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CAR-T cells in multiple myeloma: current status

CAR-T cells in multiple myeloma: current status short review memo (2020) 13:43–49 https://doi.org/10.1007/s12254-020-00571-7 Normann Steiner · Eberhard Gunsilius Received: 7 December 2019 / Accepted: 2 January 2020 / Published online: 16 January 2020 © The Author(s) 2020 Summary Starting with the approval of bortezomib, ulating drugs and monoclonal antibodies. Here, we a proteasome-inhibiting drug, tremendous progress briefly summarize current clinical knowledge about has been achieved in the treatment of multiple CAR-T cell treatment in multiple myeloma, including myeloma (MM) patients during the last 15 years. clinical data presented at the 61st American Society of Due to a plethora of novel drugs such as second gen- Hematology annual meeting held in December 2019 eration proteasome inhibitors, immunomodulating in Orlando. agents and monoclonal antibodies the 5-year sur- vival of MM patients has been extended from 33% Keywords Multiple Myeloma · CAR-T cells · at the turn of the millennium to approximately 60% Immunotherapy in younger patients (<65–70 years) who were eligible for consolidation with high-dose chemotherapy and CAR-T targeting BCMA autologous stem cell transplantation. Unfortunately, virtually all patients suffer from relapse and ultimately B-cell maturation antigen (BCMA) is a transmem- succumb to the disease, indicating the need for ad- brane receptor which belongs to the tumor necrosis ditional treatment strategies. Currently there are two factor (TNF) family [1]. In multiple myeloma (MM) promising immunologic approaches. First, bispecific BCMA shows an increased expression on malignant antibodies called BITE (bispecific T-cell enhancer), plasma cells (PC) with a variable expression rate of which act as fusion proteins with two single-chain 25–100% [2]. In normal tissue BCMA is almost exclu- variable fragments, target antigens on malignant cells sively expressed on mature B-cells and plasma cells and bind the CD3 receptor and thereby recruit T-cells (PC), especially long-lived PC. Therefore, it consti- to the target cells. The second strategy is chimeric tutes an attractive target for CAR-T cell therapy [3–6]. antigen receptor (CAR) engineered T-cell therapy that The ligands of BCMA include B-cell activating factor attacks myeloma cells by recognizing specific targets (BAFF) and a proliferation inducing ligand (APRIL), such as CD138, BCMA (B-cell maturation antigen), which promote B-cell maturation and protect malig- light-chains, SLAM-F7 (signaling lymphocytic activa- nant plasma cells from apoptosis [7, 8]. tion molecule family member 7) or the pan B-cell The first in-human clinical trial of CAR-T targeting antigen CD19. BCMA was conducted by Brudno et al. from the Na- Several early phase clinical trials show encouraging re- tional Cancer Institute (NCI), USA. The 16 relapsed/ sults in patients who have relapsed after modern treat- refractory MM (RRMM) patients had received a me- ment including proteasome inhibitors, immunomod- dian of 9.5 prior therapy lines. They were treated with 9× 10 CAR-T cells/kg, which was the highest dosage administered in this study, and showed an overall re- PD Dr. N. Steiner · Univ.-Doz. Dr. E. Gunsilius () sponse rate (ORR) of 81% with 63% very good par- University Clinic for Internal Medicine V, Hematology and Oncology, Medical University Innsbruck, tial response (VGPR) or better and approximately 68% Anichstraße 35, 6020 Innsbruck, Austria bone marrow residual disease negative status. Cy- eberhard.gunsilius@i-med.ac.at tokine release syndrome (CRS) grade ≥3 occurred in 6 of those 16 patients, but was reversible under vaso- PD Dr. N. Steiner normann.steiner@i-med.ac.at pressor support, tocilizumab and corticosteroids. The K CAR-T cells in multiple myeloma: current status 43 short review median progression-free survival (PFS) was 31 weeks Xu et al. compared clinical response in 17 RRMM [9]. patients (median of 4 previous therapy lines) who Since then, a variety of BCMA-CAR-T therapies were either treated with three or one LCAR B38M in- have been designed and preclinically/clinically tested, fusions. There was an ORR of 88.2% with 13 patients of which some are summarized in Table 1 and de- achieving stringent CR and 2 patients reaching VGPR. scribed briefly below. No difference in clinical response or CRS rate was BB2121 (Bluebird Bio, Celgene) contains a murine- detected in the two subgroups [17]. derived anti-BCMA single-chain variable fragment Cohen et al. tested the clinical activity of a fully (scFv) and a CD3ζ/4-1BB signaling domain. A phase 1 human BCMA-specific CAR in 25 patients (≥3pre- study consisting of two phases (a dose-escalation vioustherapy linesor ≥2 previous therapy lines and phase and a dose-expansion phase) was conducted dual refractory to proteasome inhibitors [PI] and im- on 33 RRMM patients who had received a median munomodulatory imide drugs [IMiD]). Patients were of 7.5 previous therapy lines in the dose-escalation divided into three cohorts: cohort 1 received 1 × 10 to group and 8 previous therapy lines in the dose-expan- 5× 10 BCMA-CAR-T cells only (ORR 44%), cohort 2 7 7 sion group. The study reported an 