This Review discusses the major advances and changes made over the past 3 years to our understanding of chimeric antigen receptor (CAR) T cell efficacy and safety. Recently, the field has gained insight into how various molecular modules of the CAR influence signalling and function. We report on mechanisms of toxicity and resistance as well as novel engineering and pharmaceutical interventions to overcome these challenges. Looking forward, we discuss new targets and indications for CAR T cell therapy expected to reach the clinic in the next 1–2 years. We also consider some new studies that have implications for the future of CAR T cell therapies, including changes to manufacturing, allogeneic products and drug-regulatable CAR T cells. This Review outlines the major advances that have been made to the efficacy and safety of chimeric antigen receptor (CAR) T cell therapies over the past 3 years and looks to new findings that will have consequences for the future of this immunotherapy.

Recent advances and discoveries in the mechanisms and functions of CAR T cells.

https://www.cell.com/cell/pdf/S0092-8674(20)30263-4.pdf

The Emerging Landscape of Immune Cell Therapies.

Despite several therapeutic advances over the past decade, multiple myeloma (MM) remains largely incurable, indicating a need for new treatment approaches. Chimeric antigen receptor (CAR) T cell therapy works by mechanisms distinct from those of other MM therapies and involves the modification of patient or donor T cells to target specific cell-surface antigens. B cell maturation antigen (BCMA) is expressed only on plasma cells, a small subset of B cells and MM cells, which makes it a suitable target antigen for such therapies. At the time of writing, data from >20 clinical trials involving anti-BCMA CAR T cells have demonstrated that patients with relapsed and/or refractory MM can achieve objective responses. These early investigations have been instrumental in demonstrating short-term safety and efficacy; however, most patients do not have disease remission lasting >18 months. Attempts to reduce or delay the onset of relapsed disease are underway and include identifying additional CAR T cell target antigens and methods of enhancing BCMA expression on MM cells. Engineering CAR T cells to enhance both the activity and safety of treatment continues to be a promising avenue for improvement. In this Review we summarize data from clinical trials that have been carried out to date, describe novel antigens that could be targeted in the future, and highlight potential future innovations that could enhance the efficacy and/or reduce the toxicities associated with CAR T cell therapies.

CAR T cell therapies for patients with multiple myeloma

B cell maturation antigen (BCMA) is a novel treatment target for multiple myeloma (MM) due to its highly selective expression in malignant plasma cells (PCs). Multiple BCMA-targeted therapeutics, including antibody-drug conjugates (ADC), chimeric antigen receptor (CAR)-T cells, and bispecific T cell engagers (BiTE), have achieved remarkable clinical response in patients with relapsed and refractory MM. Belantamab mafodotin-blmf (GSK2857916), a BCMA-targeted ADC, has just been approved for highly refractory MM. In this article, we summarized the molecular and physiological properties of BCMA as well as BCMA-targeted immunotherapeutic agents in different stages of clinical development.

/pdf/bcma-targeted-immunotherapy-for-multiple-myeloma-2asp5jqyfh.pdf

Jessica Kelliher

Papers

γ-Secretase inhibition increases efficacy of BCMA-specific chimeric antigen receptor T cells in multiple myeloma.