Blockade of Tumor-Intrinsic TGFβ Signaling Drives Hyperprogression in Small Cell Lung Cancer

Area of Science:

• Oncology
• Immunology
• Molecular Biology

Background:

• Stromal immunosuppressive pathways critically influence responses to immune checkpoint inhibitors (ICIs).
• The tumor-intrinsic effects of these pathways, particularly transforming growth factor-beta (TGF-β), are not fully understood.
• Bintrafusp alfa is a bifunctional inhibitor targeting both PD-L1 and TGF-β.

Purpose of the Study:

• To investigate the clinical efficacy and tumor-intrinsic consequences of bintrafusp alfa in small cell lung cancer (SCLC).
• To explore the role of TGF-β signaling in tumor proliferation and response to therapy.
• To identify potential biomarkers for predicting treatment outcomes.

Main Methods:

• A clinical trial of bintrafusp alfa in 34 evaluable SCLC patients.
• Analysis of blood and tumor samples for immune and molecular profiling.
• Functional studies in cell lines and tumor models to assess TGF-β's role in proliferation.
• External validation using datasets from other tumor types (n=450).

Main Results:

• Partial responses (18%) and stable disease (20%) were observed; 62% experienced progressive disease, with 38% meeting criteria for hyperprogressive disease (HPD).
• HPD occurred more frequently with bintrafusp alfa than with PD-(L)1 blockade alone across various tumor types.
• HPD correlated with systemic immune suppression and elevated TGF-β signaling.
• Tumor-intrinsic TGF-β signaling was found to restrain proliferation in a subset of SCLC, with pathway blockade leading to hyperproliferation.
• A tumor-intrinsic TGF-β-high transcriptional state was associated with inferior survival.

Conclusions:

• TGF-β exhibits a context-dependent, growth-constraining function.
• Targeting stromal immunosuppression with agents like bintrafusp alfa can trigger tumor hyperproliferation via tumor-intrinsic mechanisms.
• Tumor-intrinsic biomarkers are crucial for guiding therapeutic strategies involving TGF-β and PD-L1 inhibition.