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review memo (2020) 13:36–42 https://doi.org/10.1007/s12254-019-00541-8 Role of CAR-T cell therapy in B-cell acute lymphoblastic leukemia Hildegard T. Greinix Received: 29 August 2019 / Accepted: 17 October 2019 / Published online: 14 November 2019 © The Author(s) 2019 Summary Chimeric antigen receptor (CAR) T cells may allow longer term remissions without additional are genetically engineered cells containing fusion HSCT. proteins combining an extracellular epitope-speciﬁc binding domain, a transmembrane and signaling do- Keywords Chimeric antigen receptor T cells · CAR-T mains of the T cell receptor. The CD19-CAR T cell cells · Acute lymphoblastic leukemia · B-ALL · product tisagenlecleucel has been approved by the Allogeneic hematopoietic stem cell transplantation US Food and Drug Administration and the European Abbreviations Medicines Agency for therapy of children and young AAdults adults under 25 years with relapsed/refractory B-cell ALL Acute lymphoblastic leukemia acute lymphoblastic leukemia (ALL) due to a high ASTCT American Society of Transplantation and overall response rate of 81% at 3 months after ther- Cellular Therapy apy. The rates of event-free and overall survival were BM Bone marrow 50 and 76% at 12 months. Despite the high initial re- BU Busulfan sponse rate with CD19-CAR-T cells in B-ALL, relapses CChildren occur in a signiﬁcant fraction of patients. Current CAR Chimeric antigen receptor strategies to improve CAR-T cell efﬁcacy focus on CCR Continuous complete remission improved persistence of CAR-T cells in vivo, use of CD19 Cluster of differentiation 19 multispeciﬁc CARs to overcome immune escape and CR Complete remission new CAR designs. The approved CAR-T cell products CRh Complete remission with partial hema- are from autologous T cells generated on a custom- tologic recovery made basis with an inherent risk of production failure. CRi Complete remission with incomplete re- For large scale clinical applications, universal CAR-T generation cells serving as “off-the-shelf” agents would be of ad- CRS Cytokine release syndrome vantage. During recent years CAR-T cells have been CSF Cerebrospinal ﬂuid frequently used for bridging to allogeneic hematopoi- CY Cyclophosphamide etic stem cell transplantation (HSCT) in patients with EFS Event-free survival relapsed/refractory B-ALL since we currently are not EMA European Medicines Agency able to distinguish those CAR-T cell induced CRs that FDA Food and Drug Administration will persist without further therapy from those that Flu Fludarabine are likely to be short-lived. CAR-T cells are clearly of GvHD Graft-versus-host disease beneﬁt for treatment following relapse after allogeneic HSCT Hematopoietic stem cell transplantation HSCT. Future improvements in CAR-T cell constructs ICANS Immune-cell associated neurotoxicity syndrome ICE Immune effector cell-associated en- Univ.Prof.Dr.H.T. Greinix () cephalopathy Division of Hematology, Medical University of Graz, IFN Interferon Auenbruggerplatz 38, 8036 Graz, Austria IL Interleukin firstname.lastname@example.org 36 CAR-T cell therapy in B-ALL K review InO Inotuzumab ozogamicin patients with no previous HSCT who went directly LV Lentivirus to transplant after achieving remission to InO, the MHC Major histocompatibility complex 2-year survival probability was 46%. In a prospective MRD Minimal residual disease randomized phase III study more patients with re- NC No change lapsed/refractory B-ALL treated with blinatumomab, NR No response a bispeciﬁc T cell engager targeted to CD19 and CD3, ORR Overall response rate compared to standard-of-care chemotherapy (SOC) OS Overall survival achieved CR, CR with partial (CRh), or incomplete PB Peripheral blood (CRi) hematologic recovery and MRD-negativity . PCR Polymerase chain reaction Blinatumomab