Abstract PR11: CX3CR1+CD8+ T-cells are responsible to the clinical benefit of chemoimmunotherapy in metastatic melanoma patients after disease progression on PD-1 blockade

• Published in: Cancer immunology research 2019-02, Vol.7 (2_Supplement), p.PR11-PR11
• Main Authors: Yan, Yiyi, Dong, Haidong, Dronca, Roxana, Markovic, Svetomir
• Format: Article
• Language: English
• ISSN: 2326-6066; 2326-6074
• DOI: 10.1158/2326-6074.CRICIMTEATIAACR18-PR11

Background: Clinical management of metastatic melanoma (MM) after PD-1 blockade failure remains a challenge and lacks a standard of care. Immunotherapy or chemotherapy alone provides limited benefit in this setting. Chemo-immunotherapy (CIT) combinations have demonstrated favorable efficacy and safety profiles in lung cancer patients. Our preclinical study in MM has shown that the addition of chemotherapy to PD-1 blockade can reshape a subset of therapy-responsive CD8+ T-cells with resultant enhanced antitumor activities, suggesting the potential clinical benefits of CIT in MM patients whose disease have progressed after anti-PD-1 therapy. Further understanding of the clinical benefits and immunoregulatory mechanisms of CIT in this setting is crucial for the development of optimal combinatorial chemo-immunotherapeutic strategies to improve clinical outcomes in patients with advanced cancer. Methods: MM patients (n=22) who have failed PD-1 blockade therapy were subsequently treated with CIT (paclitaxel and carboplatin in combination with pembrolizumab). The overall survival (OS), objective response rate (ORR), time-to-next therapy (TTNT), and toxicities were assessed. Using peripheral blood (PB) from MM patients, the phenotypic and functional changes induced by chemotherapy in therapy-responsive T-cells, in the setting of anti-PD1 therapy, were examined. The immunoregulatory effects of CIT were also examined in melanoma mouse model. Results: MM patients who have received subsequent CIT had a median OS of 5 years (95% CI: 2-NR) (median follow up of 3.9 years), with ORR of 61% (CR of 23%). The median TTNT was 8 months (95% CI: 6-15). No additional toxicities were identified. CX3CR1+CD8+ therapy-responsive T-cells are low in MM patients who have failed to respond to anti-PD-1 monotherapy. However, in MM patients who responded to subsequent CIT, this subset of therapy-responsive T-cells survived the chemotherapy with increased frequency and enhanced function. The clinical benefit of CIT is only observed in CX3CR1 wild type mice, not in KO mice, and ongoing PD-1 blockade is necessary to improve its anti-tumor activities. Conclusion: In MM patients who have failed anti-PD-1 therapy, the chemo-immunotherapy combination showed favorable clinical outcomes and an acceptable toxicity profile. CX3CR1+ CD8+ effector T-cells are responsible for the clinical benefit of CIT. This novel therapy-responsive population underlies the key cellular and molecular immunoregulatory