CTLA4 and CD47 combinational therapy to extend survival in melanoma

• Published in: Journal of clinical oncology Vol. 35; no. 15_suppl; p. e21025
• Main Authors: Schwartz, Anthony L., Nath, Pulak, Lessey-Morillon, Elizabeth, Ridnour, Lisa, Allgaeuer, Michael, Roberts, David
• Format: Journal Article
• Language: English
• Published: 20.05.2017
• ISSN: 0732-183X; 1527-7755
• DOI: 10.1200/JCO.2017.35.15_suppl.e21025

Abstract only e21025 Background: Irradiation (IR) combined with chemotherapy is the post-surgical standard of care treatment for melanoma, but metastasis still results in high mortality rates. Immune checkpoint inhibitors such as cytotoxic T-lymphocyte antigen-4 (CTLA4) have proven effective for immunotherapy of melanoma. CTLA-4 is up-regulated post-T cell activation and blockade enhances tumor responses in immunocompetent rodents and humans. Trials suggest that combinations of immune checkpoint inhibitors are more efficacious than single agents, but tumors remain resistant. We are investigating CD47 blockade for the treatment of cancer. CD47 is frequently elevated in cancers and serves as an inhibitory receptor for thrombospondin-1 on immune cells in the tumor stroma. CD47 blockade on CD8 T or tumor cells significantly enhances immune-targeted tumor cell killing post-IR compared to IR alone. Here we explore the potential for antisense CD47 and anti-CTLA4 therapy alone or in combination with IR using a syngeneic mouse melanoma model. Methods: C57BL/6 mice were inoculated with 1x10 6 B16F10 melanoma cells in the hind limb and treated with 10 Gy IR combined with CTLA4 blocking antibody, CD47 translational blocking morpholino, or the combination of CTLA4/CD47 therapies. Granzyme B along with CD4/CD8 T cell infiltration were examined in tumors. Histology was evaluated for CD3 and necrosis. Results: The combination of CD47/CTLA4 with IR significantly increased survival by 25% compared to IR/CTLA4 alone at 50 days. Granzyme B expression was significantly increased in IR mice with CTLA4/CD47 combination, which correlated with infiltration of CD8+ T cells and a concomitant decrease in Gr1+CD11b suppressor cells compared to controls. In non-IR tumors, histology revealed minimal necrosis, while all IR groups showed increased necrosis. Tumor IR in combination with CTLA4 or CD47 increased immune cell infiltration. However, the combination of IR with CTLA4/CD47 showed widespread necrosis. All groups treated with the CD47 exhibited focal hemorrhage, which was more extensive when combined with CTLA4. Conclusions: Results herein suggest IR combined CTLA4/CD47 checkpoint blockade provides a survival benefit by activating a beneficial adaptive immune response.