Affinity-Enhanced TCR-Engineered T Cells Induce Antimyeloma Responses

Adoptive transfer of autologous tumor-reactive T cells has been investigated as a strategy to augment clinical responses to autologous stem cell transplantation (ASCT) in patients with multiple myeloma. The immunogenic cancer-testis antigen NY-ESO-1 is expressed in a large percentage of advanced myelomas and is associated with poor prognosis, prompting Rapoport, Stadtmauer, Binder-Scholl, and colleagues to assess the safety and antitumor activity of NY-ESO-1– and LAGE-1–specific TCR-engineered T cells in multiple myeloma in a phase I/II trial. Ex vivo–expanded autologous engineered T cells were administered to twenty patients with advanced antigen-positive myeloma two days after ASCT. Engineered T cells were detected in the marrow, which represents the primary tumor site, and exhibited cytotoxic functionality and long-term persistence that inversely correlated with NY-ESO-1 expression. Autologous engineered T cells were well tolerated and did not induce severe cytokine release syndrome or treatment-related fatalities. Furthermore, infused engineered T cells mediated durable antigen-specific antimyeloma activity, resulting in decreased expression of NY-ESO-1 and LAGE-1 in all patients and reduced numbers of CD138-positive myeloma cells. Fourteen (70%) of 20 patients achieved a near-complete or complete response, four patients experienced a partial response, and one patient had stable disease; median progression-free survival was 19.1 months and median overall survival was 32.1 months. Of note, tumor progression was associated with antigen escape in two cases and loss of modified T cells in the blood in eight cases. These findings suggest that NY-ESO-1–specific TCR-engineered T cells may result in enhanced and more durable clinical responses in antigen-positive multiple myeloma, and support efforts to further increase persistence and antigen spreading.

Rapoport AP, Stadtmauer EA, Binder-Scholl GK, Goloubeva O, Vogl DT, Lacey SF, et al. NY-ESO-1–specific TCR–engineered T cells mediate sustained antigen-specific antitumor effects in myeloma. Nat Med 2015;21:914–21.

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