BLOCKADE OF TUMOR-INTRINSIC TGF-Β SIGNALING DRIVES HYPERPROGRESSION IN SMALL CELL LUNG CANCER

Authors

• Brett A. Schroeder, National Institutes of Health Bethesda, MD United States.
• Chirayu Mohindroo, National Cancer Institute Baltimore United States.
• Anna-Lena Meinhardt, National Cancer Institute Bethesda United States.
• Nobuyuki Takahashi, National Cancer Institute Bethesda, MD United States.
• Yang Zhang, National Cancer Institute Bethesda, MD United States.
• Min-Jung Lee, National Institutes of Health Bethesda, MD United States.
• Sarthak Sahoo, Indian Institute of Science Bangalore Bangalore India.
• Renee N. Donahue, National Cancer Institute Bethesda, MD United States.
• Rajesh Kumar, National Cancer Institute Bethesda, MD United States.
• Michael Nirula, National Cancer Institute Bethesda, MD United States.
• Yuan Yang, Center for Cancer Research, National Cancer Institute Bethesda, MD United States.
• Shraddha Rastogi, National Cancer Institute Bethesda, Maryland United States.
• Nahoko Sato, National Cancer Institute Bethesda, MD United States.
• Sunmin Lee, National Cancer Institute Bethesda, MD United States.
• Yo-Ting Tsai, National Cancer Institute Bethesda, MD United States.
• Sophie Zhuang, National Cancer Institute United States.
• Amira Kazi, National Cancer Institute Gaithersburg United States.
• Yue Huang, National Cancer Institute United States.
• Parth Desai, Fox Chase Cancer Center Philadelphia United States.
• Samantha Nichols, National Cancer Institute Bethesda, MD United States.
• Linda Sciuto, National Cancer Institute Bethesda, MD United States.
• Danielle Pinkiert, National Cancer Institute Bethesda, MD United States.
• George Chrisafis, University of Michigan-Ann Arbor Ann Arbor, MI United States.
• Max Greenberg, Penn State Milton S. Hershey Medical Center Hershey, Pennsylvania United States.
• D Nathan Biery, George Washington University Washington, DC United States.
• Rusul Al-Marayaty, MedStar Washington Hospital Center Washington, DC United States.
• Howard H. Yang, National Cancer Institute Bethesda, Maryland United States.
• Maxwell P. Lee, National Cancer Institute Bethesda, MD United States.
• Christopher W. Schultz, National Cancer Institute United States.
• Rajaa El Meskini, Frederick National Laboratory for Cancer Research Frederick, MD United States.
• Devon Atkinson, Leidos Biomedical Research, Inc. Frederick National Laboratory for Cancer Research Frederick, MD United States.
• Kristen Fousek, National Cancer Institute Bethesda, MD United States.

Document Type

Journal Article

Publication Date

4-22-2026

Journal

Cancer discovery

DOI

10.1158/2159-8290.CD-25-1454

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.

APA Citation

Schroeder, Brett A.; Mohindroo, Chirayu; Meinhardt, Anna-Lena; Takahashi, Nobuyuki; Zhang, Yang; Lee, Min-Jung; Sahoo, Sarthak; Donahue, Renee N.; Kumar, Rajesh; Nirula, Michael; Yang, Yuan; Rastogi, Shraddha; Sato, Nahoko; Lee, Sunmin; Tsai, Yo-Ting; Zhuang, Sophie; Kazi, Amira; Huang, Yue; Desai, Parth; Nichols, Samantha; Sciuto, Linda; Pinkiert, Danielle; Chrisafis, George; Greenberg, Max; Biery, D Nathan; Al-Marayaty, Rusul; Yang, Howard H.; Lee, Maxwell P.; Schultz, Christopher W.; El Meskini, Rajaa; Atkinson, Devon; and Fousek, Kristen, "BLOCKADE OF TUMOR-INTRINSIC TGF-Β SIGNALING DRIVES HYPERPROGRESSION IN SMALL CELL LUNG CANCER" (2026). GW Authored Works. Paper 9025.
https://hsrc.himmelfarb.gwu.edu/gwhpubs/9025

Department

School of Medicine and Health Sciences Student Works