Harnessing Allogeneic Anti-CD38 T Cell Therapy: A Breakthrough with Novel Antigen Receptor Engineering

The introduction highlights the potential of CAR T cell therapy for treating blood cancers, while acknowledging challenges like reliance on patient's immune cells and production difficulties. Sorrento has developed an alternative approach using genetically modified allogeneic T cells to create a Dimeric Antigen Receptor (DAR), specifically targeting CD38 in multiple myeloma. Preclinical findings show strong anti-tumor effects against CD38-expressing cancers.

The methodology involved engineering T cells from healthy donors to include an anti-CD38 DAR, which replaced the TRAC gene, thus eliminating native TCR expression. Three variations of DAR constructs were tested, differing in their intracellular signaling components. These engineered T cells were then tested for their ability to kill cancer cells and induce cytokine secretion in vitro, and their anti-tumor activity was evaluated in mice with disseminated disease.

Results indicated that the anti-CD38 DAR gene was successfully integrated into the T cells with high efficiency, and the modified T cells were highly effective in killing CD38-positive tumor cells, similar to CAR-T cells, without harming CD38-negative cells. In vivo studies revealed superior tumor-killing capabilities of DAR-T cells compared to CAR-T cells, with the 4-1BB/CD3zeta construct showing the most promising results.

The conclusion emphasizes the strong in vitro and in vivo anti-tumor activity of the tested DAR-T cells. The comparison of different signaling domains within the DAR constructs led to the selection of the most effective one for clinical development. The development of CD38 DAR-T therapy for blood cancers is supported by these findings, and the production of allogeneic anti-CD38 DAR-T cells under GMP conditions has commenced.