Pre-clinical evaluation of CD38 chimeric antigen receptor engineered T cells for the treatment of multiple myeloma

Abstract

A doptive transfer of chimeric antigen receptor-transduced T cells is a promising strategy for cancer immunotherapy. The CD38 molecule, with its high expression on multiple myeloma cells, appears a suitable target for antibody therapy. Prompted by this, we used three different CD38 antibody sequences to generate second-generation retroviral CD38-chimeric antigen receptor constructs with which we transduced T cells from healthy donors and multiple myeloma patients. We then evaluated the preclinical efficacy and safety of the transduced T cells. Irrespective of the donor and antibody sequence, CD38-chimeric antigen receptor-transduced T cells proliferated, produced inflammatory cytokines and effectively lysed malignant cell lines and primary malignant cells from patients with acute myeloid leukemia and multi-drug resistant multiple myeloma in a cell-dose, and CD38-dependent manner, despite becoming CD38-negative during culture. CD38-chimeric antigen receptor-transduced T cells also displayed significant anti-tumor effects in a xenotransplant model, in which multiple myeloma tumors were grown in a human bone marrow-like microenvironment. CD38-chimeric antigen receptor-transduced T cells also appeared to lyse the CD38 + fractions of CD34 + hematopoietic progenitor cells, monocytes, natural killer cells, and to a lesser extent T and B cells but did not inhibit the outgrowth of progenitor cells into various myeloid lineages and, furthermore, were effectively controllable with a caspase-9-based suicide gene. These results signify the potential importance of CD38-chimeric antigen receptor-transduced T cells as therapeutic tools for CD38 + malignancies and warrant further efforts to diminish the undesired effects of this immunotherapy using appropriate strategies. Pre-clinical evaluation of CD38 chimeric antigen receptor engineered T cells for the treatment of multiple myeloma

The immunotherapy era of myeloma: monoclonal antibodies, vaccines, and adoptive T-cell therapies

“…84 Other targets being examined for CAR therapy include k light chain, 85 CS-1, 86 CD138, 87 and CD38. 88 Although demonstrating powerful antitumor activity, the significant toxicity associated with the CRS thus far limits its use outside of the multiply-relapsed setting.…”

Encouraging Debut of Immunotherapy In Myeloma

“…It is not expressed on primitive hematopoietic precursors (CD34+CD38-), suggesting that hematopoietic recovery would occur following CD38-targeted cytotoxic agents [1] …”

“…Isatuximab shows single-agent activity in relapsed / refractory myeloma (RRMM) [9]. Daratumumab was administered for prolonged periods at moderate to high doses with little or no toxicity, despite the fact that the CD38 molecule is also expressed at lower levels, on a fraction of hematopoietic cells, cerebellar Purkinje cells, liver and lung smooth muscle cells, and insulin-secreting cells of pancreas [1]. SAR650984 is another anti-CD38 antibody which is under investigation in clinical trials [9].…”

Chimeric antigen receptor T-cell therapies for multiple myeloma

“…79 The basis for this approach is that MM cells express higher levels of CD38 than most normal hematopoietic cells. 78,79 In addition to optimizing scFv affinity, Drent et al and Straathof et al have constructed anti-CD38 CAR-Ts with caspase-9-based suicide genes to eliminate CAR-Ts on demand.…”

“…78 Drent et al have used a process they term affinity optimization in which new anti-CD38 antibodies are generated via light-chain exchange. The CARs are then categorized based on antibody affinity and selected based on ability to lyse CD38…”