose Day 1 Pre-dose Day 1 50 mg/m (n = 4) 0.3–0.7 1.1–3.3 1.9–3.1 3.3–4.1 100 mg/m (n = 5) 0.2–2.4 0.2–9.5 3.5–5.6 5.0–11.1 200 mg/m (n = 2) 0.3–0.7 27.8–29.6 3.2–3.3 16.6–19.3 300 mg/m (n = 2) 0.5–0.7 5–28.6 1.7–3.0 5.6–16.8 400 mg/m (n = 3) 1.1–5.7 1.7–71.3 1.7–3.4 4.6–26.6 500 mg/m (n = 5) 0.5–2.1 1–47.0 1–3.7 1.9–17.6 Binding of samalizumab to CD200 on circulating CLL cells was evaluated by multi-parametric flow cytometry using a fluorescently-labeled monoclonal antibody specific for samalizumab (7B8) together with a second anti-CD200 antibody (IB2) specific for an epitope of CD200 distinct from the binding site of samalizumab CD200+ B-CLL cells and the reduction in CD200 ex- subsequent scan after dosing with samalizumab, 14 (64%) pression indicates that samalizumab is binding to and had a decrease in tumor burden post-dosing. Twelve of blocking its intended target, the immunoregulatory these patients were from all dose level cohorts and had a molecule CD200. However, even at doses of 500 mg/m , maximum decrease in lymphadenopathy ranging from 3.3 neither maximal saturation of CD200 binding nor maximal to 28.7%. Two patients had a > 50% reduction in the total sustained decreases in CD200 expression on the B-CLL tar- amount of lymphadenopathy: these patients were from get cells was achieved. Changes from Baseline in absolute the two highest dose cohorts (400 and 500 mg/m )and lymphocyte count and circulating B-CLL cells were found had maximum decreases in lymphadenopathy of 63.4 and to trend similarly: an overall reduction in peripheral B-CLL 73.7%, respectively. A 30% decrease in total lymphadenop- cells after samalizumab dosing paralleled the reduction in athy was the cut-off below which lymph node regression absolute lymphocyte count. In 14/23 (56.5%) patients, this was considered a clinically significant improvement. The increase was followed by a reduction in both peripheral maximum change in lymphadenopathy in individual pa- CLL cells and absolute lymphocyte count with multiple tients is shown in Fig. 2. samalizumab doses (% decrease 0.5 to 50%). Eight patients from all dose level cohorts had a max- Detectable levels of Th1 and Th2 cytokines (IFN-γ, IL- imum increase in lymphadenopathy (range: 2.8 to 118%). 2, IL-10, IL-12p70 and TNF-α) were observed following Two of these patients had a > 50% maximum increase in the first dose, but levels were neither sustained nor asso- lymphadenopathy, a cut-off above which lymph node en- ciated with clinical symptoms (data not shown). largement represents progressive disease. Twenty of the 22 patients (91%) showed a decrease in Response to therapy thesizeofatleast asinglelesion. Ten(45%)had amax- The ORR for CLL patients was 4% (1 of 23) with this imum reduction > 40% and five (23%) had > 50% reduc- conservative dosing schedule. Sixteen CLL patients tion. The reductions in individual lesions did not (70%) achieved SD, and five patients (22%) had PD. One always correlate with a similar reduction in the sum of patient was not evaluable and one patient had a PR that the bi-dimensional products of target lesions at the same was confirmed at cycle 12 (Patient #102–502; see case time point. Eight patients (36%) had an increase in the study in Additional file 1 – pages 3–5and 8–10). Patient sum of products of bi-dimensional target lesions at the #102–502 was a newly diagnosed with Rai stage IV and time they experienced a maximum reduction in a single was treated at the 400 mg/m dose. A reduction in CD200 lesion (Table 5). expression on CLL cells was associated with a transient in- crease in peripheral CLL cells followed by a progressive Discussion reduction peripheral CLL cells (Fig. S2), CD200+ CD4+ T Although promising novel therapies have recently become cells and T s. In contrast, CD8+ T-cells increased indi- available, the majority of patients with CLL and MM will REG cating an anti-tumor immune response (Additional file 1: ultimately relapse or become refractory to currently avail- Figure S3). Reduced CD200 expression on CLL cells paral- able therapeutic regimens, and the only known curative leled a reduction in bulky lymphadenopathy (Additional therapy for CLL and MM is stem cell transplantation, with file 1: Figure S4). One patient, maintained SD through its associated high morbidity and mortality [43, 44]. Block- cycle 18 (300 mg/m ) and two patients maintained a SD ade of the CD200-CD200R immune checkpoint using a through cycle 6 (500 mg/m ) when the study was termi- therapeutic anti-CD200 mAb was hypothesized to restore nated. All 3 MM patients had PD. and/or enhance tumor cell recognition