Although surgical resection is a reliable treatment for localized melanoma, treatment options for metastatic melanoma are limited. Melanoma Brain metastasis (MBM) is a major clinical problem in patients with advanced melanoma, and the incidence of brain metastasis is increasing every year. Thus, there is a significant unmet need for effective therapies for metastatic melanoma and MBM patients. Agonistic CD40 antibodies generate strong tumor specific CD8 T cell response and anti-tumor activity; however systemic anti-CD40 therapy has been associated with cytokine release syndrome and liver toxicity. We studied the anti-melanoma activity and mechanism of action of a non-replicating adenovirus encoding a CD40-targeting chimeric immunostimulatory protein (ISF35) by local intratumoral delivery approach to treat local and distant melanoma. Mice bearing established B16 melanomas on both right and left flanks or on right flank and in brain were treated intratumorally with ISF35 or rAd.empty to the right flank tumor and received anti-PD1 plus anti-CTLA-4 systemically. Anti-tumor effects of mono or combination therapies were determined by mice survival and tumor growth measurement. The mechanistic contribution of immune cells to this therapy was determined by using antibody blockades. Immune cell infiltrates in tumor and expression of activation markers on these cells were analyzed by flow cytometry. Intratumoral administration of ISF35 generates systemic anti-tumor immunity mediates by CD8 T cells and suppress both injected and distant uninjected wild-type B16.F10 melanomas. However, tumors did not completely regress after therapy. When combined with checkpoint inhibitors, ISF35 generates synergistic systemic anti-melanoma immunity that eradicates both injected and uninjected distant subcutaneous melanoma and uninjected brain melanoma with 40% of mice cured. The systemic anti-tumor activity of ISF35/anti-PD-1/anti-CTLA-4 was associated with greater production of melanoma-specific CD8 T cells with an activated phenotype. Immunotherapy based on intratumoral CD40 activation is potentiated by PD-1 and CTLA-4 blockade and this combination generates functional and long-lasting anti-tumor CD8 T cell immunity that systemically suppresses melanoma metastases. This approach will be a better option for treatment of patients with metastatic melanoma that does not respond to checkpoint blockage monotherapy.
Citation Format: Manisha Singh, Christina Vianden, Adi Diab, Patrick Hwu, Willem W. Overwijk. Intratumoral CD40 activation and checkpoint blockade induces systemic anti-melanoma immunity that eradicates disseminated tumors [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr B022.
- ©2016 American Association for Cancer Research.