Localized oncolytic virotherapy overcomes systemic tumor resistance to immune checkpoint blockade immunotherapy
By D. Zamarin, Rikke B. Holmgaard, S. Subudhi, J. Park, M. Mansour, P. Palese, T. Merghoub, J. Wolchok, James P. Allison. Science Translational Medicine, 2014
680 citations recorded by the source corpus.
Intratumoral treatment with an oncolytic virus results in inflammatory infiltrates in distant tumors and sensitizes the tumors to immune-mediated rejection in the setting of immunotherapy with CTLA-4 blocking antibodies. Immune Cells and a Virus Teaming Up to Fight Cancer Immunotherapy, or harnessing the patient’s own immune system to help fight cancer, is becoming increasingly popular as researchers discover newer and more successful approaches focused on different aspects of the immune system. Two of these approaches include oncolytic viruses and therapies that block immune checkpoints and thus stimulate the antitumor activity of T cells. One virus that is known to have oncolytic activity is Newcastle disease virus (NDV), an avian virus that is not pathogenic in humans. Although previous studies have successfully demonstrated the antitumor effects of NDV, these were thought to require direct injection of this virus into every tumor, thus greatly limiting its effectiveness against metastatic disease. Now, Zamarin and coauthors used mouse models of cancer with multiple tumor sites to demonstrate that NDV can be used even in the setting of distant spread of disease. Although the virus had to be injected into a tumor to have any effect, the subsequent tumor killing was not limited to the injected tumor. Additional masses that were distant in space and time, such as tumors implanted at different body sites and at later time points, were targeted by the immune system in animals that had been treated with NDV injection into the primary tumor. This immunostimulatory effect of NDV was particularly pronounced when the virotherapy was combined with immune checkpoint blockade by an anti–CTLA-4 antibody. The current study was performed in mice bearing tumors derived from established cell lines, and the findings will need to be confirmed in the setting of spontaneously arising metastatic tumors. Nevertheless, the results of this work raise the tantalizing possibility that two therapies known to be safe for human use could be combined and work with the immune system to eradicate tumors throughout the body. Preexisting lymphocytic infiltration of tumors is associated with superior prognostic outcomes in a variety of cancers. Recent studies also suggest that lymphocytic responses may identify patients more likely to benefit from therapies targeting immune checkpoints, suggesting that therapeutic efficacy of immune checkpoint blockade can be enhanced through strategies that induce tumor inflammation. To achieve this effect, we explored the immunotherapeutic potential of oncolytic Newcastle disease virus (NDV). We find that localized intratumoral therapy of B16 melanoma with NDV induces inflammatory responses, leading to lymphocytic infiltrates and antitumor effect in distant (nonvirally injected) tumors without distant virus spread. The inflammatory effect coincided with distant tumor infiltration with tumor-specific CD4+ and CD8+ T cells, which was dependent on the identity of the virus-injected tumor. Combination therapy with localized NDV and systemic CTLA-4 blockade led to rejection of preestablished distant tumors and protection from tumor rechallenge in poorly immunogenic tumor models, irrespective of tumor cell line sensitivity to NDV-mediated lysis. Therapeutic effect was associated with marked distant tumor infiltration with activated CD8+ and CD4+ effector but not regulatory T cells, and was dependent on CD8+ cells, natural killer cells, and type I interferon. Our findings demonstrate that localized therapy with oncolytic NDV induces inflammatory immune infiltrates in distant tumors, making them susceptible to systemic therapy with immunomodulatory antibodies, which provides a strong rationale for investigation of such combination therapies in the clinic.
Subfields: Genetics, Immunology, Oncology
View Paper: https://www.semanticscholar.org/paper/5f84b1647bf0580ffe30deaed25c7632683fea4c
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Citations in the corpus
- Oncolytic viruses: a new class of immunotherapy drugs (2015, background): “Preclinical studies have demonstrated the importance of tumour-specific CD8 + T cells in mediating tumour rejection with oncolytic viruses 13 .”
- Inhibiting DNA methylation causes an interferon response in cancer via dsRNA including endogenous retroviruses (2015, neutral): “Finally, our drug approach to upregulate viral defense signaling might be compared to the use of oncolytic viruses to induce inflammatory immune infiltrates at tumor sites to sensitize to immunomodulation (Zamarin et al., 2014).”
- From chemotherapy to biological therapy: A review of novel concepts to reduce the side effects of systemic cancer treatment (Review) (2018, neutral): “They can be applied into the tumor itself (i.e. intratumoral administration) (89), into the tissue environment (i.e. locoregional administration) or systemically.”
- Immune Checkpoint Targeting in Cancer Therapy: Towards Combination Strategies with Curative Potential (2015, background): “Finally, CTLA-4 could be combined with local delivery of irradiation, cryoablation, or an oncolytic virus to induce systemic tumor immunity and eradication of distant metastases (Zamarin et al., 2014; Waitz et al., 2012; Tang et al., 2014).”
- Cancer immunotherapy: the beginning of the end of cancer? (2016, background): “The coupling of agents that block the immune checkpoint with OVs has been viewed as a natural marriage demonstrated in preclinical models by combining Newcastle disease virus with antibodies against the CTLA-4 receptor [143].”