Abstract 4988: CD 137 agonists as an adjunct to immune checkpoint inhibitors to overcome resistance in melanoma
| Autor: | Sreedevi Danturti, Lena Mayer, Christina Twyman Saint Victor |
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| Rok vydání: | 2019 |
| Předmět: | |
| Zdroj: | Cancer Research. 79:4988-4988 |
| ISSN: | 1538-7445 0008-5472 |
| DOI: | 10.1158/1538-7445.am2019-4988 |
| Popis: | Background: Melanoma is currently the fifth most common cancer in men and sixth most common in women with an estimate of 9,320 deaths from the disease in the United States. Anti-PD1, an immune checkpoint inhibitor, is FDA approved to treat metastatic melanoma with durable responses observed in 53% of patients. Studies suggest that combining therapies (e.g. immune checkpoint inhibitors, radiation therapy, and/or agonist antibodies) can be more effective than monotherapy. CD137 is expressed on a variety of cell populations including T cells, dendritic cells (DCs) and macrophages. CD137 agonists have proved effective in multiple murine tumor models and have had modest responses in early clinical trials. We hypothesize that CD137 agonists can augment the anti-PD1 anti-tumor immune response resulting in improved overall survival and decreased tumor burden in melanoma. Methods: 499 melanoma cells, which were derived from B16-F10, are implanted on both flanks of C57BL6 mice. The mice are treated with anti-CD137 and/or anti-PD1 on day 10, 13 and 16 post-implantation. The anti-tumor response is assessed by both overall survival and tumor burden. Tumors are harvested on day 19 for protein, transcriptomic and immune profiling. Results: Monotherapy with either anti-CD137 agonists or anti-PD1 antagonists increases the overall survival by 8 days; whereas, combination therapy results in an increase of 25 days. To investigate the mechanisms of response and resistance to combination therapy, tumors were harvested and assessed via a proteomic array that identified 36 proteins that were upregulated in the non-responders. Transcriptomic profiling of these tumors using Nanostring IO 360 corroborated these findings and identified both the myeloid the T cell immune populations are upregulated in responders. Conclusions: These results suggest a dual role for both the innate and adaptive immune response in treating melanoma. By understanding the mechanism of response and further characterization we can further best apply the combination therapy to overcome resistance after immunotherapy. Note: This abstract was not presented at the meeting. Citation Format: Sreedevi Danturti, Lena Mayer, Christina Twyman Saint Victor. CD 137 agonists as an adjunct to immune checkpoint inhibitors to overcome resistance in melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4988. |
| Databáze: | OpenAIRE |
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