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Multiple B-cell maturation antigen (BCMA)-targeted chimeric antigen receptor (CAR) T-cell therapies are currently under investigation for their application in relapsed/refractory multiple myeloma (MM). Here, we summarize the latest on BCMA-targeted CAR T-cell therapies, presenting their up-to-date clinical data.1
In part I of this article series, we covered the latest updates on BCMA antibody-drug conjugates and BCMA-targeted bispecific antibodies which can be found here.
CAR T-cells are autologous CD3+ T-cells that are engineered to contain an extracellular ligand binding domain. These domains are most commonly a single-chain variable fragment of a monoclonal antibody that recognizes tumor-associated antigens on malignant cells. Once activated, it initiates signaling through T-cell activation, the release of proinflammatory cytokines, and cytosis.2
Prior to reinfusion of the modified autologous T-cells, the patient undergoes lymphodepleting conditioning chemotherapy, usually with fludarabine and cyclophosphamide to decrease endogenous T-cells and increase levels of proliferative cytokines interleukin-7 and interleukin-15; thus, creating the most favorable environment for CAR T-cells to expand and action. Similar to bispecific antibodies, there is a risk of cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome, with rates of immune effector cell-associated neurotoxicity syndrome tending to be higher with CAR T-cells.2
Two autologous BCMA-targeting CAR T cells have been approved, and multiple are still in clinical development; these are summarized in Table 1.
Table 1. BCMA-targeted CAR T-cell therapy*
BCMA CAR T-cell therapy |
Drug information |
Latest clinical trial data |
---|---|---|
ARI0002h |
A second-generation academic BCMA-directed CAR-T cell therapy that contains a 4-1BB co-stimulatory domain and a humanized scFv targeting BCMA. |
ORR: 96.0% sCR: 44.4% VGPR: 18.6% Median PFS and OS: not reached CRS: 87.0%3 |
CC98633
|
An investigational, BCMA-directed CAR T-cell product with a fully human CAR construct manufactured using the NEX-T process. |
ORR: 95.1% >6-month response rate: 75.0% CRS, any grade: 81.5% CRS Grade3/4: 1.5%4 |
Cilta-cel uses a lentiviral vector to create a construct with a CD3ζ activation domain with 4-1BB co-stimulatory domain. The antigen binding domain contains bispecific scFvs targeting VHH1 and VHH2, two distinct BCMA epitopes which increase binding and specificity for BCMA. Additional information: |
CARTITUDE-1 ORR: 97.9% Median PFS: 34.9 months 36-month estimated OS: 62.9%5 CARTITUDE-4 (NCT04181827) ORR: 99.0% ≥CR: 86.0% 12-month PFS rate: 90.0% SAE: 44.2%6 |
|
Uses a lentiviral vector containing a CAR construct with a fully human scFv, CD8a hinge and transmembrane, 4-1BB costimulatory- and CD3z activation- domains. Additional information: |
FUMANBA-1 ORR: 96.0% 12-month PFS: 78.8% |
|
A BCMA and CD19 dual-targeting CAR T-cell therapy. |
ORR: 93.1% Median DOR: 37.0 month MRD negativity: 100% MRD negativity at 12 months: 78.6% Median PFS: 38.0 months CRS event: 86% CRS ≥Grade 3: 7.0%8 |
|
A second-generation CAR with a lentiviral vector to transduce a BCMA-targeting scFv fused to 4-1BB co-stimulatory and CD3ζ signaling domains. Additional information: |
KARMMA-3 ORR: 71.0% CR: 39.0% Median PFS: 13.3 months AE Grade≥3: 93.0% SAE: 52.0%9
KARMMA-2 (Cohort 2c) (NCT03601078) ORR: 87.1% ≥CR: 74.2% Median PFS: 30.7 months CRS: 58.1% Neutropenia: 90.3%10 |
|
MCARH171 |
A second-generation CAR T composed of a humanized scFv, a 4-1BB co-stimulatory domain, and a truncated epidermal growth factor receptor safety signal. |
ORR: 64.0% Median DOR: 106 days CRS Grade 1/2: 40.0% CRS Grade 3: 20.0%11 |
Contains a lentiviral CAR construct with a fully human scFv, an optimized spacer, and 4-1BB co- stimulatory and CD3ζ activation domains. Additional information: |
EVOLVE ORR: 92.0% ≥VGPR: 68.0% Grade ≥3 CRS: 3.0% Grade ≥3 infections: 14.0% Grade ≥3 neutropenia: 55.0%12 |
|
A second-generation CAR utilizing a fully-human BCMA-specific scFv (25C2) with high binding affinity to BCMA bound to 4-1BB co-stimu- latory and CD3ζ activation domains. |
LUMMICAR-1 (NCT03975907) ORR: 100.0% Grade 1/2 CRS: 91.7% ≥Grade 3 neutropenia: 100.0%13
LUMMICAR-2 (NCT03915184) ORR: 100.0% Grade 1/2 CRS: 86.0% ≥Grade 3 neutropenia: 100.0%14 |
|
AE, adverse event; BCMA, B-cell maturation antigen; CAR, chimeric antigen receptor; cilta-cel, ciltacabtagene autoleucel; CR, complete response; CRS, cytokine release syndrome; DOR, duration of response; EMA, European Medicines Agency; FDA, Food and Drug Administration; ICANS, immune effector cell-associated neurotoxicity syndrome; ide-cel, Idecabtagene vicleucel; IMiD, immunomodulatory agent; mAb, monoclonal antibody; MMAF, monomethyl auristatin-F; MRD, measurable residual disease; ORR, overall response rate; OS, overall survival; PI, proteosome inhibitor; PFS, progression-free survival; RRMM, relapsed/refractory multiple myeloma; SAE, serious adverse event; sCR, stringent complete response; scFv, single-chain variable fragment; TEAE, treatment-emergent adverse event; VGPR, very good partial response. |
Combinations of multiple CAR T-cell therapies and CAR T cells targeting multiple antigens are currently in development, with the most popular combination being BCMA and CD19. CD19 expression has been found on a small component of MM cells considered to be less differentiated, and as a result, they may lack usual markers such as BCMA.2
BM38 is a bispecific CAR T-cell therapy that targets BCMA and CD38 and is currently under evaluation in a phase I clinical trial.
Allogenic CAR T-cell therapy has multiple advantages over autologous CAR T-cells, including its immediate availability, improved product standardization, redosing and combination treatments, and potential cost savings with a more scalable manufacturing process.2 ALLO-715 is under investigation and a summary of the ongoing phase I trial (NCT04093596) can be found on the Multiple Myeloma Hub.
Natural killer (NK) cells are innate immune effector cells independent of antigens and human leukocyte antigen molecules that recognize abnormal cells through a combination of surface stimulatory and inhibitory receptors that target ligands on target cells. NK cells are being investigated as an alternative to T cells for CAR constructs. A significant advantage of this treatment strategy is the ability to transplant mature NK cells into a different host without loss of function or the occurrence of graft-versus-host disease. Several trials are currently investigating these agents.2
BCMA-directed therapies are highly efficacious; however, no agent has proven curative. Each class of agent has its own logistical challenges and unique safety profile. It is thought that T-cell stimulating agents used earlier in therapy may lead to more robust and durable responses, and several studies are currently considering the optimal sequencing of treatment, including trials of BCMA-targeted therapies in newly diagnosed patients with MM. Should a patient progress on a BCMA-targeting therapy, it is still unclear whether benefit could be derived from alternative BCMA-directed therapy. While further research is required to answer these questions, BCMA-directed therapies remain a critical and long-awaited addition to the treatment armamentarium of relapsed/refractory MM.
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