LFA-1 activation enriches tumor-specific T cells in a cold tumor model and synergizes with CTLA-4 blockade

Author & Article Information Authors: Amber Hickman,1 Joost Koetsier,1 Trevin Kurtanich,1 Michael C. Nielsen,1 Glenn Winn,1 Yunfei Wang,1 Salah-Eddine Bentebibel,1 Leilei Shi,1 Simone Punt,1 Leila Williams,1 Cara Haymaker,2 Charles B. Chesson,1 Faisal Fa’ak,1 Ana L. Dominguez,1 Richard Jones,3 Isere Kuiatse,3 Amy R. Caivano,4 Sayadeth Khounlo,4 Navin D. Warier,4 Upendra Marathi,5 Robert V. Market,4 Ronald J. Biediger,4 John W. Craft Jr.,6 Patrick Hwu,1 Michael A. Davies,1 Darren G. Woodside,4 Peter Vanderslice,4 Adi Diab,1 Willem W. Overwijk,1 and Yared Hailemichael1 Published: 12 May 2022 Abstract The inability of CD8+ effector T cells (Teffs) to reach tumor cells is an important aspect of tumor resistance to cancer immunotherapy. The recruitment of these cells to the tumor microenvironment (TME) is regulated by integrins, a family of adhesion molecules that are expressed on T cells. Here, we show that 7HP349, a small-molecule activator of lymphocyte function–associated antigen-1 (LFA-1) and very late activation antigen-4 (VLA-4) integrin cell-adhesion receptors, facilitated the preferential localization of tumor-specific T cells to the tumor and improved antitumor response. 7HP349 monotherapy had modest effects on anti–programmed death 1–resistant (anti–PD-1–resistant) tumors, whereas combinatorial treatment with anti–cytotoxic T lymphocyte–associated protein 4 (anti–CTLA-4) increased CD8+ Teff intratumoral sequestration and synergized in cooperation with neutrophils in inducing cancer regression. 7HP349 intratumoral CD8+ Teff enrichment activity depended on CXCL12. We analyzed gene expression profiles using RNA from baseline and on treatment tumor samples of 14 melanoma patients. We identified baseline CXCL12 gene expression as possibly improving the likelihood or response to anti–CTLA-4 therapies. Our results provide a proof-of-principle demonstration that LFA-1 activation could convert a T cell–exclusionary TME to a T cell–enriched TME through mechanisms involving cooperation with innate immune cells. Read More See the original article here | Journal of Clinical Investigation LFA-1 activation cancer therapy Integrin activator tumor immunity T cell infiltration cold tumors CTLA-4 blockade synergy 7HP349 immunotherapy enhancer Rob Bent Previous Previous New Study Demonstrates Integrin Activation Can Bring the Heat to Cold Melanoma Tumors Next Next 7 Hills Pharma’s Clinical-stage Novel Immunostimulant 7HP349 Granted FDA Fast Track Designation for Anti-PD-1-resistant Metastatic Melanoma 2450 Holcombe Blvd, Suite J Houston, TX 77021 [email protected] © 2025. 7 Hills Pharma Inc. Menu Home About Leadership Technology News & Publications Contact Newsletter Block This newsletter signup form needs a storage option. Edit the block and enter a storage location via the Storage tab. Subscribe Sign up with your email address to receive news and updates. Email Address Sign Up We respect your privacy. Thank you!

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