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 language | English (US) |
|---|---|
| Pages (from-to) | 2470-2480 |
| Number of pages | 11 |
| Journal | Clinical Cancer Research |
| Volume | 27 |
| Issue number | 9 |
| DOIs | |
| State | Published - May 1 2021 |
ASJC Scopus subject areas
- Oncology
- Cancer Research
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A randomized trial of combined PD-L1 and CTLA-4 inhibition with targeted low-dose or hypofractionated radiation for patients with metastatic colorectal cancer. / Monjazeb, Arta M.; Giobbie-Hurder, Anita; Lako, Ana; Thrash, Emily M.; Brennick, Ryan C.; Kao, Katrina Z.; Manuszak, Claire; Gentzler, Ryan D.; Tesfaye, Anteneh; Jabbour, Salma K.; Alese, Olatunji B.; Rahma, Osama E.; Cleary, James M.; Sharon, Elad; Mamon, Harvey J.; Cho, May; Streicher, Howard; Chen, Helen X.; Ahmed, Mansoor M.; Mariño-Enríquez, Adrian; Kim-Schulze, Seunghee; Gnjatic, Sacha; Maverakis, Emanual; Marusina, Alina I.; Merleev, Alexander A.; Severgnini, Mariano; Pfaff, Kathleen L.; Lindsay, James; Weirather, Jason L.; Ranasinghe, Srinika; Spektor, Alexander; Rodig, Scott J.; Hodi, Stephen F.; Schoenfeld, Jonathan D.
In: Clinical Cancer Research, Vol. 27, No. 9, 01.05.2021, p. 2470-2480.Research output: Contribution to journal › Article › peer-review
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TY - JOUR
T1 - A randomized trial of combined PD-L1 and CTLA-4 inhibition with targeted low-dose or hypofractionated radiation for patients with metastatic colorectal cancer
AU - Monjazeb, Arta M.
AU - Giobbie-Hurder, Anita
AU - Lako, Ana
AU - Thrash, Emily M.
AU - Brennick, Ryan C.
AU - Kao, Katrina Z.
AU - Manuszak, Claire
AU - Gentzler, Ryan D.
AU - Tesfaye, Anteneh
AU - Jabbour, Salma K.
AU - Alese, Olatunji B.
AU - Rahma, Osama E.
AU - Cleary, James M.
AU - Sharon, Elad
AU - Mamon, Harvey J.
AU - Cho, May
AU - Streicher, Howard
AU - Chen, Helen X.
AU - Ahmed, Mansoor M.
AU - Mariño-Enríquez, Adrian
AU - Kim-Schulze, Seunghee
AU - Gnjatic, Sacha
AU - Maverakis, Emanual
AU - Marusina, Alina I.
AU - Merleev, Alexander A.
AU - Severgnini, Mariano
AU - Pfaff, Kathleen L.
AU - Lindsay, James
AU - Weirather, Jason L.
AU - Ranasinghe, Srinika
AU - Spektor, Alexander
AU - Rodig, Scott J.
AU - Hodi, Stephen F.
AU - Schoenfeld, Jonathan D.
N1 - Funding Information: The trial was conducted under auspices of the Experimental Therapeutics Clinical Trials Network and funded by UM1 CA186709 (to principal investigator, Geoffrey Shapiro), a Biomarker Supplement to UM1 CA186709 (to project leaders, J.D. Schoenfeld, S.J. Rodig, and S.F. Hodi), and Center for Immuno-Oncology, Dana-Farber Cancer Institute. Scientific and financial support for the CIMAC-CIDC Network was provided through the NCI Cooperative Agreements U24CA224319 (to the Icahn School of Medicine at Mount Sinai CIMAC), U24CA224331 (to the Dana-Farber Cancer Institute CIMAC), and U24CA224316 (to the CIDC at Dana-Farber Cancer Institute). Additional support was made possible through the NCI CTIMS Contract HHSN261201600002C. Scientific and financial support for the PACT project was made possible through funding support provided to the FNIH by AbbVie Inc., Amgen Inc., Boehringer-Ingelheim Pharma GmbH & Co. KG., Bristol-Myers Squibb, Celgene Corporation, Genentech Inc, Gilead, GlaxoSmithKline plc, Janssen Pharmaceutical Companies of Johnson & Johnson, Novartis Institutes for Biomedical Research, Pfizer Inc., and Sanofi. The CIMAC-CIDC website is found at https://cimac-network. org/. We acknowledge Janice Russell and all participating patients and sites. We would also like to thank John Daley and his team at the Longwood Medical Area CyTOF Core at DFCI for their technical assistance. Funding Information: A.M. Monjazeb reports grants from NIH during the conduct of the study, as well as grants, personal fees, and nonfinancial support from Merck; grants and personal fees from BMS and Incyte; personal fees from AstraZeneca and Zosano; personal fees and nonfinancial support from Dynavax; grants from Genentech and EMD Serono; grants and nonfinancial support from Transgene; and other from Multiplex Thera outside the submitted work. A. Lako reports personal fees from Bristol Myers Squibb outside the submitted work. E.M. Thrash reports personal fees from Fluidigm Corporation during the conduct of the study and employment with Fluidigm Corporation. R.D. Gentzler reports grants and nonfinancial support from NCI during the conduct of the study, as well as grants and personal fees from Pfizer; personal fees from AstraZeneca, BluePrint Medicines, Rockpointe CME, Targeted Oncology, and OncLive; grants from Jounce Therapeutics, Takeda, Bristol Myers Squibb, Merck, Mirati, and Daiichi Sankyo; and grants and other from Helsinn Therapeutics outside the submitted work. S.K. Jabbour reports grants, personal fees, and nonfinancial support from Merck & Co; grants from NCI; and personal fees from