85% ORR including received cyclophosphamide with 1 × 10 to 5 × 10 45% complete responses (CR). In all, 76% of patients BCMA-CAR-T cells (ORR 20%) and cohort 3 received 8 8 developed CRS, of which most cases were limited to cyclophosphamide with 1 × 10 to 5 × 10 BCMA-CAR-T grade 1 or 2. Other adverse events occurred in all pa- cells (ORR 64%) [18]. They found a decreased BCMA tients (97% adverse events ≥ grade 3), primarily neu- expression on residual MM cells in responders and an tropenia, leukopenia, anemia and thrombocytopenia. increased expression at progression in most patients. The median PFS was 11.8 months with 40% of the pa- C-CAR088 is a novel BCMA-CAR-T containing tients being progression-free at the 12-month mark. ascFv from a high-affinity human monoclonal anti- The study comprised two phases: a dose-escalation body. C-CAR088 is currently in an ongoing phase 1 phase and a dose-expansion phase [10]. clinical trial. Three patients with 7 prior lines of ther- KarMMa is a phase 2 study of BB2121, which com- apy have been treated so far, whereof two achieved pleted enrollment (of approximately 150 patients) in VGPR and one a PR [19]. 2019. KarMMa-2 is also a phase 2 study of BB2121, CT103A is another CAR-T containing a fully human which is still in the enrollment process and will com- scFv and additionally a CD8a hinge domain, which is pare the efficacy of BB2121 as a ≥ third line treat- supposed to improve the post-infusion expansion and ment versus as a second line treatment in patients persistence of CAR-T cells. Between September 2018 who show an insufficient response to or an early re- and August 2019, 16 patients (≥3previous therapy lapse after first line therapy. KarMMa-3 will be the first lines) were treated with CT103A, of which 4 had pre- phase 3 randomized clinical trial comparing BB2121 viously relapsed after murine BCMA CAR-T cell ther- to standard therapy in patients with 2–4 prior therapy apy. ORR was 100% with 37% CR and 13% VGPR. All lines (planned enrollment of 381 patients) [11–14]. 4 patients who had participated in prior CAR-T trials BB21217 is the successor of BB2121. The structure achieved VGPR or better [20]. of B21217 is very similar to B2121 except for the addi- CT053 is a second-generation CAR with a fully hu- tion of a phosphoinositide 3-kinase inhibitor bb007, man scFv and was studied in a phase 1 trial on a total which is meant to enhance the persistence and po- of 24 RRMM patients who had received at least two tency of the CAR-T cells. A phase 1 trial revealed prior myeloma regimens. An ORR of 87.5% included an ORR and tolerability similar to BB2121 in patients 79.2% of CR; 9 patients progressed after a median PFS who had received a median of 7 previous therapy of 9 months, while 13 subjects had ongoing CR (me- lines. However, updated data will be necessary to dian follow-up 383 days). No dose-limiting toxicities sufficiently evaluate if progression-free survival (PFS)/ were observed, CRS occurred in 62.5% of all patients overall survival (OS) rates suggest an improved effi- and did not exceed grade 2 [21]. cacy compared to BB2121 [15]. P-BCMA-101 is a BCMA-CAR-T cell produced with L-CAR B38M is a dual epitope-binding CAR-T di- the piggyBac DNA Modification system (transposon- rected targeting BCMA. Zhao et al. reported a study based) instead of a viral vector. Hence, it is less costly with 57 RRMM patients (median of 3 previous therapy and achieves a higher percentage of T-memory stem lines), who received L-CAR B38M in three separate cells. Moreover, it allows for the integration of mul- infusions instead of the usual single-administration. tiple additional genes including a safety switch and There was an ORR of 88% with 68% CR and 63% min- a selection gene. Instead of the traditional antibody- TM imal residual disease negative status and a median based scFv, P-BCMA-101 contains Centyrin , a fully PFS of 15 months. The authors reported a manage- human protein, which is smaller, more stable and po- able safety profile with CRS in 90% of patients, but tentially less immunogenic. After a phase 1 trial ob- only 7%≥ grade 3. They did not find a correlation be- tained promising results, phase 2 studies are currently tween clinical response and BCMA expression levels being initiated for patients who have received three or [16]. more lines of previous treatment [22]. 44 CAR-T cells in multiple myeloma: current status K short review Table 1 Clinical trials using CAR-T cells in multiple myeloma patients Study CAR Target No. of ORR CR VGPR Median PFS, mo. (median FU, Therapy lines prior to patients mo.) CAR-T Brudno , CAR-T-BCMA (murine BCMA 16 81% 13% 50% 31 (n. a.) Median: 9.5 2018 [9] scFv) Range: 3–19 Raje, B2121 BCMA 33 85% 45% n. a. 11.8 (11.3) Escalation: 2019 [10] Median: 7.5 Range: 3–14 Expansion: Median: 8 Range: 3–23 Berdeja, B21217 BCMA 22 83% n. a. n. a. To be evaluated Median: 7 2019 [15] Range: 4–17 Zhao, L-CAR B38M BCMA 57 88% 68% 5% 15 (8) Median: 3 2018 [16] (dual Range: 1–9 epitope) Xu, L-CAR B38M BCMA 17 88.2% 76% 12% 82% at 6 mo., Median: 4 2019 [17] (dual 53% at 12 mo. (14) Range: 3–11 epitope) Cohen, CAR-T-BCMA BCMA 25 Variable in the three different cohorts, ORR range 20–64% ≥3or ≥2 and dual 2019 [18] (human scFv) refractory to PI and