Oncolytic virus expressing PD-1 inhibitors activates a collaborative intratumoral immune response to control tumor and synergizes with CTLA-4 or TIM-3 blockade

Abstract

BackgroundOncolytic viruses (OVs) are capable to inflame the tumor microenvironment (TME) and elicit infiltrating tumor-specific T cell responses. However, OV treatment negatively alters the cancer-immune set point in tumors to attenuate the antitumor immune response, which suggests the necessity of dissecting the immune landscape of the virus-treated tumors and developing novel strategies to maximize the potential of OVs. The aim of this study is to investigate the effect of the single-chain variable fragment (scFv)-armed OVs targeting PD-1 on the TME, and ultimately overcome localized immunosuppression to sensitize tumors to immunotherapies.MethodsA tumor-selective oncolytic herpes simplex virus vector was engineered to encode a humanized scFv against human PD-1 (hPD-1scFv) (YST-OVH). The antitumor efficacy of YST-OVH was explored in multiple therapeutic mouse models. The neurotoxicity and safety of YST-OVH were evaluated in nonhuman primates. The precise dynamics in the TME involved in YST-OVH treatment were dissected using cytometry by time-of-flight (CyTOF).ResultsThe identified hPD-1scFv showed superior T-cell activating activity. Localized delivery of hPD-1scFv by YST-OVH promotes systemic antitumor immunity in humanized PD-1 mouse models of established cancer. Immune profiling of tumors using CyTOF revealed the enhanced antitumor effect of YST-OVH, which largely relied on CD8+ T cell activity by augmenting the tumor infiltration of effector CD8+ T cells and establishment of memory CD8+ T cells and reducing associated CD8+ T cell exhaustion. Furthermore, YST-OVH treatment modified the cancer-immune set point of tumors coupled to coexpression of CTLA-4 and TIM-3 on exhausted CD8+ T cells and high levels of CTLA-4+ Treg cells. A combination approach incorporating anti-CTLA-4 or anti-TIM-3 further improved efficacy by increasing tumor immunogenicity and activating antitumor adaptive immune responses. Moreover, this therapeutic strategy showed no neurotoxicity and was well tolerated in nonhuman primates. The benefit of intratumoral hPD-1scFv expression was also observed in humanized mice bearing human cancer cells.ConclusionLocalized delivery of PD-1 inhibitors by engineered YST-OVH was a highly effective and safe strategy for cancer immunotherapy. YST-OVH also synergized with CTLA-4 or TIM-3 blockade to enhance the immune response to cancer. These data provide a strong rationale for further clinical evaluation of this novel therapeutic approach.

A multidimensional pan‐cancer analysis of DCAF13 and its protumorigenic effect in lung adenocarcinoma

“…Several lines of evidence suggest that the immune microenvironment is associated with tumor development. Immune checkpoint therapy using antibodies to cytotoxic T lymphocyte‐associated antigen 4 (CTLA4), programmed death‐1 (PD‐1), and programmed death ligand 1 (PD‐L1) have shown tremendous clinical progress 2–4 . Unfortunately, many patients are insensitive to immunotherapy 5 .…”

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“…376,377 Combinational treatments with PD-L1/PD-1 blockade, CTLA-4 inhibitors, and small molecule IDO inhibitors have also resulted in strongly enhanced tumor suppression in multiple tumor models (including osteosarcoma models) because they expand infiltrating T lymphocytes and decrease Treg and MDSC numbers. [378][379][380] For The horizons for osteosarcoma treatment H Tian et al…”

Local Delivery of Immunomodulatory Antibodies for Gastrointestinal Tumors

“…Perhaps inspired by these last studies, many groups have focused on trying to simplify this combination therapy by engineering HSV vectors to express ICIs. Some of these “optimized” HSV OVs have been tested in preclinical models of GI tumors, such as CRC and liver cancer [ 110 , 111 , 112 ]. A rationale for expressing ICIs from OVs locally is that they are not completely able to overcome the immunosuppressive TME, in part because the viral infection can upregulate PD-L1 in tumors.…”

“…A rationale for expressing ICIs from OVs locally is that they are not completely able to overcome the immunosuppressive TME, in part because the viral infection can upregulate PD-L1 in tumors. For that reason, several HSV vectors have been engineered to express anti-PD-1 antibodies, either as scFvs [ 110 , 112 ] or nanobodies [ 111 ]. In fact, an HSV virus expressing an anti-PD-1 scFv was very efficient at modifying the TME in a liver cancer model based on Hepa 1–6 cells, improving antigen presentation by dendritic cells (DCs), and leading to better antitumor efficacy compared with the control virus [ 110 ].…”