Innovation in BCMA CAR-T therapy: Building beyond the Model T

Abstract

Autologous chimeric antigen receptor T-cell (CAR-T) therapies targeting B-cell maturation antigen (BCMA) have revolutionized the field of multiple myeloma in the same way that the Ford Model T revolutionized the original CAR world a century ago. However, we are only beginning to understand how to improve the efficacy and usability of these cellular therapies. In this review, we explore three automotive analogies for innovation with BCMA CAR-T therapies: stronger engines, better mileage, and hassle-free delivery. Firstly, we can build stronger engines in terms of BCMA targeting: improved antigen binding, tools to modulate antigen density, and armoring to better reach the antigen itself. Secondly, we can improve “mileage” in terms of response durability through ex vivo CAR design and in vivo immune manipulation. Thirdly, we can implement hassle-free delivery through rapid manufacturing protocols and off-the-shelf products. Just as the Model T set a benchmark for car manufacturing over 100 years ago, idecabtagene vicleucel and ciltacabtagene autoleucel have now set the starting point for BCMA CAR-T therapy with their approvals. As with any emerging technology, whether automotive or cellular, the best in innovation and optimization is yet to come.

CAR NK92 Cells Targeting BCMA Can Effectively Kill Multiple Myeloma Cells Both In Vitro and In Vivo

“…In a therapeutic environment of MM therapy, B-cell mature antigen (BCMA), one of the most specific and highly expressed antigens in bone marrow cells, occupies promising targets [21]. In CAR T-cell immunotherapy, the CAR strategy targeting BCMA is known to be innovative by combining the target specificity of mAB and the cell toxicity of T cells [22]. Most recent in March 2021, FDA approved the use of Abecma ® , a BCMA, for treating MM.…”

Beyond BCMA: the next wave of CAR T cell therapy in multiple myeloma

“…Novel non-BCMA targeted CAR T cell therapies are a potential solution to combat baseline intratumoral antigen heterogeneity, acquired antigen loss and immune exhaustion (8,60,143,144). For example, CAR T cells targeting GPRC5D are furthest in the developmental pipeline, and to date have shown promising safety and efficacy, including in patients who relapsed after prior anti-BCMA therapies (69, 71).…”

CAR T‐Cell Therapy for Multiple Myeloma: A Clinical Practice‐Oriented Review

“…Researchers are exploring ways to potentiate antigen targeting (e.g., optimizing antigen binding, modulation of antigen density, and "armoring" with cytokine receptors or secreted cytokines), improve response durability (e.g., ex vivo changes to CAR design and in vivo modulation of the immune system), and minimize delays between initial consultation and cell infusion (e.g., rapid manufacturing protocols and "offthe-shelf " allogeneic products). 74 In this scenario, investigational BCMA-directed products have shown potential to further improve patient outcomes. Orvacabtagene autoleucel (orva-cel; JCARH125) -an autologous product expressing a CAR construct with a unique fully human scFv, optimized spacer, and 4-1BB costimulatory and CD3ζ activation domains -has demonstrated compelling clinical activity.…”

“…There is still room for enhancing the efficacy and safety of anti‐BCMA CAR T‐cell therapy. Researchers are exploring ways to potentiate antigen targeting (e.g., optimizing antigen binding, modulation of antigen density, and “armoring” with cytokine receptors or secreted cytokines), improve response durability (e.g., ex vivo changes to CAR design and in vivo modulation of the immune system), and minimize delays between initial consultation and cell infusion (e.g., rapid manufacturing protocols and “off‐the‐shelf” allogeneic products) 74 …”