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Radiation therapy enhances immunotherapy response in microsatellite stable colorectal and pancreatic adenocarcinoma in a phase II trial

Abstract

Overcoming intrinsic resistance to immune checkpoint blockade for microsatellite stable (MSS) colorectal cancer (CRC) and pancreatic ductal adenocarcinoma (PDAC) remains challenging. We conducted a single-arm, non-randomized, phase II trial (NCT03104439) combining radiation, ipilimumab and nivolumab to treat patients with metastatic MSS CRC (n = 40) and PDAC (n = 25) with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. The primary endpoint was disease control rate (DCR) by intention to treat. DCRs were 25% for CRC (ten of 40; 95% confidence interval (CI), 13–41%) and 20% for PDAC (five of 25; 95% CI, 7–41%). In the per-protocol analysis, defined as receipt of radiation, DCR was 37% (ten of 27; 95% CI, 19–58%) in CRC and 29% (five of 17; 95% CI, 10–56%) in PDAC. Pretreatment biopsies revealed low tumor mutational burden for all samples but higher numbers of natural killer (NK) cells and expression of the HERVK repeat RNA in patients with disease control. This study provides proof of concept of combining radiation with immune checkpoint blockade in immunotherapy-resistant cancers.

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Fig. 1: Consort diagram of enrolled patients.
Fig. 2: PFS and OS analyses.
Fig. 3: Response to treatment by change in measurable disease.
Fig. 4: TMB and exome mutations in patient biopsies.
Fig. 5: Coding gene RNA expression and immune cell differences in patient biopsies.
Fig. 6: Repeat RNA expression differences in patient biopsies.

Data availability

All RNA-seq data have been uploaded to NCBI GEO accession GSE179351, and WES data have been uploaded to NCBI dbGaP accession phs002545.v1.p1. All other data supporting the findings of this study are available from the corresponding author on reasonable request. Source data are provided with this paper.

Code availability

There was no custom code developed for this project, but all code and statistical packages used for the study will be provided upon request. For WES, the following software resources were used: the GATK b37 resource bundle (https://gatk.broadinstitute.org/hc/en-us/articles/360035890811-Resource-bundle), Picard 2.11.0 MarkDuplicates (http://broadinstitute.github.io/picard), bam-readcount software (0.8.0-unstable-6-963acab-dirty (commit 963acab-dirty); https://github.com/genome/bam-readcount) and SnpEff version 4.3t software. Additional details for WES can be found at https://github.com/dfhoyosg/17-021_RT_IpiNivo. For RNA-seq, the following software resources were used: STAR aligner (version 2.7.7), DESeq2 (version 1.32.0) and CIBERSORTx.

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Acknowledgements

We are grateful to S. Solovyov for his help in computational and statistical consultation for this project. This work was supported by the Colorectal Dream Team: Targeting Genomic, Metabolic, and Immunological Vulnerabilities of Colorectal Cancer (SU2C-AACR-DT22-17; A.R.P., R.B.C., D.T.T., T.S.H.); National Institutes of Health grants P50CA127003 (R.B.C.), R01CA240924 (D.T.T., B.D.G.) and U01CA228963 (D.T.T., B.D.G.); the Conquer Cancer Foundation ASCO CDA (A.R.P.); the SU2C and Lustgarten Foundation (D.P.R., B.D.G., D.T.T., T.S.H.); the Robert L. Fine Cancer Research Foundation (D.T.T.); and generous donations from D. and I. Kosowsky, S. and A. Irving and R. and M. Ettl.

