Journal article
BLOCKADE OF TUMOR-INTRINSIC TGF-B SIGNALING DRIVES HYPERPROGRESSION IN SMALL CELL LUNG CANCER
Cancer discovery, Vol.16(8), pp.1529-1549
08/01/2026
DOI: 10.1158/2159-8290.CD-25-1454
PMID: 42018154
Abstract
Stromal immunosuppressive pathways are key modulators of response to immune checkpoint inhibitors, but their tumor-intrinsic consequences remain incompletely defined. We conducted a clinical trial of bintrafusp alfa, a bifunctional PD-L1/TGF-β inhibitor, in small cell lung cancer. Among 34 evaluable patients, 18% had partial responses, 20% stable disease, and 62% progressive disease; 38% of progressors met criteria for hyperprogressive disease (HPD). HPD was also observed across other tumor types (n=450), in higher frequencies with bintrafusp than PD-(L)1 blockade alone. Blood and tumor profiling showed that HPD correlated with systemic immune suppression and elevated TGF-β signaling. Functional studies demonstrated that tumor-intrinsic TGF-β signaling restrains proliferation in a subset of SCLC; pathway blockade triggers hyperproliferation. External validation across cell lines and tumor samples confirmed a tumor-intrinsic TGF-β–high transcriptional state associated with inferior survival. Together, these findings identify a context-dependent, growth-constraining function of TGF-β and support tumor-intrinsic biomarker-guidance while targeting stromal immunosuppressive pathways.
Details
- Title: Subtitle
- BLOCKADE OF TUMOR-INTRINSIC TGF-B SIGNALING DRIVES HYPERPROGRESSION IN SMALL CELL LUNG CANCER
- Creators
- Brett A. Schroeder - National Cancer InstituteChirayu Mohindroo - National Cancer InstituteAnna-Lena Meinhardt - National Cancer InstituteNobuyuki Takahashi - National Cancer Center Hospital EastYang Zhang - National Cancer InstituteMin-Jung Lee - National Cancer InstituteSarthak Sahoo - Indian Institute of Science BangaloreRenee N Donahue - National Cancer InstituteRajesh Kumar - National Cancer InstituteMichael Nirula - National Cancer InstituteYuan Yang - National Cancer InstituteShraddha Rastogi - National Cancer InstituteNahoko Sato - National Cancer InstituteSunmin Lee - National Cancer InstituteYo-Ting Tsai - National Cancer InstituteSophie Zhuang - National Cancer InstituteAmira Kazi - National Cancer InstituteYue Huang - National Cancer InstituteParth Desai - Fox Chase Cancer CenterSamantha Nichols - National Cancer InstituteLinda Sciuto - National Cancer InstituteDanielle Pinkiert - National Cancer InstituteGeorge Chrisafis - University of MichiganMax Greenberg - Penn State Milton S. Hershey Medical CenterD. Nathan Biery - George Washington UniversityRusul Al-MarayatyHoward H. Yang - National Cancer InstituteMaxwell P. Lee - National Cancer InstituteChristopher W. Schultz - National Cancer InstituteRajaa El Meskini - National Institutes of HealthDevon Atkinson - National Institutes of HealthKristen Fousek - National Cancer InstituteJames L. Gulley - National Cancer InstituteJeffrey Schlom - National Cancer InstituteMasashi Sato - Merck KGaA, Darmstadt (Germany)Roshan L. Shrestha - National Cancer InstituteAjit Kumar Sharma - National Cancer InstituteMohit Kumar Jolly - Indian Institute of Science BangaloreClaudia Palena - National Cancer InstituteLalage M. Wakefield - National Cancer InstituteAnish Thomas - National Cancer Institute
- Resource Type
- Journal article
- Publication Details
- Cancer discovery, Vol.16(8), pp.1529-1549
- DOI
- 10.1158/2159-8290.CD-25-1454
- PMID
- 42018154
- NLM abbreviation
- Cancer Discov
- ISSN
- 2159-8274
- eISSN
- 2159-8290
- Publisher
- American Association for Cancer Research
- Grant note
- National Cancer Institute (NCI): ZIABC011793
This study was supported by the Center for Cancer Research, the Intramural Program of the NCI (ZIA BC 011793). The contributions of the NIH author(s) are considered works of the US government. The findings and conclusions presented in this article are those of the author(s) and do not necessarily reflect the views of the NIH or the U.S. Department of Health and Human Services. M.K. Jolly and S. Sahoo were supported by Param Hansa Philanthropies. The authors would like to thank the healthcare business of Merck KGaA, Darmstadt, Germany (CrossRef Funder ID: 10.13039/100009945) for generously providing the additional clinical trial datasets for analysis.
- Language
- English
- Electronic publication date
- 04/22/2026
- Date published
- 08/01/2026
- Academic Unit
- Internal Medicine
- Record Identifier
- 9985179090202771
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