T Cells Redirected to a Minor Histocompatibility Antigen Instruct Intratumoral TNFα Expression and Empower Adoptive Cell Therapy for Solid Tumors

Abstract

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 TNFα expression, endothelial cell activation, and intratumoral T-cell infiltration. While neutralizing TNFα hindered GVT effects by the combined T-cell infusion, a single injection of picogram amounts of NGR-TNF, a tumor vessel-targeted TNFα 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. ©2016 AACR.

Boosting Interleukin‐12 Antitumor Activity and Synergism with Immunotherapy by Targeted Delivery with isoDGR‐Tagged Nanogold

“…Finally, we also found that low‐dose Iso1/Au/IL12 could enhance the efficacy to adoptive T cell therapy in mice with autochthonous prostate cancer. In these mice, T cells redirected to the tumor by a TCR gene transfer approach fail to evoke tumor rejection, unless combined with additional tumor‐targeting strategies . Our results show that adoptive T‐cell therapy in combination with low‐dose Iso1/Au/IL12 promotes tumor regression in the majority of mice.…”

“…Although more recent studies showed that toxicity could be limited by engineering T cells with inducible IL12 constructs,15f we reasoned that the controlled delivery of an extremely low‐dose, well‐defined, of IL12 might prove a safer approach. To test the hypothesis that low‐dose Iso1/Au/IL12 might be of help in the context of adoptive T‐cell therapy (ACT) we used the transgenic prostate adenocarcinoma mouse model (TRAMP), with autochthonous prostate cancer development, and T cells redirected by TCR gene transfer to the tumor‐associated large T antigen . Notably, previous studies have shown that in this model tumor‐redirected T cells lack significant therapeutic activity, unless used in combination of vessel‐targeted TNF or minor histocompatibility redirected T cells .…”

“…To test the hypothesis that low‐dose Iso1/Au/IL12 might be of help in the context of adoptive T‐cell therapy (ACT) we used the transgenic prostate adenocarcinoma mouse model (TRAMP), with autochthonous prostate cancer development, and T cells redirected by TCR gene transfer to the tumor‐associated large T antigen . Notably, previous studies have shown that in this model tumor‐redirected T cells lack significant therapeutic activity, unless used in combination of vessel‐targeted TNF or minor histocompatibility redirected T cells . Twenty‐week‐old TRAMP mice, a time at which all mice have established adenocarcinomas, were subjected to nonmyeloablative total body irradiation, to favor T cell engraftment, and then injected with T cells redirected against the tumor‐associated SV40 large T antigen.…”

“…Notably, previous studies have shown that in this model tumor‐redirected T cells lack significant therapeutic activity, unless used in combination of vessel‐targeted TNF or minor histocompatibility redirected T cells . Twenty‐week‐old TRAMP mice, a time at which all mice have established adenocarcinomas, were subjected to nonmyeloablative total body irradiation, to favor T cell engraftment, and then injected with T cells redirected against the tumor‐associated SV40 large T antigen. One day later mice were treated i.v.…”

“…Autochthonous Prostate Cancer Model : Heterozygous CD45.2 + C57BL/6 TRAMP mice and wild‐type CD45.1 + congenic mice, were housed, bred, and genotyped in a specific pathogen‐free animal facility in accordance with the European Union guidelines . Congenic CD45.1 + cells were transduced with a tumor (Tag‐IV)‐specific TCR as previously described . Twenty‐ week‐old male TRAMP mice were conditioned by a sublethal dose of total body irradiation (6 Gy), and the following day i.v.…”