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Authors and Affiliations

Authors

Contributions

Conceptualization, A.R.P., A.S., D.T.T. and T.S.H.; methodology, A.R.P., A.S., M.R., H.T., D.H., A.M., D.J.L., B.D.G., D.T.T. and T.S.H.; formal analysis, A.R.P., A.S., M.R., H.T., D.H., A.M., D.J.L., B.Y.Y., B.D.G. and D.T.T.; investigation, A.R.P., A.S., M.R., H.T., D.H., A.M., D.J.L., B.D.G., D.T.T. and T.S.H.; resources, A.R.P., J.N.A., J.W.C., J.Y.W., L.C.D., L.S.B., B.J.G., C.D.W., A.X.Z., L.G., R.D.N., J.S.D., N.H., D.P.R., R.B.C., B.D.G., D.T.T. and T.S.H.; data curation, A.R.P., M.R., D.H., E.E.v.S., B.E.F., L.E.M., L.L. and J.A.M.; writing (original draft), A.R.P., A.S., D.T.T. and T.S.H.; writing (review and editing), A.R.P., J.W.C., J.Y.W., A.M., E.E.v.S., D.P.R., B.Y.Y., R.B.C., B.D.G., D.T.T. and T.S.H.; visualization, A.R.P., A.S., M.R., H.T., A.M., D.J.L., B.Y.Y. and D.T.T.; supervision, A.R.P., A.S., D.T.T. and T.S.H.; project administration, A.R.P., A.S., E.E.v.S., L.L., D.T.T. and T.S.H.; funding acquisition, A.R.P., D.P.R., R.B.C., B.D.G., D.T.T. and T.S.H.

Corresponding authors

Correspondence to David T. Ting or Theodore S. Hong.

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Competing interests

A.R.P is a consultant and/or advisory board member for Eli Lilly, Natera, Checkmate Pharmaceuticals, Inivata and Pfizer; holds equity in C2I; serves on the DSMC for Roche; and has research funding from PureTech, PMV Pharmaceuticals, Plexxicon, Takeda, BMS, Novartis, Genentech, Guardant, Array and Eli Lilly. J.W.C. is an author for McGraw Hill and UpToDate. A.M. is a consultant and/or advisory board member for Third Rock Ventures, Asher Biotherapeutics, Abata Therapeutics, Rheos Medicines and Checkmate Pharmaceuticals; and holds equity in Asher Biotherapeutics and Abata Therapeutics, which are not related to this work. C.D.W. is a consultant and/or advisory board member for Ipsen, Bristol Myers Squibb and Eli Lilly; and receives research funding from Deciphera, EMD Serono, Ability Pharmaceuticals, Actuate Therapeutics and Novartis. A.X.Z. is a consultant and/or advisory board member for AstraZeneca, Bayer, Bristol Myers Squibb, Eisai, Eli Lilly, Exelixis, Merck, Novartis and Roche–Genentech; and received research funding from Bayer, Bristol Myers Squibb, Eli Lilly, Merck and Novartis. L.G. is a consultant and/or advisory board member for Alentis, AstraZeneca, Exelixis, Sirtex, Genetech, Genentech, H3 Biomedicine, Incyte, QED Therapeutics, Servier and Taiho; and has research funding from Adaptimmune, Bayer, Bristol Myers Squibb, Eisai, Leap Therapeutics, Loxo Oncology, MacroGenics, Merck, Novartis, NuCana, Relay Therapeutics, Genentech, H3 Biomedicine, Incyte, QED Therapeutics, Servier and Taiho. N.H. is an advisor and equity holder for Related Sciences, holds equity in BioNTech and receives research funding from Bristol Meyers Squibb. D.P.R. is a consultant and/or advisory board member for MPM Capital, Gritstone Oncology, Oncorus, Maverick Therapeutics, 28/7 Therapeutics, Thrive–Exact Sciences; has equity in MPM Capital, Acworth Pharmaceuticals and Thrive–Exact Sciences; is a legal consultant for Boeringer Ingelheim; and serves as an author for Johns Hopkins University Press, UpToDate and McGraw Hill. R.B.C. is a consultant and/or advisory board member for AbbVie, Amgen, Array Biopharma–Pfizer, Asana BioSciences, Astex Pharmaceuticals, AstraZeneca, Avidity Biosciences, BMS, C4 Therapeutics, Chugai, Elicio, Erasca, Fog Pharma, Genentech, Guardant Health, Ipsen, Kinnate Biopharma, Loxo, Merrimack, Mirati Therapeutics, Natera, Navire, N-of-One–Qiagen, Novartis, nRichDx, Remix Therapeutics, Revolution Medicines, Roche, Roivant, Shionogi, Shire, Spectrum Pharmaceuticals, Symphogen, Tango Therapeutics, Taiho, Warp Drive Bio and Zikani Therapeutics; holds equity in Avidity Biosciences, C4 Therapeutics, Erasca, Kinnate Biopharma, nRichDx, Remix Therapeutics and Revolution Medicines; and has research funding from Asana, AstraZeneca, Lilly, Novartis and Sanofi. B.D.G. is a consultant for or received honoraria from Darwin Health, Merck, PMV Pharma, ROME Therapeutics, Merck, Bristol Meyers Squibb and Chugai Pharmaceuticals; is a founder and has equity in ROME Therapeutics; and has research funding from Bristol Meyers Squibb. D.T.T. is a consultant and/or advisory board member for Pfizer, ROME Therapeutics, Merrimack Pharmaceuticals, Ventana Roche, NanoString Technologies, Foundation Medicine, EMD MilliporeSigma and Third Rock Ventures, which are not related to this work; is a founder and has equity in PanTher Therapeutics, ROME Therapeutics and TellBio, which are not related to this work; and has research funding from ACD-Biotechne, PureTech Health and Ribon Therapeutics, which was not used in this work. D.T.T.‘s interests were reviewed and are managed by Massachusetts General Hospital and Mass General Brigham in accordance with their conflict-of-interest policies. T.S.H. is consultant and/or advisory board member for Merck, EMD Serono, PanTher Therapeutics, Boston Scientific, Novocure and Synthetic Biologics; and has research funding from Taiho, AstraZeneca, Bristol Myers Squibb, IntraOp, Puma and Ipsen. All other authors have no disclosures.