prolonged OS with a median OS of PD Progressive disease 7.7 months versus 4.0 months for SOC, respectively. PR Partial remission Patients achieving CR, CRh, or CRi after therapy with RV Retrovirus blinatumomab reportedly achieved durable responses scFv Single-chain variable antibody fragment and promising OS rates withor without subsequent SD Stable disease HSCT . Due to study limitations it is currently un- SOC Standard of care clear whether patients responding to blinatumomab TALEN Transcription activator-like effector nu- and obtaining MRD-negativity should undergo HSCT. clease A novel cellular immunotherapeutic approach in- TCR T cell receptor volves the genetic modiﬁcation of T cells to express TNF Tumor necrosis factor a chimeric antigen receptor (CAR) thereby redirecting TRUCK T cells redirected for universal cytokine- their speciﬁcity through a mechanism independent mediated killing of major histocompatibilitycomplex (MHC) to target TSLPR Thymic stromal lymphopoietin receptor speciﬁc tumor antigens . CARs are engineered fu- UCART19 Universal CD19-CAR-T cell sion proteins combining an extracellular epitope-spe- ciﬁc binding domain (most commonly an antibody- derived single-chain variable fragment, scFv), a hinge Take home message and transmembrane domain and signaling domains CD19-CAR-T cells are of enormous benefit for patients of the T cell receptor (TCR) (mostly consisting of the with relapsed/refractory ALL. CD3ζ chain). Current second-generation CAR-T con- Further improvements in CAR-T cell constructs may structs are combined with additional costimulatory allow longer term remissions without additional HSCT. domains such as CD28, 4-1BB, and OX40. This en- ables a strong antigen-speciﬁc T cell activation with- out the need of TCR-MHC interactions. By their inte- Introduction grative capacity into the host genome, expression of First-line chemotherapy for patients with B-cell acute CAR transgenic construct can persist independent of lymphoblastic leukemia (B-ALL) younger than 65 years cell division. is intensive chemotherapy, e.g., Hoelzer protocol or hyper-CVAD (1). Allogeneic hematopoietic stem cell Clinical results with CAR-T cells in relapsed and transplantation (HSCT) is indicated in B-ALL for pa- refractory B-ALL tients with a second complete remission (CR), after failure of ﬁrst-line chemotherapy or upfront in ﬁrst CR Most of the targeting immunotherapies involving in B-ALL with unfavorable prognostic factors, includ- CAR-T cells in B-ALL are against the B cell surface ing complex karyotype and positive minimal residual protein CD19 and CAR-T cell products may vary de- disease (MRD) . Relapsed or refractory B-ALL pending on the institutional design, doses, T cell is associated with a dismal prognosis with a cure activation and transduction methods. Table 1 sum- rate of less than 10% . CR rates with standard marizesthe resultsofCAR-T cell studiesin patients chemotherapy regimens are 30–40% in ﬁrst relapse with relapsed and refractory B-ALL. and 20–25% in second relapse . Only 10–30% of In a phase 2 multicenter study, 107 patients with adult patients with relapsed B-ALL proceed to HSCT, relapsed or refractory B-ALL were screened, 92 were which is the only curative therapy in this situation. enrolled and 75 (70%) received a single infusion of tis- Novel therapeutic options including blinatumomab agenlecleucel, a CD19-CAR-T cell product . Among and inotuzumab ozogamicin (InO) have resulted in evaluable patients, the overall response rate (ORR) higher response rates and longer survival (OS) than at 3 months was 81% with all responding patients conventional chemotherapy . Response to these negative for MRD as assessed by ﬂow cytometry. In agents enables patients to undergo HSCT as has been an intent-to-treat analysis of all enrolled 92 patients recently reported by Marks and