CAR T cells better than BiTEs

Abstract

This article has a companion Counterpoint by Subklewe. Despite significant advances in treatment regimens and outcomes in B-cell acute lymphoblastic leukemia (B-ALL), long-term survival remains poor for the 15% to 20% of pediatric patients and 50% of adults with relapsed or refractory (r/r) disease. 1-3 The emergence of immunotherapeutic strategies that use B-cell antigen-targeted single-chain variable fragments to direct T cells to specific surface antigens on BALL cells has revolutionized outcomes. These strategies include the US Food and Drug Administration (FDA)-approved bispecific T-cell engager (BiTE) blinatumomab and chimeric antigen receptor (CAR) T-cell therapy tisagenlecleucel. 4 Even though both therapies target CD19, outcomes vary significantly. We discuss considerations and potential benefits of the preferential use of CAR T-cell therapy over BiTE in r/r BALL , which can serve as a framework for evaluation of approaches with alternative antigen-targeting strategies. Efficacy of CAR vs BiTE: response rates, trafficking, and durability In the phase 2/3 trials leading to the FDA approval of blinatumomab in 2014, the objective response rate to blinatumomab in adult patients was 36% to 44%. Of those achieving a complete remission (CR), 63% to 88% had a minimal residual disease (MRD)-negative remission. 5-9 Importantly, of 70 pediatric patients evaluated, 39% achieved CR with only 14 (20%) being MRD negative. 10 Despite an improvement over responses with conventional salvage chemotherapy, as well as improved response rates for those with MRD-level disease, 11 results of the blinatumomab phase 2/3 and retrospective adult trials indicate that a significant portion of patients are resistant to blinatumomab (Table 1). 12

Principles and Current Clinical Landscape of Multispecific Antibodies against Cancer

“…In addition, multispecific antibodies appear to have better tolerability, since they do not require lymphodepletion prior to infusion, while cytokine-release syndrome (approximately 5% vs. 50%) and neurotoxicity (<10% vs. 12–32%) have generally been less frequent, less severe, and better manageable with the short-acting CD19-specific BiTE blinatumomab than after infusion of the long-persisting CD19-specific CAR-T cells [ 212 ]. On the other hand, efficacy appears to be somewhat better with CAR-T cells than blinatumomab, with higher response rates in r/r acute lymphoblastic leukemia (approximately 80% vs. 40%), especially in cases of high tumor burden (e.g., bone marrow blasts >50%), extramedullary disease, and central nervous system involvement [ 213 ]. Likewise, in r/r MM BCMA-specific CAR-T cells achieve response rates >90%, while the response rate in the recent phase 1 trial of a BCMA/CD3 bispecific was 33–75% [ 214 , 215 ].…”

Targeted Therapy in the Treatment of Pediatric Acute Lymphoblastic Leukemia—Therapy and Toxicity Mechanisms

“…Despite the implementation of innovative therapies in clinical practice, numerous cases have shown adverse reactions. Toxicity may vary in terms of its severity, and, because higher-degree toxicities may be life-threatening, they need to be thoroughly examined and properly managed [ 68 , 69 ].…”

Associação Brasileira de Hematologia, Hemoterapia e Terapia Celular Consensus on genetically modified cells. II: CAR-T cell therapy for patients with CD19+ acute lymphoblastic leukemia

“…The use of CAR-T cells for the treatment of patients with B-ALL results in high response rates in patients with relapsed or refractory (R/R) disease. 7 The first, and to date the only, product approved for commercialization by the American and European medication control agencies, namely, the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the treatment of patients with B-ALL is tisagenlecleucel (KYMRIAH; Novartis Pharmaceuticals Corp.), an autologous anti-CD19 CAR-T cell containing the 4-1BB as co-stimulatory molecule. 8 , 9 This approval was based on the results of the multicentric phase 2 study ELIANA, which demonstrated a MRD-negative CR in 81% of the pediatric and young adult patients treated and an overall survival (OS) of 76% at 12 months.…”

“… 10 With the development of new cellular therapy products involving other types of cells and/or target antigens, indications and patient eligibility for CAR-T cell treatments will be adapted for each new product in accordance with the results of clinical trials. 7 The current scenario allows for some considerations: For tisagenlecleucel, the indication approved by the EMA includes pediatric and young adult patients up to 25 years of age with refractory B-ALL, relapsed after HSCT or in the second or subsequent relapse. 11 Regarding the FDA, the approved indication is also for patients up to 25 years of age and refractory ALL or after the second relapse.…”

“…This therapy results in high rates of MRD-negative CR. 7 Considering the imminent approval of some commercial anti-CD19 CAR-T cell products by the Agência Nacional de Vigilância Sanitária (ANVISA), the Brazilian Association of Hematology, Hemotherapy and Cellular Therapy (ABHH) invited a panel of specialists in hematological neoplasms, cellular therapy and HSCT to elaborate recommendations for this new treatment modality for B-ALL patients in Brazil.…”