CAR T-Cell Therapies Target BCMA and Alternative Antigens in Multiple Myeloma
New CAR T-cell approaches targeting BCMA and CD19 simultaneously show encouraging early results, while researchers develop control strategies for CAR-T therapies including antibody-drug conjugates.
Patients with relapsed/refractory multiple myeloma are now being treated with several different therapies targeting B-cell maturation antigen (BCMA), including chimeric antigen receptor (CAR) T-cell therapies, bispecific antibodies, and antibody-drug conjugates, but repeat targeting of BCMA may be less effective. The GPRC5DxCD3-targeted bispecific antibody talquetamab (Talvey) presents an alternative for BCMA-exposed patients.
The MonumenTAL-1 trial (NCT04634552) was the phase 1 trial that eventually led to the approval for talquetamab. These are patients with more than or equal to 3 prior lines of therapy. They have been all exposed to a proteosome inhibitors immunomodulatory agent, and anti-CD38 agent. There were 2 different dosing strategies that were explored, the 0.4 mg/kg weekly, and the 0.8 mg/kg every other week. There was a smaller cohort of patients who have previously been exposed to a T-cell redirection therapy. This is a heavily pretreated patient population with a median of 5 prior lines of therapy. About 33% had bispecific antibodies and 73% of them had a CAR T, with 6% having had both of them.
The overall response rate is about 65% to 70%, and interestingly enough, if you take any bispecific antibody, the overall response rate is somewhere in that 60% to 70%. That tells you that the mechanism of action is probably more important than the antigen that you're targeting for somebody who hasn't seen a bispecific before. The median progression-free survival with the 0.4 mg/kg was 7.5 months and the median duration of response was 9.5 months, and for 0.8 mg/kg every 2 weeks, progression-free survival was 11.2 months and the median duration of response was about a year and a half. The prior T-cell redirection group had quite a bit lower median progression-free survival at 7.7 months. The duration of response was 19.2 months, although the overall response rate is a bit lower in this patient population.
Looking at the high-risk patient population subgroups, the overall response rate appears to be quite comparable, except for those patients with extramedullary disease. The progression-free survival, looking at the cytogenetic risk, is not that different. But the extramedullary disease makes a difference. That seems to be the case with all these immune therapies. Extramedullary disease is one place where things really tend to drop, especially the progression-free survival. The response rates are still maybe good enough, but the progression-free survival doesn't seem to be that good in that patient population.
Dual-Targeted CAR T Approach
AZD0120 is a dual-targeted CAR T targeting 2 antigens. First is BCMA, which is very common and the most common antigen that is targeted in myeloma via CAR T cells of various T-cell–directed therapies. CD19, on the other hand, is much less common in myeloma. It's usually expressed in most phases of B cell development and is lower intensity on some subsets of myeloma cells and progenitor cells. The hypothesis behind putting these 2 antigens together in this dual CAR T product was that we know that myeloma tends to be very clonally heterogeneous, and it's an attempt to reduce the risk of antigen-negative relapses. Also, the hypothesis was that we are maybe targeting a myeloma stem cell, so to speak; a progenitor to myeloma cells. There have been, in fact, in vitro studies that show that this combination seems to target more myeloma cells than either CAR T product individually.
This product uses a fast CAR manufacturing technology. While traditional manufacturing can take several weeks for the CAR T cells to be made, this particular one results in a fast turnaround with CAR T cells being manufactured in fewer than 3 days. Preliminary results from the DURGA-1 phase 1b/2 study show good toxicity and efficacy.
Control Strategies for CAR-T Therapies
Recent advances in chimeric antigen receptor T cell therapy have transformed the treatment landscape of multiple myeloma, yet almost all patients ultimately relapse. Chromosomal 1q gains are associated with a higher risk of disease progression and poor prognosis, suggesting that CAR-T targeting of chromosome 1-encoded antigens, such as SLAMF7, may be particularly relevant in advanced disease. However, novel CAR targets raise the risk of on-target, off-tumor toxicities, underscoring the need for controllable CAR-T systems.
Researchers systematically assessed pharmacologic and antibody-based strategies to modulate CD19- and SLAMF7-directed CAR-T cells. Tyrosine-kinase inhibitor dasatinib rapidly and reversibly inhibited CAR-T activation, serving as an efficient "on/off" switch with the limitation of also inhibiting unmodified T cells. To surpass this issue, antibody-dependent cell cytotoxicity was used to inhibit CAR-T cells. However, conditioning with fludarabine/cyclophosphamide profoundly depletes NK cells, limiting antibody-dependent CAR-T clearance in patients. Moreover, as NK cells express SLAMF7, they are susceptible to fratricidal cytotoxicity by SLAMF7 CAR-T cells, further reducing this potential off-switch mechanism.
To bypass this immune effector cell dependence, a novel strategy using antibody-drug conjugates was developed. The BCMA-targeting antibody-drug conjugate belantamab-mafodotin selectively eliminates BCMA co-expressing CAR-T cells without affecting unmodified T cells. These findings suggest antibody-drug conjugates as a potent, effector cell-independent safety mechanism for CAR-T therapies, potentially enhancing controllability and safety in future clinical applications.