IMiD Yao, C-CAR088 BCMA 3 (as of n. a. n. a. ≥3 2019 [19] July 2015) Li, 2019 [20] CT103A BCMA 16 100% 38% 13% n. a. ≥3 Jie, CT053 BCMA 24 87.5% 79.2% n. a. 9 patients progressed after a me- ≥2 2019 [21] dian of 9 mo. PFS, 13 patients with ongoing CR Fu, CAR-T-BCMA + safety BCMA 44 79.6% 40% 18% 15 (n. a.) ≥2 2019 [23] switch (tEGFR) Raje, 2019 PF-3135 BCMA, 17 6% 0% 0% Ongoing clinical trial Median: 11 [24] CD3 Li, BM38 BCMA, 16 87.5 50 12.5 PFS at 9 mo. 75% ≥2 2019 [25] CD38 Popat , AUTO2 BCMA, 7 43% 0 14 n. a. ≥2 or dual refractory to 2019 [26] TACI PI and IMiD Garfall, CTL019 + ASCT CD19 10 80% n. a. n. a. PFS 1 = after prior ASCT, Median: 6 2018 [32] PFS 2 = after ASCT + CTL019; Range: 2–10 PFS 2 > PFS 1 in 2 patients Yan, CAR-T-BCMA, CD19, 27 92.6% 40.7% 29.6% n. a. Median: 3 2019 [34] CAR-T-CD19 BCMA Range: 2–8 Zhang, Bispecific CD19, 5 100% 20% 60% n. a. Median: 3 2019 [36] BCMA-CD19-CAR-T BCMA Range: 1–5 Guo, CAR-T138 CD138 5 0% 0% n. a. n. a. Median: 8 2015 [45] Range: 5–18 Mo. Months, ORR overall response rate, CR complete remission, VGPR very good partial remission, n. a. not available, FU follow-up, scFv single-chain variable fragment, PI proteasome inhibitor, IMiD immunomodulatory imide drugs a 6 These 16 patients were the patients treated with 9 × 10 CAR-T cells/kg b 6 The results listed here refer to the 7 out of the 12 patients who were in the ≥225 × 10 dose cohorts Fu Sr. et al. developed a BCMA-CAR-T cell prod- is a promising target for CAR-T cell therapy in RRMM uctwithanintegratedsafetyswitchin the form of patients. a truncated epidermal growth factor receptor (tEGFR). A phase 1 trial conducted on 46 RRMM patients Bispecific BCMA-CAR-T cell therapy (≥2 previous therapy lines) reached an ORR of 79.6% in the 44 evaluable patients, with 40% CR or better. PF-3135: BCMA+ CD3 Only a strikingly small number of patients developed CRS (23% grade 1–2, 7% grade 3) [23]. PF-3135 is a bispecific, humanized monoclonal an- All of these clinical trials mainly included RRMM tibody consisting of BCMA- and CD3-targeting arms patients, who did not show an adequate response to and thus binding myeloma cells and T-cells. There is conventional therapy regimens (≥3therapy lines pre- an ongoing dose-escalation multicenter phase 1 study ceded CAR-T cell therapy in most studies listed here). evaluating the efficacy of PF-3135 in RRMM patients Overall response rates up to 100% suggest that BCMA who had received a median of 11 previous therapy K CAR-T cells in multiple myeloma: current status 45 short review lines. Interim results showed a clinical benefit rate due to antigen loss [33]. Recently, there have been of 41% (defined as best response ≥ stable disease) and trials investigating the efficacy of the combination moderate CRS events. Results of additional dose co- BCMA-CD19 CAR-T. horts will be reported in the future [24]. Yan et al. performed a phase 1 clinical trial on 28 RRMM patients (median of 3 previous therapy lines) who received sequential infusion of autologous BM38: BCMA+ CD38 CD19-CAR-T cells and BCMA-CAR-T cells. Among the Li et al. conducted the first in-human phase 1 clin- 27 patients available to follow-up the ORR was 92.6% ical trial of a dual-target BM38 CAR containing an with 40.7% complete remissions [34]. anti-BCMA and an anti-CD38 scFv. As of July 2019, Shi et al. compared the efficacy of combined infu- 16 RRMM patients (≥2 previous therapy lines) received sion of anti-CD19 and anti-BCMA CAR-T cells follow- treatment with BM38. The ORR was 87.5 with 50% CR. ing ASCT (infused on day 14 to day 20 after transplan- The elimination of 5 extramedullary lesions (100% in tation) in different therapy lines. The ORR was 100% this study) was reported as well as manageable toxicity with 72% CR. ASCT and CAR-T therapy were either and prolonged CR [25]. administered as first-line therapy (group 1), as second line (group 2) or as salvage therapy at third line or more. They found that efficacy was higher in front AUTO2: BCMA+ TACI line. The response (CR or better) was 78% in group 1, Popatetal. designed anovel CAR, usingatruncated 100% in group 2 and 44% in group 3 [35]. form of APRIL (a proliferation-inducing ligand) as In a study by Zhang et al., a bispecific BCMA-CD19- the tumor-targeting domain which recognizes both CAR was produced by joining BCMA and CD19 scFv BCMA and TACI (transmembrane activator and cal- with a CD8 hinge. Preclinical as well as clinical data il- cium-modulator and cyclophilin ligand interactor) lustrate that the bispecific CAR-T cells are effective in on MM cells. Similar to BCMA, TACI also belongs the treatment of MM. In their clinical study 5 patients to the TNF family and promotes B-cell maturation. (median of 3 previous therapy lines) were treated and Interim phase 1 results (n=12 patients, ≥2previous evaluated 15–59 days later: 1 patient achieved CR, therapy lines or dual refractory to PI and IMiD) show 3 achieved VGPR and 1 achieved PR. The toxicity was that the therapy was well-tolerated at doses up to remarkably low with three cases of only grade 1 CRS 900 × 10 CAR-T cells and achieved an ORR of 43% in and no neurotoxicity [36]. the ≥225 × 10 dose cohorts [26]. CAR-T targeting SLAM-F7 CAR-T targeting CD19 SLAMF7, also known as CS1, belongs to the