colleagues where including subjects who discontinued study partici- 101 of 236 patients (43%) with relapsed/refractory pation before tisagenlecleucel infusion, the ORR was B-ALL given InO, an anti-CD22 antibody conjugated 66%. The rates of event-free survival (EFS) and OS to calicheamicin, proceeded to HSCT . Of note, for were 73 and 90% at 6 months and 50 and 76% at K CAR-T cell therapy in B-ALL 37 review Table 1 Clinical results of CAR-T cell therapy in relapsed and refractory ALL Author No. patients Gene transfer Co-stim. domain Lymphodepl. chemo CAR-T cell doses Outcome Brentjens (2011)  1 Gamma RV CD28 CY 1.4 × 10 N/A Brentjens (2013)  5A Gamma RV CD28 CY 1.4–3.2 × 10 5CR 7 8 Cruz (2013)  8 RV CD28 – 1.9 × 10 –1.13 × 10 1CR 2 CCR 1PR 3PD 1SD 6 7 Grupp (2013)  2C LV CD28 – 1.4 × 10 –1.2 × 10 /kg 2CR Davila (2014)  16 A Gamma RV CD28 CY 3× 10 /kg 15 CR Maude (2014)  30 LV 4-1BB CY/Flu or CY/VP or 0.76–17.36 × 10 /kg 27 CR (25C/5A) other 3NR (19 CCR) 6 7 Dai (2015)  9 LV 4-1BB C-MOAD 3× 10 –1 × 10 /kg 6CR 3PR 6 6 Lee (2015)  21 C+A Gamma RV CD28 CY/Flu 1× 10 vs 3 × 10 /kg 14 CR 4PD 3SD Park (2015)  33 A N/A N/A N/A N/A 91% CR 6 7 Gardner (2016)  9 N/A N/A Chemo 2× 10 –1 × 10 /kg 7CR 2 Relapse 5 7 – Turtle (2016)  30 A LV CD28 CY/Flu 2× 10 –2 × 10 /kg 29 CR (27 MRD ) Zhu (2016)  2 LV 4-1BB CY/Flu 1× 10 /kg 2CR Callahan (2017)  59 LV + RV N/A Chemo N/A 55 CR 20 Relapse 7 8 – Chen (2017)  6 LV CD28 CY/Flu 3.8 × 10 –4.1 × 10 /kg 5CR (MRD ) 1NR 4 Relapse 5 7 – Gardner (2017)  45 C+A LV 4-1BB CY, CY/Flu 5× 10 –1 × 10 /kg 40 CR (MRD ) 3NC 18 Relapse 3 7 – Pan (2017)  51 LV 4-1BB CY/Flu 5× 10 –1.4 × 10 /kg 45 CR (9 MRD ) 3NR 3 died 2 Relapse Wang (2017)  6 N/A N/A CY/BU/Flu 1.2–8.5 × 10 /kg 3CR 1 died 2NR 2 Relapse 5 6 – Fry (2018)  21 LV 4-1BB CY/Flu 3× 10 –3 × 10 /kg 12 CR (9 MRD ) 8 relapse 6 – Maude (2018)  75 C+A LV 4-1BB CY/Flu 0.2–5.4 × 10 /kg 45 CR+16 CRi (61 MRD ) 22 Relapse Park (2018)  53 A Gamma RV CD28 CY/Flu N/A 44 CR (32 MRD ) 25 Relapse Park (2018)  2 LV 4-1BB CY/Flu 4.6 × 10 /kg 1CR Wei (2018)  22 LV 4-1BB CY/Flu 3–10 × 10 /kg 20 CR 2SD 1 died 8 Relapse 4 6 Weng (2018)  5 LV CD28 CY/Flu 5× 10 –1 × 10 /kg 3CR 2 Relapse N/A Not applicable, No. number, co-stim co-stimulatory, lymphodepl lymphodepleting, chemo chemotherapy, A adults, C children, RV retrovirus, LV lentivirus, CY cyclophosphamide, VP etoposide, Flu Fludarabine, BU busulfan, CR complete remission, CCR continuous complete remission, PR partial remission, PD progressive disease, SD stable disease, NR no response, NC no change, MRD minimal residual disease negative 12 months, respectively. The median duration of per- by the US Food and Drug Administration (FDA) and sistence of tisagenlecleucel in blood was 168 (range, the European Medicines Agency (EMA) for refrac- 20–617) days and the median duration of remission tory or relapsed B-cell precursor ALL in children and was not reached at the time of reporting. Based on young adults <25 years old. these results tisagenlecleucel was recently approved 38 CAR-T cell therapy in B-ALL K review Using quantitative polymerase chain reaction (PCR) T cell activation and degree of T cell expansion as to quantify levels of tisagenlecleucel, responding pa- well as intensity of lymphodepletion prior to CAR-T tients (n = 62/79) of two studies in pediatric B-ALL cell infusion have an impact on development of CRS had an approximately 2-fold higher tisagenlecleucel remains controversial. Since pre-existing inﬂamma- expansion in peripheral blood (PB) than nonrespon- tion and endothelial activation seem to be associated ders with persistence measurable beyond 2 years in with severity of CRS, CAR-T cells should not be ad- responding patients . Clinical responses were ob- ministered to patients with pre-existing inﬂammation served across the entire dose range evaluated with no and infection . Recently, the