A randomized trial of combined PD-L1 and CTLA-4 inhibition with targeted low-dose or hypofractionated radiation for patients with metastatic colorectal cancer

Arta M. Monjazeb, Anita Giobbie-Hurder, Ana Lako, Emily M. Thrash, Ryan C. Brennick, Katrina Z. Kao, Claire Manuszak, Ryan D. Gentzler, Anteneh Tesfaye, Salma K. Jabbour, Olatunji B. Alese, Osama E. Rahma, James M. Cleary, Elad Sharon, Harvey J. Mamon, May Cho, Howard Streicher, Helen X. Chen, Mansoor M. Ahmed, Adrian Mariño-EnríquezSeunghee Kim-Schulze, Sacha Gnjatic, Emanual Maverakis, Alina I. Marusina, Alexander A. Merleev, Mariano Severgnini, Kathleen L. Pfaff, James Lindsay, Jason L. Weirather, Srinika Ranasinghe, Alexander Spektor, Scott J. Rodig, Stephen F. Hodi, Jonathan D. Schoenfeld

Research output: Contribution to journalArticlepeer-review

Abstract

Purpose: Prospective human data are lacking regarding safety, efficacy, and immunologic impacts of different radiation doses administered with combined PD-L1/CTLA-4 blockade. Patients and Methods: We performed a multicenter phase II study randomly assigning patients with metastatic microsatellite stable colorectal cancer to repeated low-dose fractionated radiation (LDFRT) or hypofractionated radiation (HFRT) with PD-L1/ CTLA-4 inhibition. The primary endpoint was response outside the radiation field. Correlative samples were analyzed using multiplex immunofluorescence (IF), IHC, RNA/T-cell receptor (TCR) sequencing, cytometry by time-of-flight (CyTOF), and Olink. Results: Eighteen patients were evaluable for response. Median lines of prior therapy were four (range, 1-7). Sixteen patients demonstrated toxicity potentially related to treatment (84%), and 8 patients had grade 3-4 toxicity (42%). Best response was stable disease in 1 patient with out-of-field tumor shrinkage. Median overall survival was 3.8 months (90% confidence interval, 2.3- 5.7 months). Correlative IF and RNA sequencing (RNA-seq) revealed increased infiltration of CD8+ and CD8+/PD-1+/Ki- 67+ T cells in the radiation field after HFRT. LDFRT increased foci of micronuclei/primary nuclear rupture in two subjects. CyTOF and RNA-seq demonstrated significant declines in multiple circulating immune populations, particularly in patients receiving HFRT. TCR sequencing revealed treatment-associated changes in T-cell repertoire in the tumor and peripheral blood. Conclusions:Wedemonstrate the feasibility and safety of adding LDFRT and HFRT to PD-L1/CTLA-4 blockade. Although the best response of stable disease does not support the use of concurrent PD-L1/CTLA-4 inhibition with HFRT or LDFRT in this population, biomarkers provide support that both LDFRT and HFRT impact the local immune microenvironment and systemic immunogenicity that can help guide future studies.

Original languageEnglish (US)
Pages (from-to)2470-2480
Number of pages11
JournalClinical Cancer Research
Volume27
Issue number9
DOIs
StatePublished - May 1 2021

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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