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Supplementary Figure S8 from A Phase II Window of Opportunity Study of Neoadjuvant PD-L1 versus PD-L1 plus CTLA-4 Blockade for Patients with Malignant Pleural Mesothelioma

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posted on 2023-04-01, 00:24 authored by Hyun-Sung Lee, Hee-Jin Jang, Maheshwari Ramineni, Daniel Y. Wang, Daniela Ramos, Jong Min Choi, Taylor Splawn, Monica Espinoza, Michelle Almarez, Leandria Hosey, Eunji Jo, Susan Hilsenbeck, Christopher I. Amos, R. Taylor Ripley, Bryan M. Burt

Supplementary Figure 8. Phenotyping of circulating CD8 and CD4 T cells in MPM patients that received neoadjuvant ICB

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Cancer Prevention and Research Institute of Texas (CPRIT)

National Cancer Institute (NCI)

United States Department of Health and Human Services

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AstraZeneca (AstraZeneca PLC)

National Center for Research Resources (NCRR)

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ARTICLE ABSTRACT

We report the results of a phase II, randomized, window-of-opportunity trial of neoadjuvant durvalumab versus durvalumab plus tremelimumab followed by surgery in patients with resectable malignant pleural mesothelioma (MPM; NCT02592551). The primary objective was alteration of the intratumoral CD8/regulatory T cell (Treg) ratio after combination immune checkpoint blockade (ICB) therapy. Secondary and exploratory objectives included other changes in the tumor microenvironment, survival, safety, tumor pathologic response (PR), and systemic immune responses. Nine patients received monotherapy and 11 received combination therapy. Seventeen of the 20 patients (85%) receiving ICB underwent planned thoracotomy. Both ICB regimens induced CD8 T-cell infiltration into MPM tumors but did not alter CD8/Treg ratios. At 34.1 months follow-up, patients receiving combination ICB had longer median overall survival (not reached) compared with those receiving monotherapy (14.0 months). Grade ≥3 immunotoxicity occurred in 8% of patients in the monotherapy group and 27% of patients in the combination group. Tumor PR occurred in 6 of 17 patients receiving ICB and thoracotomy (35.3%), among which major PR (>90% tumor regression) occurred in 2 (11.8%). Single-cell profiling of tumor, blood, and bone marrow revealed that combination ICB remodeled the immune contexture of MPM tumors; mobilized CD57+ effector memory T cells from the bone marrow to the circulation; and increased the formation of tertiary lymphoid structures in MPM tumors that were rich in CD57+ T cells. These data indicate that neoadjuvant durvalumab plus tremelimumab orchestrates de novo systemic immune responses that extend to the tumor microenvironment and correlate with favorable clinical outcomes.

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