Journal article
BLOCKADE OF TUMOR-INTRINSIC TGF-B SIGNALING DRIVES HYPERPROGRESSION IN SMALL CELL LUNG CANCER
Cancer discovery
04/22/2026
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
- DOI
- 10.1158/2159-8290.CD-25-1454
- PMID
- 42018154
- ISSN
- 2159-8274
- eISSN
- 2159-8290
- Publisher
- American Association for Cancer Research
- Language
- English
- Electronic publication date
- 04/22/2026
- Academic Unit
- Internal Medicine
- Record Identifier
- 9985179090202771
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