signal- While CD19 is present on normal PC, myeloma cells ing lymphocyte activating-molecule-related receptor typically do not express CD19 [27, 28]. However, family [37]. It has been found to be expressed at high patients with monoclonal gammopathy of unde- levels on PC and MM cells and at lower levels on nat- termined significance (MGUS) have a high expres- ural killer cells, CD8+ cells, activated monocytes and sion of CD19 on their bone-marrow plasma cells, dendritic cells [38]. which indicates that CD19-expressing PC might act SLAMF7 is targeted by the monoclonal antibody as myeloma stem cells [29, 30]. CTL019 (tisagen- elotuzumab, which is approved for the treatment of lecleucel) is a CAR-T cell therapy approved for the MM [39]. treatment of advanced acute lymphoid leukemia and Gogishvili et al. designed a CAR targeting SLAMF7, diffuse large B cell lymphoma [31]. An early phase which is derived from the huLuc63 antibody (elo- clinical trial by Garfall et al. assessed the efficacy of tuzumab). A single administration of SLAMF7- CTL019 combined with ASCT in MM. All 10 patients CAR-T cells was able to eliminate extramedullary and who were treated with ASCT and CTL019 had previ- medullary MM manifestations in a murine xenograft ously undergone ASCT as a component of first-line model. They confirmed that the fratricide caused by +/high therapy and had received a median of 6 therapy lines SLAMF7-CAR-T cells only affects SLAMF7 cells. –/low in total. In all, 8 of the 10 patients showed partial Due to the fact that SLAMF7 cells of all cell sub- response (PR) or better 100 days after ASCT. To deter- sets (natural killer cells, CD4+, CD8+, B-cells) are mine how greatly CTL019 contributed to this ORR, the spared, a number of functional lymphocytes remain authors compared the PFS following ASCT + CTL019 [40]. A compound CAR (cCAR) T-cell consisting of to the PFS following prior ASCT. They found a signifi- two complete and independent anti-BCMA and anti- cantly longer PFS after ASCT + CTL019 in only 2 out of SLAMF7 CAR receptors has shown promising in vitro 10 subjects. Possible explanations for this low clinical and in vivo anti-myeloma activity [41]. Phase 1 clinical benefit might be inadequate in vivo engraftment and trials of SLAMF7 CAR-T cells are currently ongoing. the low dosage of CTL019 used [32]. In multiple studies, CAR-T cells with different tar- gets have been combined, aiming to reduce resistance 46 CAR-T cells in multiple myeloma: current status K short review clinical as well as clinical research is moving rapidly CAR-T targeting CD138 forward and the gain of knowledge is growing contin- CD138, also known as syndecan-1, is an integral mem- uously. Clinical phase 3 trials will provide more robust brane proteoglycan containing both heparan sulfate data on their efficacy and tolerability in myeloma pa- and chondroitin sulfate [42]. A preclinical study in- tients and should provide the basis for consensus vestigated the capability of CD138 antibody therapy guidelines that will help to identify the optimal can- in conjunction with radioimmunotherapy in the ther- didates for this promising but also potentially toxic apy of MM in mice [43]. Moreover, CD138 CAR-T cells and expensive treatment. both from healthy donors and MM patients showed Funding Open access funding provided by University of Inns- promising anti-myeloma activity without any on-tar- bruck and Medical University of Innsbruck. get/off-tumor cytotoxicity against normal epithelial/ Conflict of interest N. Steiner and E. Gunsilius declare that endothelial cells in vitro and in a mouse model [44]. they have no competing interests. CD138 CAR-T cells administered to 5 patients (me- dian of 8 previous therapy lines) in a phase 1 clinical Open Access This article is licensed under a Creative Com- trial in China led to stable disease in 4 of 5 patients mons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in and showed a manageable toxicity profile [45]. Other any medium or format, as long as you give appropriate credit phase I trials using anti-CD138 CAR-T are ongoing. to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were Conclusion made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless Using CAR-T cell therapy, impressive results have indicated otherwise in a credit line to the material. If material been achieved in mostly heavily pretreated patients is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or with multiple myeloma (MM). However, this treat- exceeds the permitted use, you will need to obtain permis- ment harbors potentially life-threatening compli- sion directly from the copyright holder. To view a copy of this cations and requires careful patient selection and licence, visit http://creativecommons.org/licenses/by/4.0/. a treatment team that is experienced in autologous and allogeneic cell therapies. Moreover, the responses using current CAR-T strategies are frequently not References durable and most of the patients suffer a relapse. 1. Madry C, Laabi Y, Callebaut I, Roussel J, Hatzoglou A, Le The mechanisms of resistance against CAR-T in MM Coniat M, et al. The characterization of murine BCMA gene are not completely understood. 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CAR-T cells in multiple myeloma: current status

