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

Details

• Alternative Title:
  Clin Cancer Res
• Personal Author:
  Lee, Hyun-Sung ; Jang, Hee-Jin ; Ramineni, Maheshwari ; Wang, Daniel Y. ; Ramos, Daniela ; Choi, Jong Min ; Splawn, Taylor ; Espinoza, Monica ; Almarez, Michelle ; Hosey, Leandria ; Jo, Eunji ; Hilsenbeck, Susan ; Amos, Christopher I. ; Ripley, R. Taylor ; Burt, Bryan M.
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• Description:
  Purpose: ; We report the results of a phase 2, randomized, window-of-opportunity trial of neoadjuvant durvalumab versus durvalumab plus tremelimumab followed by surgery in patients with resectable malignant pleural mesothelioma (MPM)(NCT02592551). ; Patients and Methods: ; The primary objective was alteration of the intratumoral CD8/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. ; Results: ; 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 to 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. ; Conclusions: ; 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.
• Subjects:
  • Humans
  • B7-H1 Antigen
  • CTLA-4 Antigen
  • Lung Neoplasms
  • Mesothelioma
  • Mesothelioma, Malignant
  • Neoadjuvant Therapy
  • Pleural Neoplasms
  • Tumor Microenvironment
• Keywords:
  • malignant pleural mesothelioma
  • neoadjuvant immunotherapy
  • immune checkpoint blockade
  • tertiary lymphoid structures
  • systems onco-immunology
  • Naltrexone
  • Buprenorphine
  • Methadone
  • Mortality
  • Treatment
• Source:
  Clin Cancer Res. 29(3):548-559
• Pubmed ID:
  36469573
• Pubmed Central ID:
  PMC9898180
• Document Type:
  Journal Article
• Funding:
  R37 CA248478/CA/NCI NIH HHSUnited States/ ; P30 CA125123/CA/NCI NIH HHSUnited States/ ; U24 OH009077/OH/NIOSH CDC HHSUnited States/ ; R50 CA243707/CA/NCI NIH HHSUnited States/ ; S10 RR024574/RR/NCRR NIH HHSUnited States/
• Volume:
  29
• Issue:
  3
• Download URL:
  https://stacks.cdc.gov/view/cdc/149758/cdc_149758_DS1.pdf
• File Type:
  [PDF - 4.39 MB]
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha-512:206c57e49dbdd708d9a44155fdf5c5e3ed4bad0bae76bebef77d37ffac2c717f9ed18be5f75c5a0aac38a6d9e49b791bc8ab602f3699815501e769f4a806de34