American Society of relationship between cell dose and safety. Tisagenle- Transplantation and Cellular Therapy (ASTCT) con- cleucel persistence was signiﬁcantly associated with sensus grading has been published distinguishing CRS durable remission . grades according to practitioner intervention . Park and colleagues reported long-term follow-up The reported incidences of grade 3 to 4 ICANS after results of a single-center phase I clinical trial with CAR-T cell therapy in patients with B-ALL are between CD19-CAR-T cells in 53 adult patients with relapsed 13%  and 42%  and could be inﬂuenced by the or refractory B-ALL . CR was observed in 83% of CAR design used. The earliest symptoms of ICANS patients including 63% free of MRD. At a median fol- are tremor, dysgraphia, mild difﬁculty with expressive low-up of 29 (range, 1–65) months, median EFS was speech, impaired attention, apraxia, and mild lethargy 6.1 months and median OS was 12.9 months, respec- . Expressive aphasia, starting as impaired nam- tively. Patients with a low disease burden deﬁned as ing of objects, hesitant speech, and verbal persever- less than 5% bone marrow (BM) blasts before ther- ation, may progress to global aphasia. Within hours apy had longer remission duration and survival with or days severe neurotoxicity including seizures, dif- a median EFS of 10.6 months and a median OS of 20.1 fuse cerebral edema, stupor, or even coma may occur. months. All 9 patients with detectable residual disease The ASTCT consensus recently recommended use of relapsed, while among 32 patients without MRD after the Immune Effector Cell-Associated Encephalopathy CAR-T cell therapy, 16 patients (50%) relapsed. (ICE) score for objective grading of ICANS . Among 30 adult patients with B-ALL treated with The pathophysiology of ICANS is poorly under- + + a deﬁned composition of CD4 and CD8 CAR-T cells, stood. IL-1 triggered activation of by-standing mono- 29 patients achieved a CR including 27 MRD CR . cytes then producing IL-6 und leading to systemic Gardner and colleagues administered a CAR-T cell inﬂammation could be an important mechanism and product of deﬁned CD4/CD8 composition to 45 chil- blockade of IL-1 with anakinra ameliorated ICANS’ dren and young adults with relapsed or refractory symptoms in a xenograft mouse model . San- B-ALL resulting in MRD CR in 40 (89%) patients . tomasso and colleagues reported a signiﬁcant associ- The estimated 12-month EFS was 50.8% and the esti- ation of severe neurotoxicity with high pretreatment mated 12-month OS 69.5% with a median follow-up disease burden, higher peak CAR-T cell expansion, of 9.6 months. Eighteen of the 40 patients with MRD and early and higher elevations of proinﬂammatory CR experienced relapse including 7 with loss of cell- cytokines in PB . Patients with severe neurotoxi- surface detection of CD19. Median time from CAR-T city had evidence of blood–cerebrospinal ﬂuid (CSF) cell infusion to relapse was 5.98 months. barrier disruption and enrichment of proinﬂamma- tory cytokines in the CSF with disproportionately high levels of IL-6, IL-8, MCP1, and IP10 . Side-effects of CAR-T cell therapy Management of ICANS is based on corticosteroids The potent systemic immune activation responsible in escalating doses depending on the severity of dis- for the success of CAR-T cells also drives novel life- ease and supportive care measures . Patients un- threatening toxicities associated with immune effec- responsive to steroids could beneﬁt from siltuximab tor cells including cytokine release syndrome (CRS) (anti-IL-6 chimeric monoclonal antibody), anakinra and immune-cell associated neurotoxicity syndrome (recombinant human IL-1 receptor antagonist) or in- (ICANS) . hibition of GM-CSF using lenzilumab . CRS has been deﬁned as a disorder characterized by fever, tachypnea, headache, tachycardia, hypoten- Novel