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CD137 (4-1BB; TNFSR9) is an activation-induced surface receptor that through costimulation effects provide antigen-primed T cells with augmented survival, proliferation and effector functions as well as metabolic advantages. These immunobiological mechanisms are being utilised for cancer immunotherapy with agonist CD137-binding and crosslinking-inducing agents that elicit CD137 intracellular signaling. In this study, side-by-side comparisons show that provision of CD137 costimulation in-cis with regard to the TCR-CD3-ligating cell is superior to that provided in-trans in terms of T cell activation, proliferation, survival, cytokine secretion and mitochondrial fitness in mouse and human. Cis ligation of CD137 relative to the TCR-CD3 complex results in more intense canonical and non-canonical NF-κB signaling and provides a more robust induction of cell cycle and DNA damage repair gene expression programs. Here we report that the superiority of cis versus trans CD137-costimulation is readily observed in vivo and is relevant for understanding the immunotherapeutic effects of CAR T cells and CD137 agonistic therapies currently undergoing clinical trials, which may provide costimulation either in cis or in trans. Costimulation has been shown to be required for optimal activation of T cells and it could be delivered either in trans with respect to the source of CD3-TCR ligation or in cis on the same cell. Here the authors show that CD137 costimulation is more effective when delivered in cis to enhance T cell proliferation and activation. [ABSTRACT FROM AUTHOR]

Recent studies have found that tumor-infiltrating lymphocytes (TIL) expressing PD-1 can recognize autologous tumor cells, suggesting that cells derived from PD-1+ TILs can be used in adoptive T-cell therapy (ACT). However, no study thus far has evaluated the antitumor activity of PD-1-selected TILs in vivo. In two mouse models of solid tumors, we show that PD-1 allows identification and isolation of tumor-specific TILs without previous knowledge of their antigen specificities. Importantly, despite the high proportion of tumor-reactive T cells present in bulk CD8 TILs before expansion, only T-cell products derived from sorted PD-1+, but not from PD-1- or bulk CD8 TILs, specifically recognized tumor cells. The fold expansion of PD-1+ CD8 TILs was 10 times lower than that of PD-1- cells, suggesting that outgrowth of PD-1- cells was the limiting factor in the tumor specificity of cells derived from bulk CD8 TILs. The highly differentiated state of PD-1+ cells was likely the main cause hampering ex vivo expansion of this subset. Moreover, PD-1 precisely identified marrow-infiltrating, myeloma-specific T cells in a mouse model of multiple myeloma. In vivo, only cells expanded from PD-1+ CD8 TILs contained tumor progression, and their efficacy was enhanced by PDL-1 blockade. Overall, our data provide a rationale for the use of PD-1-selected TILs in ACT. [ABSTRACT FROM AUTHOR]

Three hundred fifty millions people are estimated to be infected by the hepatitis B virus (HBV). Eighty-seven millions of them would develop HBV-related liver cancer or cirrhosis. In this study we developed a high-capacity adenovirus (HC-Ad), characterized by its low toxicity and long-term expression, encoding for the murine interleukin 12 (mIL12) directed by a liver-specific promoter and inducible by the administration of mifepristone (HC-RU-mIL12). We assayed its antiviral effect using two animal models of chronic HBV infection: transgenic mice for the HBV genome and woodchucks chronically infected by the woodchuck hepatitis virus (WHV).HBV transgenic mice received 2x10e8 infective units (iu) of HC- RU-mIL12. Two weeks later they received five daily doses of inductor (mifepristone). Treated animals showed a complete abrogation of serum viral load and the concentration of viral antigens (HBsAg y HBeAg) decreased significantly, whereas the viremia of control groups remained stable.Two woodchucks (w173 and w762) received 9x10e9 iu of HC- RU-mIL12. A third one (w752) received only inductor and was used as control. Woodchucks were treated daily during eleven days with 500 μg of mifepristone per kg of body-weight. Woodchuck w762 expressed low levels of mIL12 and its viremia remained unchanged during the whole treatment period. However woodchuck w173 expressed high levels of mIL12 in peripheral blood and suffered a spectacular decrease of its viremia higher than 6 logarithms. At the end of the treatment, the viremia of this animal remained constant during more than one year, below our detection limit. In both treated woodchucks the recombinant virus induced a significant activation of cellular immune response against core antigen (WHcAg). No changes were observed in control woodchuck. No toxicity was detected due to the virus or IL12.These experiments demonstrate the antiviral efficacy of our treatment using HC-Ad expressing mIL12 in HBV transgenic mice and more importantly in WHV chronically infected woodchucks. Furthermore, we were able to induce a strong antigen-specific immune response in this animal model. We validate the HC-RU-mIL12 as a safe and innocuous vector, probably due to the localized and controlled expression of the cytokine. Studies with a larger number of animals are being conducted.Molecular Therapy (2006) 13, S224–S224; doi: 10.1016/j.ymthe.2006.08.654 [ABSTRACT FROM AUTHOR]

Retroviral gene transfer of interleukin-12 (IL-12) into T cells markedly enhances antitumor efficacy upon adoptive transfer but has clinically shown unacceptable severe side effects. To overcome the toxicity, we engineered tumor-specific CD8 + T cells to transiently express IL-12. Engineered T cells injected intratumorally, but not intravenously, led to complete rejections not only of the injected lesion but also of distant concomitant tumors. Efficacy was further enhanced by co-injection with agonist anti-CD137 mAb or by transient co-expression of CD137 ligand. This treatment induced epitope spreading of the endogenous CD8 + T cell immune response in a manner dependent on cDC1 dendritic cells. Mouse and human tumor-infiltrating T lymphocyte cultures can be transiently IL-12 engineered to attain marked immunotherapeutic effects., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Recent studies have found that tumor-infiltrating lymphocytes (TIL) expressing PD-1 can recognize autologous tumor cells, suggesting that cells derived from PD-1 + TILs can be used in adoptive T-cell therapy (ACT). However, no study thus far has evaluated the antitumor activity of PD-1-selected TILs in vivo In two mouse models of solid tumors, we show that PD-1 allows identification and isolation of tumor-specific TILs without previous knowledge of their antigen specificities. Importantly, despite the high proportion of tumor-reactive T cells present in bulk CD8 TILs before expansion, only T-cell products derived from sorted PD-1 + , but not from PD-1 - or bulk CD8 TILs, specifically recognized tumor cells. The fold expansion of PD-1 + CD8 TILs was 10 times lower than that of PD-1 - cells, suggesting that outgrowth of PD-1 - cells was the limiting factor in the tumor specificity of cells derived from bulk CD8 TILs. The highly differentiated state of PD-1 + cells was likely the main cause hampering ex vivo expansion of this subset. Moreover, PD-1 precisely identified marrow-infiltrating, myeloma-specific T cells in a mouse model of multiple myeloma. In vivo , only cells expanded from PD-1 + CD8 TILs contained tumor progression, and their efficacy was enhanced by PDL-1 blockade. Overall, our data provide a rationale for the use of PD-1-selected TILs in ACT. Cancer Res; 77(13); 3672-84. ©2017 AACR ., (©2017 American Association for Cancer Research.)