Data from Blockade of Tumor-Intrinsic TGFβ Signaling Drives Hyperprogression in Small Cell Lung Cancer
Year: 2026
Type: other
Abstract: Stromal immunosuppressive pathways are key modulators of response to immune checkpoint inhibitors, but the tumor-intrinsic consequences of blocking these pathways remain incompletely defined. We conducted a clinical trial of bintrafusp alfa, a bifunctional PD-L1/TGFβ inhibitor, in small cell lung cancer (SCLC). Among 34 evaluable patients, 18% had partial responses, 20% stable disease, and 62% progressive disease; 38% of progressors met the criteria for hyperprogressive disease (HPD). HPD was also observed across other tumor types (n = 450), in higher frequencies with bintrafusp alfa than PD-(L)1 blockade alone. Blood and tumor profiling showed that HPD correlated with systemic immune suppression and elevated TGFβ signaling. Functional studies demonstrated that tumor-intrinsic TGFβ signaling restrains proliferation in a subset of SCLC; pathway blockade triggers hyperproliferation. External validation across cell lines and tumor samples confirmed a tumor-intrinsic TGFβ–high transcriptional state associated with inferior survival. These findings identify a context-dependent, growth-constraining function of TGFβ and support tumor-intrinsic biomarker guidance while targeting stromal immunosuppressive pathways. Significance: This study identifies tumor-intrinsic TGFβ signaling as a context-dependent growth restraint in SCLC and a driver of HPD following TGFβ blockade. A reproducible TGFβ–high mesenchymal state is linked to inferior survival, supporting biomarker-guided use of TGFβ–targeted immunotherapy.
Authors: Brett A. Schroeder, Chirayu Mohindroo, Anna-Lena Meinhardt, Nobuyuki Takahashi, Yang Zhang, Min-Jung Lee, Sarthak Sahoo, Renee N. Donahue, Rajesh Kumar, Michael Nirula, Yuan Yang, Shraddha Rastogi, Nahoko Sato, Sunmin Lee, Yo-Ting Tsai, Sophie Zhuang, Amira Kazi, Yue Huang, Parth Desai, Samantha Nichols, Linda Sciuto, Danielle Pinkiert, George Chrisafis, Max Greenberg, D. Nathan Biery, Rusul Al-Marayaty, Howard H. Yang, Maxwell P. Lee, Christopher W. Schultz, Rajaa El Meskini, Devon Atkinson, Kristen Fousek, James L. Gulley, Jeffrey Schlom, Masashi Sato, Roshan L. Shrestha, Ajit Kumar Sharma, Mohit Kumar Jolly, Claudia Palena, Lalage M. Wakefield, Anish Thomas
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
OpenAlex ID: W7172344672
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