developments for improving CAR-T cell sion, rash, arthralgia, myalgia, and/or hypoxia by the therapy release of proinﬂammatory cytokines including in- terferon gamma (IFN-γ), tumor necrosis factor alpha Despite the high initial response rate with CD19- (TNF-α), interleukin-6 (IL-6), and interleukin-10 (IL- CAR-T cells in B-ALL, relapses occur in a signiﬁ- 10) . The ﬁrst symptoms occur within hours up to cant fraction of patients [6, 8, 10, 18]. Relapse with 14 days after CAR-T cell therapy. Reported incidence CD19 leukemia cells can be the result of short in rates of CRS vary from 40–100% with severe forms vivo persistence of CAR-T cells, either from intrinsic in 20–30% of patients afﬂicted. Disease burden has deﬁciencies of the T cell product or an immune re- most consistently been associated with CRS severity sponse to the CAR scFv . Strategies to improve after CAR-T cell therapy . Whether strength of CAR-T cell efﬁcacy focus on improved persistence of K CAR-T cell therapy in B-ALL 39 review + + CAR-T cells by combining CD4 CAR-T cells and CD8 with minimal evidence of graft-versus-host disease CAR-T cells [10, 11], enriching for central memory (GvHD). Currently, international multicenter off-the- T cells, naive and stem memory T cells or reducing shelf universal UCART19 trials are ongoing for CD19 the immunogenicity of the CAR construct applying ALL. humanized CARs . Efﬁcacy of CAR-T cell im- munotherapy can be improved by use of bispeciﬁc CAR-T cells in the context of allogeneic HSCT CARs targeting CD19 and CD22 or CARs with multispeciﬁcity to overcome immune escape . The available data demonstrate that CAR-T cells are The thymic stromal lymphopoietin receptor (TSLPR) highly active in children and adults with refractory or that is overexpressed on some B-ALL cells could be relapsed B-ALL resulting in a high complete remission a new target for developing novel CAR constructs. rate. In a subset of patients MRD-negative remissions Furthermore, new designs of CAR-T cells are being persist with no further treatment. However, follow- explored including universal CARs that can recog- up times are short and relapse after CAR-T cell ther- nize multiple targets without the need to re-engineer apy has remained a challenging problem. CAR-T cell T cells, T cells redirected for universal cytokine-medi- therapy could be applied to obtain remissions for ated killing (TRUCKs), CARs and armored CAR-T cells patients in ﬁrst relapse who are refractory or not el- modiﬁed to express cytokines, ligands, or single-chain igible for other therapies to achieve remission prior variable fragments to elicit an enhanced antitumor to allogeneic HSCT. Shalabi and colleagues reported immune response through turning a suppressive tu- on 52 children and young adults given CD19 and mor microenvironment into a proinﬂammatory one. 33 patients given CD22-CAR-T cells for treatment In addition, combining CAR-T cells with checkpoint of relapsed/refractory B-ALL . Fifty-one patients blockade therapy may reinvigorate endogenous tu- achieved a CR including 43 with MRD-negativity and mor-reactive T cells that have been suppressed by the 25 subsequently underwent allogeneic HSCT. The 24- tumor microenvironment . month cumulative incidences of post HSCT relapses Recently, Ruella and colleagues reported a unique were 13.5 and 11.3% after CD19 and CD22-CAR-T cell case of a pediatric patient with B-ALL who relapsed therapy without an increased risk of severe GvHD. with CD19-negative disease after CAR-T cell therapy Park and colleagues observed no difference in OS be- due to introduction of anti-CD19 CAR into a single tween patients who completed HSCT and those who leukemic B cell blast clone during CAR-T manufac- did not when comparing outcomes of the 32 patients turing . This case demonstrates that more strin- who achieved an MRD-negative