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short review memo (2020) 13:43–49 https://doi.org/10.1007/s12254-020-00571-7 Normann Steiner · Eberhard Gunsilius Received: 7 December 2019 / Accepted: 2 January 2020 / Published online: 16 January 2020 © The Author(s) 2020 Summary Starting with the approval of bortezomib, ulating drugs and monoclonal antibodies. Here, we a proteasome-inhibiting drug, tremendous progress briefly summarize current clinical knowledge about has been achieved in the treatment of multiple CAR-T cell treatment in multiple myeloma, including myeloma (MM) patients during the last 15 years. clinical data presented at the 61st American Society of Due to a plethora of novel drugs such as second gen- Hematology annual meeting held in December 2019 eration proteasome inhibitors, immunomodulating in Orlando. agents and monoclonal antibodies the 5-year sur- vival of MM patients has been extended from 33% Keywords Multiple Myeloma · CAR-T cells · at the turn of the millennium to approximately 60% Immunotherapy in younger patients (<65–70 years) who were eligible for consolidation with high-dose chemotherapy and CAR-T targeting BCMA autologous stem cell transplantation. Unfortunately, virtually all patients suffer from relapse and ultimately B-cell maturation antigen (BCMA) is a transmem- succumb to the disease, indicating the need for ad- brane receptor which belongs to the tumor necrosis ditional treatment strategies. Currently there are two factor (TNF) family [1]. In multiple myeloma (MM) promising immunologic approaches. First, bispecific BCMA shows an increased expression on malignant antibodies called BITE (bispecific T-cell enhancer), plasma cells (PC) with a variable expression rate of which act as fusion proteins with two single-chain 25–100% [2]. In normal tissue BCMA is almost exclu- variable fragments, target antigens on malignant cells sively expressed on mature B-cells and plasma cells and bind the CD3 receptor and thereby recruit T-cells (PC), especially long-lived PC. Therefore, it consti- to the target cells. The second strategy is chimeric tutes an attractive target for CAR-T cell therapy [3–6]. antigen receptor (CAR) engineered T-cell therapy that The ligands of BCMA include B-cell activating factor attacks myeloma cells by recognizing specific targets (BAFF) and a proliferation inducing ligand (APRIL), such as CD138, BCMA (B-cell maturation antigen), which promote B-cell maturation and protect malig- light-chains, SLAM-F7 (signaling lymphocytic activa- nant plasma cells from apoptosis [7, 8]. tion molecule family member 7) or the pan B-cell The first in-human clinical trial of CAR-T targeting antigen CD19. BCMA was conducted by Brudno et al. from the Na- Several early phase clinical trials show encouraging re- tional Cancer Institute (NCI), USA. The 16 relapsed/ sults in patients who have relapsed after modern treat- refractory MM (RRMM) patients had received a me- ment including proteasome inhibitors, immunomod- dian of 9.5 prior therapy lines. They were treated with 9× 10 CAR-T cells/kg, which was the highest dosage administered in this study, and showed an overall re- PD Dr. N. Steiner · Univ.-Doz. Dr. E. Gunsilius () sponse rate (ORR) of 81% with 63% very good par- University Clinic for Internal Medicine V, Hematology and Oncology, Medical University Innsbruck, tial response (VGPR) or better and approximately 68% Anichstraße 35, 6020 Innsbruck, Austria bone marrow residual disease negative status. Cy- eberhard.gunsilius@i-med.ac.at tokine release syndrome (CRS) grade ≥3 occurred in 6 of those 16 patients, but was reversible under vaso- PD Dr. N. Steiner normann.steiner@i-med.ac.at pressor support, tocilizumab and corticosteroids. The K CAR-T cells in multiple myeloma: current status 43 short review median progression-free survival (PFS) was 31 weeks Xu et al. compared clinical response in 17 RRMM [9]. patients (median of 4 previous therapy lines) who Since then, a variety of BCMA-CAR-T therapies were either treated with three or one LCAR B38M in- have been designed and preclinically/clinically tested, fusions. There was an ORR of 88.2% with 13 patients of which some are summarized in Table 1 and de- achieving stringent CR and 2 patients reaching VGPR. scribed briefly below. No difference in clinical response or CRS rate was BB2121 (Bluebird Bio, Celgene) contains a murine- detected in the two subgroups [17]. derived anti-BCMA single-chain variable fragment Cohen et al. tested the clinical activity of a fully (scFv) and a CD3ζ/4-1BB signaling domain. A phase 1 human BCMA-specific CAR in 25 patients (≥3pre- study consisting of two phases (a dose-escalation vioustherapy linesor ≥2 previous therapy lines and phase and a dose-expansion phase) was conducted dual refractory to proteasome inhibitors [PI] and im- on 33 RRMM patients who had received a median munomodulatory imide drugs [IMiD]). Patients were of 7.5 previous therapy lines in the dose-escalation divided into three cohorts: cohort 1 received 1 × 10 to group and 8 previous therapy lines in the dose-expan- 5× 10 BCMA-CAR-T cells only (ORR 44%), cohort 2 7 7 sion group. The study reported an 85% ORR including received cyclophosphamide with 1 × 10 to 5 × 10 