Abstract
Over 500 clinical trials are investigating combination radiotherapy and immune checkpoint blockade (ICB) as cancer treatments; however, the majority of trials have found no positive interaction. Here we perform a comprehensive molecular analysis of a randomized phase I clinical trial of patients with non-small cell lung cancer (NSCLC) treated with concurrent or sequential ablative radiotherapy and ICB. We show that concurrent treatment is superior to sequential treatment in augmenting local and distant tumor responses and in improving overall survival in a subset of patients with immunologically cold, highly aneuploid tumors, but not in those with less aneuploid tumors. In addition, radiotherapy alone decreases intratumoral cytotoxic T cell and adaptive immune signatures, whereas radiotherapy and ICB upregulates key immune pathways. Our findings challenge the prevailing paradigm that local ablative radiotherapy beneficially stimulates the immune response. We propose the use of tumor aneuploidy as a biomarker and therapeutic target in personalizing treatment approaches for patients with NSCLC treated with radiotherapy and ICB.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1498-1512 |
| Number of pages | 15 |
| Journal | Nature Cancer |
| Volume | 3 |
| Issue number | 12 |
| DOIs | |
| State | Published - Dec 2022 |
Funding
We would like to thank A. Taylor, R. Beroukhim, Y. Li, A. Cherniack, M. Kaufman and A. Arina for their guidance and advice regarding genomic, transcriptomic and immunologic analyses. This work was supported by the Ludwig Cancer Research Foundation (S.P.P. and R.R.W.), a Career Development Award from the LUNGevity Foundation (S.P.P.), an Ullman Scholarship in Translational Cancer Immunology from the University of Chicago Comprehensive Cancer Center (UCCCC) (S.P.P.), a Cancer Spotlight Grant (S.P.P.) from the UCCCC, a Fight Against Cancer Grant from the United-4 A Cure Foundation (S.P.P.), an NIH NCI-SOAR Grant 1R25CA240134-01 (L.F.S.), NSF2016307 (M.C.), R01 grants GM126553 and HG011883 (M.C.), a Sloan Research Foundation fellowship (M.C.) and an NCI CCSG grant (Y.Z.). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. S.M. is an advisor for Olympus America, Medtronic, Johnson & Johnson, ERBE, Boston Scientific, Cook and Pinnacle Biologics. E.E.V. has served as an advisor for AbbVie, AstraZeneca, BeiGene, BioNTech, Eli Lilly, ED Serono, Genentech/Roche, GlaxoSmithKline, Merck and Novartis. C.M.B. reports serving in a consulting or advisory role for AbbVie, AstraZeneca, Genentech, Pfizer, Seattle Genetics and Takeda. J.D.P. serves as an advisor for AstraZeneca, Takeda and Genentech, and receives research funding from Bristol Myers Squibb (institution). M.D. reports personal fees from Roche Sequencing Solutions; grants and personal fees from Astra-Zeneca, Illumina and Genentech; personal fees from Novartis, Gritstone Oncology, BioNTech and Boehringer Ingelheim; grants from Varian Medical Systems; other support from CiberMed Foresight Diagnostics; a patent for ctDNA detection issued and licensed to Roche; and patents for ctDNA detection pending and licensed to Foresight Diagnostics. R.R.W. reports having stock and other ownership interests in Boost Therapeutics, ImmVira, Reflexion Pharmaceuticals, Coordination Pharmaceuticals, Magi Therapeutics and Oncosenescence; serving in a consulting or advisory role for Aettis, AstraZeneca, Coordination Pharmaceuticals, Genus, Merck Serono, NanoProteagen, NKMax America, Shuttle Pharmaceuticals and Highlight Therapeutics, S.L. holds research grants with Varian and Regeneron, and receives compensation (including cost of travel and accommodations and other expenses) from AstraZeneca, Boehringer Ingelheim and Merck Serono. S.J.C. reports participating in the advisory boards for Genentech and AstraZeneca; receiving research support from Bristol Myers Squibb, Merck, EMD Serono and AstraZeneca; and having his spouse who works for Astellas. S.P.P. has patents outside of the submitted work. The remaining authors declare no competing interests.
ASJC Scopus subject areas
- Oncology
- Cancer Research