CR following CAR-T gent CAR-T cell manufacturing methods that remove cell infusion . In the ELIANA trial which included all tumor cells from the genetically engineered prod- 75 patients with relapsed or refractory B-ALL only uct are necessary, especially for protocols that involve 8 patients (9%) underwent allogeneic HSCT in remis- lentiviral vectors capable of transducing nondividing sion after CAR-T cell therapy . In view of the small cells. patient numbers and the many differences in study design and conduct, the question whether CAR-T cells should be administered as bridging therapy to Allogeneic CAR-T cells allogeneic HSCT or are sufﬁciently effective by them- Currently, the approved CAR-T cell products are from selves cannot be answered for certain. When patients autologous T cells generated on a custom-made basis have not undergone an allogeneic HSCT previously by a costly and lengthy production process with an in- this follow-up therapy must at least be considered. herent risk of production failure. For large scale clini- CAR-T cells are clearly of beneﬁt for treatment fol- cal applications universal CAR-T cells that can serve as lowing relapse after allogeneic HSCT since in this pa- “off-the-shelf” ready-to-use therapeutic agents would tient population second transplant is associated with be of advantage. Recently, gene editing technolo- increased toxicity and low success rates . In the gies including TALEN (transcription activator-like ef- ELIANA study, 61% of patients had relapsed/refractory fector nuclease) and CRISPR/Cas9 are being used to B-ALL after allogeneic HSCT . T cells were success- improve CAR-T cells and to generate universal third fully collected from patients after HSCT and high re- party CAR-T cells . These represent a totally new mission rates without GvHD have been reported [6, 9, generation of CAR-T cells capable of targeting multi- 17]. Thus, previous HSCT does not impact outcomes ple antigens and/or being delivered to multiple recip- after CD19-CAR-T cell therapy. ients without re-editing of T cells. Qasim and colleagues used TALENs and a lentivi- Conclusions ral vector to generate a universal CD19-CAR-T cell (UCART19) with disrupted expression of both CD52 During the last few years CAR-T cells have been fre- and the αβ TCR for treatment of 2 pediatric patients quently used for bridging to allogeneic HSCT in pa- with relapsed B-ALL . Both patients achieved tients with refractory or relapsed B-ALL since we a CR within 28 days of CAR-T cell therapy and then currently are not able to distinguish those CAR-T cell underwent successfully a second allogeneic HSCT induced CRs that will persist without further therapy 40 CAR-T cell therapy in B-ALL K review 13. Borrega JG, Gödel P, Rüber MA, et al. In the eye of the from those that are likely to be short lived. The choice storm: Immune-mediated toxicities associated with CAR-T to offer HSCT to patients following CAR-T cell ther- cell therapy. HemaSphere. 2019;3(2):e191. apy relies on historical experience that transplantation 14. Hay KA, Hanaﬁ LA, Li D, et al. Kinetics and biomark- has been the only curative option for patients with re- ers of severe cytokine release syndrome after CD19 fractory or relapsed B-ALL. Future improvements in chimeric antigen receptor-modiﬁed T-cell therapy. Blood. CAR-T cell constructs may allow longer term remis- 2017;130(21):2295–306. 15. Santomasso BD, Park JH, Salloum D, et al. Clinical and sions without additional HSCT. biological correlates of neurotoxicity associated with CAR Funding Open access funding provided by Medical Univer- T-cell therapy in patients with B-cell acute lymphoblastic sity of Graz. leukemia. Cancer Discov. 2018;8(8):958–71. 16. Norelli M, Camisa B, Barbiera G, et al. Monocyte-derived Conﬂict of interest H.T. 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