Abstract
The development of chimeric antigen receptor (CAR) and bispecific T-cell engager (BiTE) has led to the successful application of cancer immunotherapy. The potential reactivity mediated by CAR- and BiTE-redirected T cells needs to be assessed to facilitate the application of these treatment options to a broader range of patients. Here, we have generated CAR and BiTE possessing the same single chain fragment variable (scFv) specific for the HLA-A2/NY-ESO-1157-165 complex (A2/NY-ESO-1157). Using HLA-A2+NY-ESO-1+ myeloma cells and peptides presented by HLA-A2 molecules as a model, both sets of redirected T cells recognized and killed HLA-A2+NY-ESO-1+ myeloma cells in an A2/NY-ESO-1157-specific manner in vitro. Moreover, CAR- and BiTE-activated T cells showed similar functional avidity, as assessed by cytokine production and killing activity, both displaying antitumor reactivity against HLA-A2+NY-ESO-1+ myeloma cells in vivo. Interestingly, cross-reactivity for homologous peptides presented by HLA-A*02:01 and NY-ESO-1157 peptide presented by HLA-A2 alleles was not identical between CAR- and BiTE-redirected T cells, probably due to structural differences of modified antibodies. These results have demonstrated that both antitumor CAR- and BiTE-activated T cells have comparable potential to recognize tumors, while paying attention to unknown off-target reactivity that would differ for each antibody-based modality even if the same scFv was employed.
Highlights
Clinical trials have demonstrated that T-cell therapy can suppress tumor growth even in patients with refractory malignancies[1]
Employing A2/NY-ESO-1157-specific chimeric antigen receptor (CAR) and bispecific T-cell engager (BiTE) and myeloma cells as a model, we investigated the potential target-specific reactivity and cross-reactivity of CAR- and BiTE-redirected T cells for NY-ESO-1157 peptide and its homologous peptides presented by the human leukocyte antigen (HLA)-A2 molecule as well as HLA-A2+NY-ESO-1+ myeloma cells in vitro and in vivo, and compared them directly
Cytotoxicity against HLA-A2+NY-ESO-1+ myeloma cells mediated by CAR-T cells was more efficient than that mediated by BiTE-redirected T cells in vitro, it must be noted that we employed freshly isolated peripheral blood T cells for experiments using BiTEs. These results indicate that BiTE-redirected T cells as well as CAR-redirected T cells possess sufficient avidity to recognize endogenously processed and presented A2/NY-ESO-1157, resulting in cytokine production and specific killing of HLA-A2+NY-ESO-1+ myeloma cells
Summary
Clinical trials have demonstrated that T-cell therapy can suppress tumor growth even in patients with refractory malignancies[1]. To clarify the benefits and risks of antitumor CAR and BiTE, direct comparison of reactivities mediated by CAR- and BiTE-redirected T cells possessing the same scFv recognizing an HLA/peptide complex as a model would reveal in more detail their target-specific reactivity and cross-reactivity by changing specific peptides and HLA alleles. Such knowledge would help facilitate the application of these treatment options to a broader range of patients with refractory malignancies. Employing A2/NY-ESO-1157-specific CAR and BiTE and myeloma cells as a model, we investigated the potential target-specific reactivity and cross-reactivity of CAR- and BiTE-redirected T cells for NY-ESO-1157 peptide and its homologous peptides presented by the HLA-A2 molecule as well as HLA-A2+NY-ESO-1+ myeloma cells in vitro and in vivo, and compared them directly
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