and CTL mediated Of the 22 patients whose primary target lesions were anti-tumor responses in advanced CLL and MM patients measured by CT scans at baseline and at least one with limited therapeutic options. Samalizumab is a novel, Mahadevan et al. Journal for ImmunoTherapy of Cancer (2019) 7:227 Page 9 of 13 Fig. 1 Each panel displays data for a single patient (indicated at the top of each graph) at baseline (Day 0) and after samalizumab dosing at the indicated time points. For simplicity, no more than the first 4 dosing cycles are shown. a. Percent change from baseline in CLL CD200 expression (mean channel fluorescence (MFI)) in CLL patients. b. Percent change from baseline in CD200+ CD4+ T cells (%) in CLL and MM patients Mahadevan et al. Journal for ImmunoTherapy of Cancer (2019) 7:227 Page 10 of 13 Fig. 2 Each vertical bar represents the maximum change obtained for a single patient, identified by the six digit code at the bottom of the graph, that had a baseline CT scan and at least one subsequent scan. The horizontal dotted line at 50% represents a cut-off above which lymph node enlargement represents progressive disease whereas the horizontal dotted line at − 30% represent a cut-off below which lymph node regression represents clinically significant improvement. Patient 107–602 (500 mg/m cohort) did not have a post-dose CT scan and was not evaluable first-in-class, recombinant humanized anti-CD200 mAb, observed. TEAEs were generally mild or moderate in se- engineered to ablate effector function, that specifically verity and, overall, were considered manageable. None of binds to the immune checkpoint CD200, blocks receptor the patients discontinued samalizumab treatment due to engagement and signaling and antagonizes CD200-driven SAEs and the frequency of SAEs appears not to be dose- immune suppression, thereby allowing the patient’sim- related. However, two patients discontinued participa- mune surveillance to detect tumor cells and mount an tion in the post-dose follow-up period due to SAEs that anti-tumor immune response. were unrelated to study drug. Samalizumab dosing was Samalizumab at doses of 50 to 600 mg/m was well not associated with clinically significant cytokine re- tolerated, MTD was not determined and no DLTs were sponses at any time (data not shown). ADA frequency Mahadevan et al. Journal for ImmunoTherapy of Cancer (2019) 7:227 Page 11 of 13 Table 5 Maximum reduction in the sum of lesions and a single lesion after samalizumab dosing b b Samalizumab Patient ID Single Lesion Sum of Lesions Treatment Group % Change Cycle Day % Change Cycle Day 50 mg/m (N = 4) 101–103 −3.45 C1 D28 2.77 C1 D28 101–104 −45.29 C1 D77 −9.8 C1 D35 102–101 −19.75 C4 D16 4.32 C4 D16 102–102 −9.77 C1 D35 −9.46 C1 D35 2 a 100 mg/m (N =4) 101–202 −37.78 C4 D0 −6.83 C4 D0 101–203 −11.54 C4 D0 7.0 C1 D28 102–201 −95.31 C4 D0 −20.7 C4 D0 102–205 −41.36 C3 D26 −18.7 C3 D26 2 a 200 mg/m (N =2) 101–301 − 48.67 C1 D28 −28.7 C1 D28 102–303 −42.05 C3 D21 −4.75 C3 D21 300 mg/m (N = 3) 101–402 −14.29 C4 D43 8.3 C4 D43 101–403 −23.81 C1 D29 −12.5 C1 D29 102–401 −58.73 C1 D35 −16.1 C16 D1 400 mg/m (N = 3) 102–502 −87.02 C13 D35 −63.4 C13 D35 107–503 −54.55 C4 D27 −3.34 C1 D42 107–504 −29.34 C1 D29 9.52 C1 D29 2 a 500 mg/m (N =4) 101–606 −48.15 C6 D0 −6.91 C6 D0 102–601 −86.36 C2 D28 −73.7 C2 D28 102–603 −5.13 C1 D25 1.84 C1 D25 102–607 −37.36 C1 D28 −19.4 C1 D28 a 2 2 2 Patient 107–602 (500 mg/m cohort) did not have a post-dose CT scan and was not evaluable; Patients 104–204 (100 mg/m cohort) and 104–302 (200 mg/m cohort) had no reduction in any of their target lesions and are not included Maximum reduction for a single lesion (product of bi-dimensional tumor measurement) and maximum reduction for sum of lesions (sum of the products of bi- dimensional tumor measurements) are presented as a % Change from baseline on the indicated Cycle and Day was consistent with that in literature reports of other T-cell subsets were consistently observed, although one therapeutic mAbs [45, 46]. patient with no prior chemotherapy demonstrated the The mean T for samalizumab increased with increas- predicted immunomodulatory changes following mul- 1/2 2 2 ing doses (100 mg/m –600 mg/m ). The high clearance of tiple doses of samalizumab: increases in frequencies of samalizumab at low doses likely represents saturation bind- activated T cells and CD8+ T cells during prolonged ing to membrane-associated CD200 surface antigen. At samalizumab treatment, with concomitant reduction of higher doses, antibody clearance is likely due to nonspecific T (Additional file 1 pages 3–5and 