Chimeric antigen receptor (CAR)-T cells have demonstrated profound clinical responses against CD19+ B cell malignancies, with ongoing trials in multiple myeloma (MM). Although BCMA CAR-T cells show promise in MM, development of CAR-T against other MM targets has been problematic due to target expression on T cells themselves. Specifically, efforts to develop CAR-T cell therapies targeting CD38 have been hampered by the upregulation of CD38 on activated T cells and consequent induction of CAR-T mediated autolysis that occurs during manufacturing. To overcome this challenge during CAR-T production, investigators have taken several approaches including multiple rounds of T cell expansion, addition of CD38 blocking antibody, and CD38 gene knockout in T cells prior to CAR transduction (1,2,3).
The Antibody-Coupled T Cell Receptor (ACTR) technology is a universal, engineered T cell therapy that combines the Fc receptor, CD16, with endogenous T cell signaling and costimulatory domains (4). ACTR T cells function by engaging the Fc domain of therapeutic antibodies opsonized on target cells, resulting in T cell activation and tumor cell killing. In contrast to CAR-T cell constructs that express the antigen targeting single chain variable fragment (scFv), ACTR T cell activity is regulated through antibody administration and is therefore not susceptible to target-mediated autolysis during T cell production.
The recent approval of the CD38-targeting antibody, daratumumab, has improved the treatment of multiple myeloma through its tumor targeting and immunomodulating capabilities. Here, we leveraged the ability of the ACTR T cell platform to decouple the targeting antibody from the engineered T cell signaling moieties, and evaluated the anti-myeloma activity of ACTR T cells in combination with daratumumab. We demonstrated that in contrast to CD38-targeting CAR-T cells, ACTR T cells exhibited enhanced viability and expansion of the chimeric construct throughout the manufacturing process. We then evaluated the anti-myeloma activity of ACTR T cells in combination with daratumumab. ACTR T cells mediated robust cytotoxicity, cytokine production, and proliferation in response to a range of daratumumab-opsonized target cell lines. Notably, the target specific killing and cytokine production mediated by ACTR T cells in combination with daratumumab was greater than the activity mediated by daratumumab alone. Recognizing the augmented activity of ACTR T cells in combination with daratumumab, we systematically investigated the potential for on-target off-tumor toxicity. In a peripheral blood mononuclear cell coculture assay, ACTR T cells in combination with daratumumab selectively targeted CD38-expressing multiple myeloma cells over CD38-expressing normal B cells, T cells, and natural killer cells. Furthermore, despite low levels of CD38 expression reported on erythrocytes, ACTR T cells in combination with daratumumab did not mediate hemolysis. Taken together, our findings demonstrate the adaptability of the ACTR platform to function in combination with daratumumab, and bypass the challenges of scFv-based CAR-T cell production to safely and effectively target CD38-positive multiple myeloma.
Drent E, et al. Pre-clinical evaluation of CD38 chimeric antigen receptor engineered T cells for the treatment of multiple myeloma. Haematologica 2016 May; 101(5):616-25.
Mihara K, et al. Activated T-cell-mediated immunotherapy with a chimeric receptor against CD38 in B-cell non-Hodgkin Lymphoma. J Immunotherapy 2009 Sep; 32(7):737-43.
Dusseaux M, et al. Allogeneic TCRα/CD38 double knockout T-cells bearing an anti-CD38 chimeric antigen receptor (CAR): an improved immunotherapy for the treatment of T-cell acute lymphoblastic leukemia (T-ALL) and multiple myeloma (MM). European Hematology Association 2016. P365.
Kudo K, et al. T lymphocytes expressing a CD16 signaling receptor exert antibody-dependent cancer cell killing. Cancer Res 2014 Jan; 74(1):93-103.
Hickman: Unum Therapeutics Inc.: Employment. Graziano: Unum Therapeutics Inc.: Employment. O'Callaghan: Unum Therapeutics Inc.: Employment. Boomer: Unum Therapeutics Inc.: Employment. Choi: Unum Therapeutics Inc.: Employment. Nelson: Unum Therapeutics Inc.: Employment. Motz: Unum Therapeutics Inc.: Employment. Sachs: Unum Therapeutics Inc.: Employment. Schultes: Unum Therapeutics Inc.: Employment. Ettenberg: Unum Therapeutics Inc.: Employment. Cheema: Unum Therapeutics Inc.: Employment.
Asterisk with author names denotes non-ASH members.