Oncolytic virotherapy: Potentially a game-changing tumor treatment

Keßler, Tobias; Wick, Wolfgang

doi:10.1016/j.ccell.2021.05.014

Cited by 10 publications

(7 citation statements)

References 12 publications

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“… 33 OV treatment is the key factor in this regimen, and OVs have several advantages related to inducing extensive effects on the TME of solid tumors, especially noninflamed tumors, including direct tumor cell killing, recruitment of the innate and adaptive cells, and activation of the T cells. 34 Furthermore, OVs reverse the immune balance within T cells and lead to an increased ratio of effector T cells to Treg cells. 12 …”

Section: Discussionmentioning

confidence: 99%

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

Luo

Lin

et al. 2022

J Immunother Cancer

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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.

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Section: Discussionmentioning

confidence: 99%

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

Luo

Lin

et al. 2022

J Immunother Cancer

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“…Based on reported results it has been shown that OVs are able to modulate and alter TME landscape, resulting in enhanced anti-cancer activity alone or in a combination with other agents. Therefore, OVs are potent immune activators able to promotes profound, long-lasting anti-cancer immune responses and clinical efficacy [33][34][35][36].…”

Section: Resultsmentioning

confidence: 99%

From Immunosuppression to Immunomodulation - Turning Cold Tumours into Hot

Garofalo¹,

Pancer²,

Wieczorek³

et al. 2022

J. Cancer

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Cancer cells employ various mechanisms to evade and suppress anti-cancer immune responses generating a "cold" immunosuppressive tumour microenvironment. Oncolytic viruses are a promising tool to convert tumour immunosuppression to immunomodulation and improve the efficacy of cancer treatment. Emerging preclinical and clinical findings confirm that oncolytic viruses act in a multimodal scheme, triggering lyses, immunogenic cell death and finally inducing anti-cancer immune responses. In this paper, we tested the local administration of a novel oncolytic adenovirus AdV-D24-ICOSL-CD40L expressing co-stimulatory molecules ICOSL and CD40L to induce the production of tumour infiltrating lymphocytes to the site of injection. Subsequently, in immunocompetent mouse models, we studied possible correlation between tumour infiltrates and anti-cancer efficacy. Described results showed that the delivery of oncolytic viruses encoding immunomodulatory transgenes in combination with anti-PD1 resulted in synergistic inhibition of both melanoma and mesothelioma tumours. Importantly anti-cancer effect positively correlated with cytotoxic CD8+ tumour-infiltrating lymphocytes exerting a central role in the tumour volume control thus generating beneficial outcomes that will undoubtedly provide new insights into possible future treatment strategies to combat cancer. Altogether our findings highlight the importance of oncolytic vectors able to modulate anti-cancer immune responses that can correlate with efficacy in solid malignancies.

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“…Oncolytic immunotherapy involves the use of oncolytic viruses that are naturally occurring or genetically altered to kill tumor cells by selectively replicating in cancer cells, but not in normal cells [ 62 ]. Like CAR T-cell-based HCC therapy, oncolytic immunotherapy for treating HCC is still in the early development stages.…”

Section: Hcc Immunotherapymentioning

confidence: 99%

Immunotherapeutic Approaches for Treating Hepatocellular Carcinoma

Shen

Chen

Pan

et al. 2022

Cancers

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Liver cancer is a life-threatening disease, and its incidence is increasing globally. The most common form of liver cancer is hepatocellular carcinoma (HCC). Approximately half of patients with HCC, especially those at advanced disease stages, receive systemic therapies, including the tyrosine kinase inhibitors sorafenib and lenvatinib. Over the past few years, immune checkpoint inhibitors (ICIs) have changed the landscape of HCC treatment. In particular, the combination therapy with atezolizumab (an anti-PD-L1 antibody) and bevacizumab (an anti-VEGF antibody) significantly improved survival benefits compared with sorafenib as a single agent, a finding that has stimulated further preclinical and clinical development of immunotherapeutic approaches for treating HCC. In addition to ICIs, oncolytic immunotherapy and adoptive T cell therapy have also emerged as immunotherapeutic strategies. A major challenge is that the tumor microenvironment of HCC is usually immunosuppressive, leading to immune escape and immunotherapy resistance. Hence, combination therapies that could sensitize HCC to immunotherapy have become a growing area of investigation. In this review, we summarize recent advances in HCC immuno-oncology and review immunotherapeutic strategies that are under development for treating HCC.

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Oncolytic virotherapy: Potentially a game-changing tumor treatment

Cited by 10 publications

References 12 publications

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

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

From Immunosuppression to Immunomodulation - Turning Cold Tumours into Hot

Immunotherapeutic Approaches for Treating Hepatocellular Carcinoma

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