45% complete responses (CR). In all, 76% of patients BCMA-CAR-T cells (ORR 20%) and cohort 3 received 8 8 developed CRS, of which most cases were limited to cyclophosphamide with 1 × 10 to 5 × 10 BCMA-CAR-T grade 1 or 2. Other adverse events occurred in all pa- cells (ORR 64%) [18]. They found a decreased BCMA tients (97% adverse events ≥ grade 3), primarily neu- expression on residual MM cells in responders and an tropenia, leukopenia, anemia and thrombocytopenia. increased expression at progression in most patients. The median PFS was 11.8 months with 40% of the pa- C-CAR088 is a novel BCMA-CAR-T containing tients being progression-free at the 12-month mark. ascFv from a high-affinity human monoclonal anti- The study comprised two phases: a dose-escalation body. C-CAR088 is currently in an ongoing phase 1 phase and a dose-expansion phase [10]. clinical trial. Three patients with 7 prior lines of ther- KarMMa is a phase 2 study of BB2121, which com- apy have been treated so far, whereof two achieved pleted enrollment (of approximately 150 patients) in VGPR and one a PR [19]. 2019. KarMMa-2 is also a phase 2 study of BB2121, CT103A is another CAR-T containing a fully human which is still in the enrollment process and will com- scFv and additionally a CD8a hinge domain, which is pare the efficacy of BB2121 as a ≥ third line treat- supposed to improve the post-infusion expansion and ment versus as a second line treatment in patients persistence of CAR-T cells. Between September 2018 who show an insufficient response to or an early re- and August 2019, 16 patients (≥3previous therapy lapse after first line therapy. KarMMa-3 will be the first lines) were treated with CT103A, of which 4 had pre- phase 3 randomized clinical trial comparing BB2121 viously relapsed after murine BCMA CAR-T cell ther- to standard therapy in patients with 2–4 prior therapy apy. ORR was 100% with 37% CR and 13% VGPR. All lines (planned enrollment of 381 patients) [11–14]. 4 patients who had participated in prior CAR-T trials BB21217 is the successor of BB2121. The structure achieved VGPR or better [20]. of B21217 is very similar to B2121 except for the addi- CT053 is a second-generation CAR with a fully hu- tion of a phosphoinositide 3-kinase inhibitor bb007, man scFv and was studied in a phase 1 trial on a total which is meant to enhance the persistence and po- of 24 RRMM patients who had received at least two tency of the CAR-T cells. A phase 1 trial revealed prior myeloma regimens. An ORR of 87.5% included an ORR and tolerability similar to BB2121 in patients 79.2% of CR; 9 patients progressed after a median PFS who had received a median of 7 previous therapy of 9 months, while 13 subjects had ongoing CR (me- lines. However, updated data will be necessary to dian follow-up 383 days). No dose-limiting toxicities sufficiently evaluate if progression-free survival (PFS)/ were observed, CRS occurred in 62.5% of all patients overall survival (OS) rates suggest an improved effi- and did not exceed grade 2 [21]. cacy compared to BB2121 [15]. P-BCMA-101 is a BCMA-CAR-T cell produced with L-CAR B38M is a dual epitope-binding CAR-T di- the piggyBac DNA Modification system (transposon- rected targeting BCMA. Zhao et al. reported a study based) instead of a viral vector. Hence, it is less costly with 57 RRMM patients (median of 3 previous therapy and achieves a higher percentage of T-memory stem lines), who received L-CAR B38M in three separate cells. Moreover, it allows for the integration of mul- infusions instead of the usual single-administration. tiple additional genes including a safety switch and There was an ORR of 88% with 68% CR and 63% min- a selection gene. Instead of the traditional antibody- TM imal residual disease negative status and a median based scFv, P-BCMA-101 contains Centyrin , a fully PFS of 15 months. The authors reported a manage- human protein, which is smaller, more stable and po- able safety profile with CRS in 90% of patients, but tentially less immunogenic. After a phase 1 trial ob- only 7%≥ grade 3. They did not find a correlation be- tained promising results, phase 2 studies are currently tween clinical response and BCMA expression levels being initiated for patients who have received three or [16]. more lines of previous treatment [22]. 44 CAR-T cells in multiple myeloma: current status K short review Table 1 Clinical trials using CAR-T cells in multiple myeloma patients Study CAR Target No. of ORR CR VGPR Median PFS, mo. (median FU, Therapy lines prior to patients mo.) CAR-T Brudno , CAR-T-BCMA (murine BCMA 16 81% 13% 50% 31 (n. a.) Median: 9.5 2018 [9] scFv) Range: 3–19 Raje, B2121 BCMA 33 85% 45% n. a. 11.8 (11.3) Escalation: 2019 [10] Median: 7.5 Range: 3–14 Expansion: Median: 8 Range: 3–23 Berdeja, B21217 BCMA 22 83% n. a. n. a. To be evaluated Median: 7 2019 [15] Range: 4–17 Zhao, L-CAR B38M BCMA 57 88% 68% 5% 15 (8) Median: 3 2018 [16] (dual Range: 1–9 epitope) Xu, L-CAR B38M BCMA 17 88.2% 76% 12% 82% at 6 mo., Median: 4 2019 [17] (dual 53% at 12 mo. (14) Range: 3–11 epitope) Cohen, CAR-T-BCMA BCMA 25 Variable in the three different cohorts, ORR range 20–64% ≥3or ≥2 and dual 2019 [18] (human scFv) refractory to PI and IMiD Yao, C-CAR088 BCMA 3 (as of n. a. n. a. ≥3 2019 [19] July 