TY - JOUR
T1 - Understanding Suboptimal Response to Immune Checkpoint Inhibitors
AU - Zhu, Mojun
AU - Zhang, Henan
AU - Pedersen, Katrina S.
AU - Foster, Nathan R.
AU - Jaszewski, Brandy L.
AU - Liu, Xin
AU - Hirdler, Jacob B.
AU - An, Zesheng
AU - Bekaii-Saab, Tanios S.
AU - Halfdanarson, Thorvardur R.
AU - Boland, Patrick M.
AU - Yan, Yiyi
AU - Hubbard, Joleen H.
AU - Ma, Wen Wee
AU - Yoon, Harry H.
AU - Revzin, Alexander
AU - Fernandez-Zapico, Martin E.
AU - Overman, Michael J.
AU - McWilliams, Robert R.
AU - Dong, Haidong
N1 - Funding Information:
M.Z. and H.Z. contributed equally to this work. The authors wish to thank all patients and acknowledge the International Rare Cancers Initiative (IRCI) and Academic and Community Cancer Research United (ACCRU) for successful completion of this trial. The studies of CX3CR1, Bim, and NKG7 were funded by Mayo Clinic Center of Individualized Medicine's Immunotherapy with Precision Biomarkers (IMPRESS), Mayo Clinic Center for Biomedical Discovery, Mayo Clinic Cancer Center David F. and Margaret T. Grohne Cancer Immunology and Immunotherapy Program. Primary study funding and investigational product was provided by the Merck Investigator Studies Program (R.R.M.), and additional site‐specific funding was provided by the Kavanagh Family Foundation (M.J.O.) and Kevin T. Doner Memorial Fund (M.J.O.).
Funding Information:
M.Z. and H.Z. contributed equally to this work. The authors wish to thank all patients and acknowledge the International Rare Cancers Initiative (IRCI) and Academic and Community Cancer Research United (ACCRU) for successful completion of this trial. The studies of CX3CR1, Bim, and NKG7 were funded by Mayo Clinic Center of Individualized Medicine's Immunotherapy with Precision Biomarkers (IMPRESS), Mayo Clinic Center for Biomedical Discovery, Mayo Clinic Cancer Center David F. and Margaret T. Grohne Cancer Immunology and Immunotherapy Program. Primary study funding and investigational product was provided by the Merck Investigator Studies Program (R.R.M.), and additional site-specific funding was provided by the Kavanagh Family Foundation (M.J.O.) and Kevin T. Doner Memorial Fund (M.J.O.).
Funding Information:
R.R.M. reports relevant advisory board (NewLink Genetics, Zeno Pharmaceuticals) and support for investigator‐initiated studies (Bristol Meyer Squibb, Glaxo Smith Kline). M.J.O. reports consulting for Merck Sharp and Dohme Corp, AbbVie, Agilvax, Acrotech Biopharma and Novartis Pharmaceuticals Corp and a scientific/advisory committee member for Takeda Pharmaceuticals. T.R.H. reports research support from Ipsen, Thermo Fisher Scientific, Advanced Accelerator Applications, Basilea, Turnstone Biologics, and Agios and consulting for Ipsen, Lexicon, ScioScientific, Curium, Advanced Accelerator Applications, Terumo, Isotope Technologies Munich, and Crinetics. P.M.B. reports consulting for Bayer and Ipsen and research support from Athenex, Bayer, Boehringer Ingelheim, Boston Biomedical, Genentech/Roche, Ipsen, and Merck. Other authors declared no conflict of interest.
Publisher Copyright:
© 2022 Wiley-VCH GmbH.
PY - 2023/4
Y1 - 2023/4
N2 - Immune checkpoint inhibitors (ICIs), as a novel class of anticancer therapy, can be more efficacious and less toxic than chemotherapy, but their clinical success is confined to certain tumor types. Elucidating their targets, mechanisms and scope of action, and potential synergism with chemotherapy and/or targeted therapies are critical to widen their clinical indications. Treatment response to an ICI targeting programmed death-1 (anti-PD-1) is sought to be understood here by conducting a preplanned correlative analysis of a phase II clinical trial in patients with small bowel adenocarcinoma (SBA). The cytolytic capacity of circulating immune cells in cancer patients using a novel ex vivo cytotoxicity assay is evaluated, and the utility of circulating biomarkers is investigated to predict and monitor the treatment effect of anti-PD-1. Baseline expression of Bim and NKG7 and upregulation of CX3CR1 in circulating T cells are associated with the clinical benefit of anti-PD-1 in patients with SBA. Overall, these findings suggest that the frequency and cytolytic capacity of circulating, effector immune cells may differentiate clinical response to ICIs, providing a strong rationale to support immune monitoring using patient peripheral blood.
AB - Immune checkpoint inhibitors (ICIs), as a novel class of anticancer therapy, can be more efficacious and less toxic than chemotherapy, but their clinical success is confined to certain tumor types. Elucidating their targets, mechanisms and scope of action, and potential synergism with chemotherapy and/or targeted therapies are critical to widen their clinical indications. Treatment response to an ICI targeting programmed death-1 (anti-PD-1) is sought to be understood here by conducting a preplanned correlative analysis of a phase II clinical trial in patients with small bowel adenocarcinoma (SBA). The cytolytic capacity of circulating immune cells in cancer patients using a novel ex vivo cytotoxicity assay is evaluated, and the utility of circulating biomarkers is investigated to predict and monitor the treatment effect of anti-PD-1. Baseline expression of Bim and NKG7 and upregulation of CX3CR1 in circulating T cells are associated with the clinical benefit of anti-PD-1 in patients with SBA. Overall, these findings suggest that the frequency and cytolytic capacity of circulating, effector immune cells may differentiate clinical response to ICIs, providing a strong rationale to support immune monitoring using patient peripheral blood.
KW - PD-1
KW - circulating biomarker
KW - small bowel
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U2 - 10.1002/adbi.202101319
DO - 10.1002/adbi.202101319
M3 - Article
C2 - 35343107
AN - SCOPUS:85127250924
SN - 2701-0198
VL - 7
JO - Advanced Biology
JF - Advanced Biology
IS - 4
M1 - 2101319
ER -