8–10). REGs elimination through the cells of the reticuloendothelial sys- The clinical responses reported support the study’s tem [47]. These findings are consistent with those of other central hypothesis that blockade of the immune inhibi- therapeutic mAbs reported in the literature [48]. tory ligand CD200 by samalizumab promotes anti-tumor Samalizumab binding dampens CD200 overexpression activity: serial CT scans revealed that more than half on CLL cells in a dose-dependent manner, and the re- (64%) of evaluable CLL patients had reductions in tumor duction in CD200 expression is sustained at higher doses burden, with two patients having > 50% reduction. Most (300–500 mg/m ). However, it is apparent from these CLL patients had a decrease in size of at least one lesion, early data that the concentrations of samalizumab achieved with 22.7% of CLL patients experiencing a reduction of in this phase I study were insufficient to completely saturate > 50% in at least one lesion. However, in 8 patients, 4 of cell-surface CD200 on the CLL cells. The PK and PD assays whom had SD, the maximum reductions in a single le- incorporated in this study may provide a strategy to guide sion did not always correlate with the maximum reduc- optimal dosing in future trials. Sustained decreases in tion in the sum of the products of all lesions at the same CD200 expression on peripheral CD200+ CD4+ T cells time point. This may represent an immune-modulated (reduction in the percentage of CD200+ CD4+ T cells) response consistent with pseudoprogression [49]. In is observed in CLL and MM patients at higher doses clinical trials of solid tumors, increases in tumor burden (300–600 mg/m ). No other dose-dependent changes in that can precede responses led to novel evaluation Mahadevan et al. Journal for ImmunoTherapy of Cancer (2019) 7:227 Page 12 of 13 criteria (immune-related response criteria (irRC)) [49]. Authors’ contributions DM, MCL, LTH, MP and CF were the principle investigators at each study site An increase in tumor burden prior to response evalu- and enrolled patients. All co-authors contributed to data collection, analysis ation may reflect either continued tumor growth until a and writing of the manuscript. All authors read and approved the final sufficient immune response develops or transient manuscript. immune-cell infiltrate. Similar patterns of stable disease Funding or improvement after an initial increase in tumor burden The authors express their appreciation to the patients and their families and have been observed with other immune checkpoint in- acknowledge the contributions of Alexion Pharmaceuticals, Inc. The study was sponsored by Alexion Pharmaceuticals, Inc. hibitors such as ipilimumab and anti-PD-1 mAbs [28, 32, 33]. Although the irRC have been implemented in Availability of data and materials solid tumors, mechanisms underlying these increases Supporting data is available at the journals request. may also apply to lymphadenopathy in B-cell Ethics approval and consent to participate malignancies. All sites consented patients per site IRB and WIRB. SD was achieved in sixteen CLL patients: one patient received 18 cycles of samalizumab and maintained SD Consent for publication All authors read the manuscript and agree to publication. through cycle 18 (300 mg/m ) and two patients main- tained SD through cycle 6 (500 mg/m ). All 3 patients Competing interests remained on samalizumab until the trial was concluded. Academic authors have nothing to disclose. MW, SJF, TU, AK, LL, CLB, and XP are employed by Alexion Pharmaceuticals, Inc. One treatment-naïve Rai Stage IV CLL patient (Patient# 102–502) who received 13 cycles of samalizumab achieved Author details a durable PR lasting for > 6 years with no further interven- Department of Medicine Division of Hematology/Oncology, University of Arizona Cancer Center, 1515. N. Campbell Avenue, Room 1905, Tucson, AZ tions and is reported to be healthy at the time of this 2 3 85724, USA. Duke University Medical Center, Durham, NC, USA. Summit manuscript. This patient may have had a superior clinical Medical Center, MD Anderson Cancer Center, Morristown, NJ, USA. The response to samalizumab because of his preserved im- West Cancer Center, University of Tennessee, Memphis, TN, USA. Alexion Pharmaceuticals, Inc., New Haven, CT, USA. Winship Cancer Institute of mune function prior to treatment. Emory University, Atlanta, GA, USA. 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Journal for ImmunoTherapy of Cancer – Springer Journals

Published: Aug 23, 2019

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