2015) Li, 2019 [20] CT103A BCMA 16 100% 38% 13% n. a. ≥3 Jie, CT053 BCMA 24 87.5% 79.2% n. a. 9 patients progressed after a me- ≥2 2019 [21] dian of 9 mo. PFS, 13 patients with ongoing CR Fu, CAR-T-BCMA + safety BCMA 44 79.6% 40% 18% 15 (n. a.) ≥2 2019 [23] switch (tEGFR) Raje, 2019 PF-3135 BCMA, 17 6% 0% 0% Ongoing clinical trial Median: 11 [24] CD3 Li, BM38 BCMA, 16 87.5 50 12.5 PFS at 9 mo. 75% ≥2 2019 [25] CD38 Popat , AUTO2 BCMA, 7 43% 0 14 n. a. ≥2 or dual refractory to 2019 [26] TACI PI and IMiD Garfall, CTL019 + ASCT CD19 10 80% n. a. n. a. PFS 1 = after prior ASCT, Median: 6 2018 [32] PFS 2 = after ASCT + CTL019; Range: 2–10 PFS 2 > PFS 1 in 2 patients Yan, CAR-T-BCMA, CD19, 27 92.6% 40.7% 29.6% n. a. Median: 3 2019 [34] CAR-T-CD19 BCMA Range: 2–8 Zhang, Bispecific CD19, 5 100% 20% 60% n. a. Median: 3 2019 [36] BCMA-CD19-CAR-T BCMA Range: 1–5 Guo, CAR-T138 CD138 5 0% 0% n. a. n. a. Median: 8 2015 [45] Range: 5–18 Mo. Months, ORR overall response rate, CR complete remission, VGPR very good partial remission, n. a. not available, FU follow-up, scFv single-chain variable fragment, PI proteasome inhibitor, IMiD immunomodulatory imide drugs a 6 These 16 patients were the patients treated with 9 × 10 CAR-T cells/kg b 6 The results listed here refer to the 7 out of the 12 patients who were in the ≥225 × 10 dose cohorts Fu Sr. et al. developed a BCMA-CAR-T cell prod- is a promising target for CAR-T cell therapy in RRMM uctwithanintegratedsafetyswitchin the form of patients. a truncated epidermal growth factor receptor (tEGFR). A phase 1 trial conducted on 46 RRMM patients Bispecific BCMA-CAR-T cell therapy (≥2 previous therapy lines) reached an ORR of 79.6% in the 44 evaluable patients, with 40% CR or better. PF-3135: BCMA+ CD3 Only a strikingly small number of patients developed CRS (23% grade 1–2, 7% grade 3) [23]. PF-3135 is a bispecific, humanized monoclonal an- All of these clinical trials mainly included RRMM tibody consisting of BCMA- and CD3-targeting arms patients, who did not show an adequate response to and thus binding myeloma cells and T-cells. There is conventional therapy regimens (≥3therapy lines pre- an ongoing dose-escalation multicenter phase 1 study ceded CAR-T cell therapy in most studies listed here). evaluating the efficacy of PF-3135 in RRMM patients Overall response rates up to 100% suggest that BCMA who had received a median of 11 previous therapy K CAR-T cells in multiple myeloma: current status 45 short review lines. Interim results showed a clinical benefit rate due to antigen loss [33]. Recently, there have been of 41% (defined as best response ≥ stable disease) and trials investigating the efficacy of the combination moderate CRS events. Results of additional dose co- BCMA-CD19 CAR-T. horts will be reported in the future [24]. Yan et al. performed a phase 1 clinical trial on 28 RRMM patients (median of 3 previous therapy lines) who received sequential infusion of autologous BM38: BCMA+ CD38 CD19-CAR-T cells and BCMA-CAR-T cells. Among the Li et al. conducted the first in-human phase 1 clin- 27 patients available to follow-up the ORR was 92.6% ical trial of a dual-target BM38 CAR containing an with 40.7% complete remissions [34]. anti-BCMA and an anti-CD38 scFv. As of July 2019, Shi et al. compared the efficacy of combined infu- 16 RRMM patients (≥2 previous therapy lines) received sion of anti-CD19 and anti-BCMA CAR-T cells follow- treatment with BM38. The ORR was 87.5 with 50% CR. ing ASCT (infused on day 14 to day 20 after transplan- The elimination of 5 extramedullary lesions (100% in tation) in different therapy lines. The ORR was 100% this study) was reported as well as manageable toxicity with 72% CR. ASCT and CAR-T therapy were either and prolonged CR [25]. administered as first-line therapy (group 1), as second line (group 2) or as salvage therapy at third line or more. They found that efficacy was higher in front AUTO2: BCMA+ TACI line. The response (CR or better) was 78% in group 1, Popatetal. designed anovel CAR, usingatruncated 100% in group 2 and 44% in group 3 [35]. form of APRIL (a proliferation-inducing ligand) as In a study by Zhang et al., a bispecific BCMA-CD19- the tumor-targeting domain which recognizes both CAR was produced by joining BCMA and CD19 scFv BCMA and TACI (transmembrane activator and cal- with a CD8 hinge. Preclinical as well as clinical data il- cium-modulator and cyclophilin ligand interactor) lustrate that the bispecific CAR-T cells are effective in on MM cells. Similar to BCMA, TACI also belongs the treatment of MM. In their clinical study 5 patients to the TNF family and promotes B-cell maturation. (median of 3 previous therapy lines) were treated and Interim phase 1 results (n=12 patients, ≥2previous evaluated 15–59 days later: 1 patient achieved CR, therapy lines or dual refractory to PI and IMiD) show 3 achieved VGPR and 1 achieved PR. The toxicity was that the therapy was well-tolerated at doses up to remarkably low with three cases of only grade 1 CRS 900 × 10 CAR-T cells and achieved an ORR of 43% in and no neurotoxicity [36]. the ≥225 × 10 dose cohorts [26]. CAR-T targeting SLAM-F7 CAR-T targeting CD19 SLAMF7, also known as CS1, belongs to the signal- While CD19 is present on normal PC, myeloma cells ing