BLOCKADE OF TUMOR-INTRINSIC TGF-Β SIGNALING DRIVES HYPERPROGRESSION IN SMALL CELL LUNG CANCER
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.
Authors
- D. N. Biery (ORCID: https://orcid.org/0009-0007-6561-8409)
- Howard H. Yang (ORCID: https://orcid.org/0000-0002-9291-631X)
- Linda Sciuto (ORCID: https://orcid.org/0000-0001-6314-8991)
- Anna-Lena Meinhardt
- Devon Atkinson (ORCID: https://orcid.org/0000-0002-6675-1531)
- Christopher W. Schultz (ORCID: https://orcid.org/0000-0001-5731-2847)
- Ajit Kumar Sharma (ORCID: https://orcid.org/0000-0002-4811-7342)
- George Chrisafis
- Yo-Ting Tsai (ORCID: https://orcid.org/0000-0002-7556-1633)
- Chirayu Mohindroo (ORCID: https://orcid.org/0000-0002-5825-3356)
- Brett Schroeder
- Masashi Sato (ORCID: https://orcid.org/0009-0009-3852-4591)
- Renee N. Donahue (ORCID: https://orcid.org/0000-0002-6828-3073)
- Lalage M. Wakefield (ORCID: https://orcid.org/0000-0003-4124-5250)
- Sophie Zhuang
- Maxwell P. Lee (ORCID: https://orcid.org/0000-0003-3738-1292)
- Max Greenberg (ORCID: https://orcid.org/0000-0003-2133-7908)
- Jeffrey Schlom (ORCID: https://orcid.org/0000-0001-7932-4072)
- Sarthak Sahoo (ORCID: https://orcid.org/0000-0002-7771-5894)
- Min-Jung Lee (ORCID: https://orcid.org/0000-0003-3943-8133)
- Samantha Nichols (ORCID: https://orcid.org/0000-0003-4003-6780)
- Danielle Pinkiert (ORCID: https://orcid.org/0009-0003-0751-9622)
- James L. Gulley (ORCID: https://orcid.org/0000-0002-6569-2912)
- N Sato (ORCID: https://orcid.org/0009-0007-1772-3183)
- Anish Thomas (ORCID: https://orcid.org/0000-0003-3293-3115)
- Kristen Fousek (ORCID: https://orcid.org/0000-0002-2307-5000)
- Rusul Almarayaty (ORCID: https://orcid.org/0000-0002-5851-0121)
- Claudia Palena (ORCID: https://orcid.org/0000-0002-0445-4486)
- Rajaâ El Meskini (ORCID: https://orcid.org/0000-0003-3238-7038)
- Mohit Kumar Jolly (ORCID: https://orcid.org/0000-0002-6631-2109)
- Yang Zhang (ORCID: https://orcid.org/0000-0002-7833-1817)
- Michael Nirula (ORCID: https://orcid.org/0009-0003-5861-0872)
- Rajesh Kumar (ORCID: https://orcid.org/0000-0002-9835-3650)
- Yue Huang (ORCID: https://orcid.org/0000-0002-3099-5366)
- Sunmin Lee (ORCID: https://orcid.org/0000-0001-6011-151X)
- Shraddha Rastogi (ORCID: https://orcid.org/0000-0003-0680-0407)
- Parth Desai (ORCID: https://orcid.org/0000-0002-7715-4919)
- Roshan L. Shrestha
- Amira Kazi (ORCID: https://orcid.org/0000-0003-2926-9575)
Institutions
- Leidos (United States) (US)
- MedStar Washington Hospital Center (US)
- Fox Chase Cancer Center (US)
- National Institutes of Health (US)
- Merck KGaA, Darmstadt (Germany) (DE)
- George Washington University (US)
- University of Michigan (US)
- Washington Hospital (US)
- Michigan Medicine (US)
- Frederick National Laboratory for Cancer Research (US)
- National Cancer Institute (MY)
- National Cancer Institute (US)
- Ann Arbor Center for Independent Living (US)
- National Institutes of Health Clinical Center (US)
- Indian Institute of Management Bangalore (IN)
- Indian Institute of Science Bangalore (IN)
- Penn State Milton S. Hershey Medical Center (US)
Publication Details
- Journal
- Cancer Discovery
- Published
- 2026-04-22
- DOI
- https://doi.org/10.1158/2159-8290.cd-25-1454
- Primary Topic
- Cancer Immunotherapy and Biomarkers
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- U.S. Department of Health and Human Services
- Merck KGaA
- National Institutes of Health
- National Cancer Institute