IMX Medical and Syntactx during the conduct of the study, as well as grants from NCI outside the submitted work. O.B. Alese reports grants from NCI during the conduct of the study, other from AstraZeneca, and grants from Bristol Myers Squibb and GlaxoSmithKline outside the submitted work. O.E. Rahma reports personal fees from Sobi, Genentech, Bayer, GlaxoSmithKline, Imvax, Puretech, Maverick Therapeutics, Five Prime, and Merck outside the submitted work, as well as a patent for methods of using pembrolizumab and trebananib pending. J.M. Cleary reports grants from Merck and Tesaro, nonfinancial support from AstraZeneca and Esperas Pharma, and personal fees from BMS outside the submitted work. H.J. Mamon reports grants from Dana Farber Cancer Institute during the conduct of the study, as well as personal fees from Merck and other from UpToDate outside the submitted work. M. Cho reports personal fees from AstraZeneca outside the submitted work. S. Gnjatic reports grants from NCI during the conduct of the study, as well as grants from Genentech, Regeneron, Bristol-Myers Squibs, Janssen R&D, Takeda, and Immune Design and personal fees from OncoMed and Merck outside the submitted work. A. Spektor reports grants from NCI and Burroughs-Wellcome Fund and personal fees from Janssen Pharmaceutical, Bayer Pharmaceuticals, and Astellas Pharma outside the submitted work. S.J. Rodig reports research funding from Merck, Bristol-Myers-Squibb, Affimed, and KITE/Gilead for research unrelated to this project. S.F. Hodi reports grants from NIH during the conduct of the study, as well as grants from Sanofi; personal fees from Merck, EMD Serono, Apricity, Aduro, Pionyr, Checkpoint, Surface, Compass, Torque, Rheos, Bicara, Psioxus, Genentech, Takeda, Eisai, Iovance, Bioentre, and Idera; and grants and personal fees from Novartis outside the submitted work; in addition, S.F. Hodi has patents for MICA-related disorders pending, licensed, and with royalties paid, tumor antigens and uses thereof issued, angiopoiten-2 biomarkers predictive of anti-immune checkpoint response pending, compositions and methods for identification, assessment, prevention, and treatment of melanoma using PD-L1 isoforms pending, therapeutic peptides pending, vaccine compositions and methods for restoring NKG2D pathway function against cancers pending, licensed, and with royalties paid, antibodies that bind to MHC class I polypeptide-related sequence A pending, licensed, and with royalties paid, and anti-galectin antibody biomarkers predictive of anti-immune checkpoint and anti-angiogenesis responses pending. J.D. Schoenfeld reports grants from NCI during the conduct of the study, as well as grants from Merck, Regeneron, and BMS; grants and personal fees from Debiopharm; personal fees from ACI, Kline & Spector PC, Heidell, Pittoni, Murphy and Bach, Catenion, LEK, TILOS, Astellas, STIMIT, and Pearson Doyle Mohre & Pastis; and personal fees and other from Immunitas outside the submitted work. No disclosures were reported by the other authors. Funding Information: The trial was conducted under auspices of the Experimental Therapeutics Clinical Trials Network and funded by UM1 CA186709 (to principal investigator, Geoffrey Shapiro), a Biomarker Supplement to UM1 CA186709 (to project leaders, J.D. Schoenfeld, S.J. Rodig, and S.F. Hodi), and Center for Immuno- Oncology, Dana-Farber Cancer Institute. Scientific and financial support for the CIMAC-CIDC Network was provided through the NCI Cooperative Agreements U24CA224319 (to the Icahn School of Medicine at Mount Sinai CIMAC), U24CA224331 (to the Dana-Farber Cancer Institute CIMAC), and U24CA224316 (to the CIDC at Dana-Farber Cancer Institute). Additional support was made possible through the NCI CTIMS Contract HHSN261201600002C. Scientific and financial support for the PACT project was made possible through funding support provided to the FNIH by AbbVie Inc., Amgen Inc., Boehringer- Ingelheim Pharma GmbH & Co. KG., Bristol-Myers Squibb, Celgene Corporation, Genentech Inc, Gilead, GlaxoSmithKline plc, Janssen Pharmaceutical Companies of Johnson & Johnson, Novartis Institutes for Biomedical Research, Pfizer Inc., and Sanofi. The CIMAC-CIDC website is found at https://cimac-network. org/. We acknowledge Janice Russell and all participating patients and sites. We would also like to thank John Daley and his team at the Longwood Medical Area CyTOF Core at DFCI for their technical assistance. Publisher Copyright: © 2021 American Association for Cancer Research.
PY - 2021/5/1
Y1 - 2021/5/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85105265926&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85105265926&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-20-4632
DO - 10.1158/1078-0432.CCR-20-4632
M3 - Article
C2 - 33568343
AN - SCOPUS:85105265926
VL - 27
SP - 2470
EP - 2480
JO - Clinical Cancer Research
JF - Clinical Cancer Research
SN - 1078-0432
IS - 9
ER -