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Extended data

Extended Data Fig. 1 Tumor Mutational Burden of all samples between responders and progressive disease.

Mutations per megabase shown with mean (bar) for patients with SD/PR/CR (n = 5) or PD (n = 12). Unpaired 2-tailed t-test p = 0.7738 was not significant.

Source data

Extended Data Fig. 2 Expression analysis of paired pre-XRT and post-XRT biopsy samples.

a, Heatmap of cell RNA-seq expression of myCAF and iCAF in pre-XRT and post-XRT biopsies from patients with SD/PR/CR (n = 3) and PD (n = 5). Scale −2 to 2 represents minimum and maximum values within the heatmap. b, Heatmap of cell percentage of immune cells in pre-XRT and post-XRT biopsies from patients with SD/PR/CR (n = 3) and PD (n = 5).

Source data

Supplementary information

Reporting Summary

Supplementary Tables

Supplementary Tables 1–12.

Source data

Source Data Fig. 2

Survival data for Kaplan–Meier curves.

Source Data Fig. 3

Computed tomography scan response data.

Source Data Fig. 4

TMB at each time point by patient (mutations per Mb).

Source Data Fig. 5

Expression heatmap of EMT genes in log2 (RPM).

Source Data Fig. 6

Fold change of pre- and post-treatment biopsies for selected repeat RNA species.

Source Data Extended Data Fig. 1

TMB (mutations per Mb).

Source Data Extended Data Fig. 2

Cell type composition from RNA-seq deconvolution.

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Parikh, A.R., Szabolcs, A., Allen, J.N. et al. Radiation therapy enhances immunotherapy response in microsatellite stable colorectal and pancreatic adenocarcinoma in a phase II trial. Nat Cancer 2, 1124–1135 (2021). https://doi.org/10.1038/s43018-021-00269-7

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