| First Author | Manzo T | Year | 2017 |
| Journal | Cancer Res | Volume | 77 |
| Issue | 3 | Pages | 658-671 |
| PubMed ID | 27872095 | Mgi Jnum | J:239404 |
| Mgi Id | MGI:5828695 | Doi | 10.1158/0008-5472.CAN-16-0725 |
| Citation | Manzo T, et al. (2017) T Cells Redirected to a Minor Histocompatibility Antigen Instruct Intratumoral TNFalpha Expression and Empower Adoptive Cell Therapy for Solid Tumors. Cancer Res 77(3):658-671 |
| abstractText | Donor-derived allogeneic T cells evoke potent graft versus tumor (GVT) effects likely due to the simultaneous recognition of tumor-specific and host-restricted minor histocompatibility (H) antigens. Here we investigated whether such effects could be reproduced in autologous settings by TCR gene-engineered lymphocytes. We report that T cells redirected either to a broadly expressed Y-encoded minor H antigen or to a tumor-associated antigen, although poorly effective if individually transferred, when simultaneously administered enabled acute autochthonous tumor debulking and resulted in durable clinical remission. Y-redirected T cells proved hyporesponsive in peripheral lymphoid organs, whereas they retained effector function at the tumor site, where in synergy with tumor-redirected lymphocytes, they instructed TNFalpha expression, endothelial cell activation, and intratumoral T-cell infiltration. While neutralizing TNFalpha hindered GVT effects by the combined T-cell infusion, a single injection of picogram amounts of NGR-TNF, a tumor vessel-targeted TNFalpha derivative currently in phase III clinical trials, substituted for Y-redirected cells and enabled tumor debulking by tumor-redirected lymphocytes. Together, our results provide new mechanistic insights into allogeneic GVT, validate the importance of targeting the tumor and its associated stroma, and prove the potency of a novel combined approach suitable for immediate clinical implementation. Cancer Res; 77(3); 658-71. (c)2016 AACR. |
