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Combination Therapy With Reovirus and Anti-PD-1 Blockade Controls Tumor Growth Through Innate and Adaptive Immune
Karishma Rajani1, Christopher Parrish2, Timothy Kottke1
1Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA.
Abstract:
Oncolytic reovirus can be delivered both systemically and intratumorally, in both preclinical models and in early phase clinical trials. Reovirus has direct oncolytic activity against a variety of tumor types and antitumor activity is directly associated with immune activation by virus replication in tumors. Immune mechanisms of therapy include both innate immune activation against virally infected tumor cells, and the generation of adaptive antitumor immune responses as a result of in vivo priming against tumor-associated antigens. We tested the combination of local oncolytic reovirus therapy with systemic immune checkpoint inhibition. We show that treatment of subcutaneous B16 melanomas with a combination of intravenous (i.v.) anti-PD-1 antibody and intratumoral (i.t.) reovirus significantly enhanced survival of mice compared to i.t. reovirus (P < 0.01) or anti-PD-1 therapy alone. In vitro immune analysis demonstrated that checkpoint inhibition improved the ability of NK cells to kill reovirus-infected tumor cells, reduced T(reg) activity, and increased the adaptive CD8(+) T-cell-dependent antitumor T-cell response. PD-1 blockade also enhanced the antiviral immune response but through effector mechanisms which overlapped with but also differed from those affecting the antitumor response. Therefore, combination with checkpoint inhibition represents a readily translatable next step in the clinical development of reovirus viroimmunotherapy.
Insights
Combining oncolytic reovirus therapy with immune checkpoint inhibition, specifically anti-PD-1 antibodies, significantly improved survival in preclinical melanoma models by enhancing immune cell activity against tumors.
Area of Science:
- Oncology
- Immunology
- Virology
Background:
- Oncolytic reovirus demonstrates direct tumor cell killing and immune activation.
- Therapeutic mechanisms involve innate immune activation and adaptive antitumor responses.
- Reovirus is administered systemically or intratumorally in preclinical and clinical settings.
Purpose of the Study:
- To evaluate the combination of intratumoral reovirus and systemic anti-PD-1 immune checkpoint inhibition.
- To assess the impact of this combination on survival and immune responses in a preclinical melanoma model.
Main Methods:
- Subcutaneous B16 melanomas were treated with intratumoral reovirus, intravenous anti-PD-1 antibody, or the combination.
- Survival rates were compared between treatment groups.
- In vitro immune analyses were performed to investigate the effects on NK cells, regulatory T cells (Tregs), and CD8+ T cells.
Main Results:
- Combination therapy significantly enhanced mouse survival compared to either monotherapy (P < 0.01).
- Immune analysis showed improved NK cell cytotoxicity against reovirus-infected tumor cells.
- Checkpoint inhibition reduced Treg activity and boosted CD8+ T-cell-dependent antitumor responses.
Conclusions:
- Combination of oncolytic reovirus and immune checkpoint inhibition is a promising strategy for cancer therapy.
- This combination enhances both innate and adaptive immune responses against tumors.
- Further clinical development of reovirus viroimmunotherapy combined with checkpoint inhibitors is warranted.
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