Sungjune Kim, MD, PhD, PI ? PA-14-046 (K08 Resubmission) 11/12/15 Title: Epigenetic modulation of immune tolerance by ionizing radiation and chemotherapy Cancer immunotherapy represents a paradigm shift in the management of cancer. Recent successes with antibody directed therapies for immune modulators CTLA4 and PD1/PDL-1 have altered the landscape of systemic therapy for melanoma and other solid cancers. While felt to be the most immunogenic among cancers, melanoma exhibits a wide spectrum of immune tolerance mechanisms, and a majority of patients fail to elicit clinically significant antitumor immune responses. The response rates for other solid cancers are even lower. Therefore, developing modalities to enhance immunotherapy, such as radiation therapy (XRT) or conventional chemotherapy, represent an active area of investigation. Because most cancer patients receive XRT or chemotherapy at some point in their disease process, harnessing the immunogenic potential of these modalities is of pivotal importance. Our preliminary clinical and preclinical data suggest cytotoxic therapy induce a net positive impact on immune activation, but limited by tolerogenic mechanisms also evoked. Interestingly, cytotoxic therapy induces a profound up-regulation of HDAC6, a positive regulator of tolerogenic cytokine IL-10 mediating immune tolerance. HDAC6 inhibition resulted in radiosensitization and enhanced immunogenicity by cytotoxic therapy. Based on these observations, we propose to overcome the tolerogenic effects of HDAC6 induction by cytotoxic therapy. The central hypotheses to be tested in this grant are whether manipulation of HDAC6 augments therapeutic efficacy and immunogenicity of cytotoxic therapy in melanoma. This research will translate into clinical trials testing HDAC6-specific inhibitors as a novel class of therapeutic agents to sensitize melanoma for cytotoxic therapy alone, or in combination with immunotherapy. The proof in concept defined in melanoma will be applicable to other cancers.
Sungjune Kim, MD, PhD, PI ? PA-14-046 (K08 Resubmission) 11/12/15 Title: Epigenetic modulation of immune tolerance by ionizing radiation and chemotherapy Recent focus on epigenetic tolerance mechanisms in melanoma identifies histone deacetylase 6 (HDAC6) as a central epigenetic modulator for antigen presentation and IL-10 production inducing a tolerogenic tumor microenvironment. Interestingly, XRT and chemotherapy induces up-regulation of HDAC6 in murine and human melanoma cells. Pharmacologic and genetic disruption of HDAC6 enhances antigen presentation by XRT and chemotherapy. HDAC6 is identified as a novel mediator of immune tolerance mechanisms by XRT and chemotherapy, and thus a promising therapeutic target. With this research proposal, we aim to further characterize the tolerogenic effects of HDAC6 induction by XRT and chemotherapy and investigate whether these findings may be translated into a clinical trial ultimately to enhance therapeutic efficacy and immunogenicity of XRT and chemotherapy via HDAC6 manipulation in clinic.
| Abuodeh, Yazan; Ahmed, Kamran; Echevarria, Michelle et al. (2017) Priming radioimmunotherapy with external beam radiation in patients with relapsed low grade non-Hodgkin lymphoma. Ther Adv Hematol 8:129-138 |