lymphocyte activating-molecule-related receptor typically do not express CD19 [27, 28]. However, family [37]. It has been found to be expressed at high patients with monoclonal gammopathy of unde- levels on PC and MM cells and at lower levels on nat- termined significance (MGUS) have a high expres- ural killer cells, CD8+ cells, activated monocytes and sion of CD19 on their bone-marrow plasma cells, dendritic cells [38]. which indicates that CD19-expressing PC might act SLAMF7 is targeted by the monoclonal antibody as myeloma stem cells [29, 30]. CTL019 (tisagen- elotuzumab, which is approved for the treatment of lecleucel) is a CAR-T cell therapy approved for the MM [39]. treatment of advanced acute lymphoid leukemia and Gogishvili et al. designed a CAR targeting SLAMF7, diffuse large B cell lymphoma [31]. An early phase which is derived from the huLuc63 antibody (elo- clinical trial by Garfall et al. assessed the efficacy of tuzumab). A single administration of SLAMF7- CTL019 combined with ASCT in MM. All 10 patients CAR-T cells was able to eliminate extramedullary and who were treated with ASCT and CTL019 had previ- medullary MM manifestations in a murine xenograft ously undergone ASCT as a component of first-line model. They confirmed that the fratricide caused by +/high therapy and had received a median of 6 therapy lines SLAMF7-CAR-T cells only affects SLAMF7 cells. –/low in total. In all, 8 of the 10 patients showed partial Due to the fact that SLAMF7 cells of all cell sub- response (PR) or better 100 days after ASCT. To deter- sets (natural killer cells, CD4+, CD8+, B-cells) are mine how greatly CTL019 contributed to this ORR, the spared, a number of functional lymphocytes remain authors compared the PFS following ASCT + CTL019 [40]. A compound CAR (cCAR) T-cell consisting of to the PFS following prior ASCT. They found a signifi- two complete and independent anti-BCMA and anti- cantly longer PFS after ASCT + CTL019 in only 2 out of SLAMF7 CAR receptors has shown promising in vitro 10 subjects. Possible explanations for this low clinical and in vivo anti-myeloma activity [41]. Phase 1 clinical benefit might be inadequate in vivo engraftment and trials of SLAMF7 CAR-T cells are currently ongoing. the low dosage of CTL019 used [32]. In multiple studies, CAR-T cells with different tar- gets have been combined, aiming to reduce resistance 46 CAR-T cells in multiple myeloma: current status K short review clinical as well as clinical research is moving rapidly CAR-T targeting CD138 forward and the gain of knowledge is growing contin- CD138, also known as syndecan-1, is an integral mem- uously. Clinical phase 3 trials will provide more robust brane proteoglycan containing both heparan sulfate data on their efficacy and tolerability in myeloma pa- and chondroitin sulfate [42]. A preclinical study in- tients and should provide the basis for consensus vestigated the capability of CD138 antibody therapy guidelines that will help to identify the optimal can- in conjunction with radioimmunotherapy in the ther- didates for this promising but also potentially toxic apy of MM in mice [43]. Moreover, CD138 CAR-T cells and expensive treatment. both from healthy donors and MM patients showed Funding Open access funding provided by University of Inns- promising anti-myeloma activity without any on-tar- bruck and Medical University of Innsbruck. get/off-tumor cytotoxicity against normal epithelial/ Conflict of interest N. Steiner and E. Gunsilius declare that endothelial cells in vitro and in a mouse model [44]. they have no competing interests. CD138 CAR-T cells administered to 5 patients (me- dian of 8 previous therapy lines) in a phase 1 clinical Open Access This article is licensed under a Creative Com- trial in China led to stable disease in 4 of 5 patients mons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in and showed a manageable toxicity profile [45]. Other any medium or format, as long as you give appropriate credit phase I trials using anti-CD138 CAR-T are ongoing. to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were Conclusion made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless Using CAR-T cell therapy, impressive results have indicated otherwise in a credit line to the material. If material been achieved in mostly heavily pretreated patients is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or with multiple myeloma (MM). However, this treat- exceeds the permitted use, you will need to obtain permis- ment harbors potentially life-threatening compli- sion directly from the copyright holder. To view a copy of this cations and requires careful patient selection and licence, visit http://creativecommons.org/licenses/by/4.0/. a treatment team that is experienced in autologous and allogeneic cell therapies. Moreover, the responses using current CAR-T strategies are frequently not References durable and most of the patients suffer a relapse. 1. Madry C, Laabi Y, Callebaut I, Roussel J, Hatzoglou A, Le The mechanisms of resistance against CAR-T in MM Coniat M, et al. The characterization of murine BCMA gene are not completely understood. 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Published: Mar 16, 2020

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