Cancer Immunotherapy: Targeting Tumor Cells’ ‘Guardians’ Shows Promise in Lung & Ovarian Cancer
Scientists at the Icahn School of Medicine at Mount Sinai have developed an experimental immunotherapy that takes aim at metastatic cancer by targeting the cells that protect tumors, rather than the cancer cells themselves. The research, published in the January 22 online issue of Cancer Cell, demonstrated promising results in preclinical models of aggressive ovarian and lung cancers, suggesting a potential novel approach for treating advanced solid tumors that have proven resistant to existing therapies.
The therapy centers on tumor-associated macrophages, immune cells that, unlike their counterparts in healthy tissue, actively suppress immune responses within tumors, fostering cancer growth, and spread. The Mount Sinai team engineered CAR T cells – typically designed to directly kill cancer cells – to instead recognize and selectively eliminate these tumor-protecting macrophages, effectively dismantling the tumor’s defenses.
“What we call a tumor is really cancer cells surrounded by cells that feed and protect them. It’s a walled fortress,” explained Jaime Mateus-Tique, PhD, a faculty member in Immunology and Immunotherapy at the Icahn School of Medicine, and lead study author. “With immunotherapy, we kept running into the same problem — we can’t get past this fortress’s guards. So, we thought: what if we targeted these guards, turned them from protectors to friends, and used them as a gateway to bring a wrecking force within the fortress.”
The engineered CAR T cells were further modified to release interleukin-12, a molecule known to stimulate the immune system and activate killer T cells. In experiments with mice bearing metastatic lung and ovarian cancer, treatment with these modified cells led to significantly prolonged survival and, in many cases, complete tumor eradication.
Advanced spatial genomics techniques revealed that the therapy reshaped the tumor environment by removing immune-suppressing cells and attracting immune cells capable of destroying cancer. This shift is particularly significant due to the fact that it renders the therapy “antigen-independent,” meaning it doesn’t rely on identifying specific markers on cancer cells. This broadens its potential applicability to a wider range of cancers, including those that have historically been hard to treat with conventional immunotherapy.
“Macrophages are found in every type of tumor, sometimes outnumbering the cancer cells. They’re there because the tumor uses them as a shield,” said Brian Brown, PhD, Director of the Icahn Genomics Institute, Vice Chair of Immunology and Immunotherapy, Associate Director of the Marc and Jennifer Lipschultz Precision Immunology Institute, and Mount Sinai Professor of Genetic Engineering, at the Icahn School of Medicine at Mount Sinai. “What’s so exciting is that our treatment converts these cells from protecting the cancer to killing it. We’ve turned foe into ally.”
Researchers are currently focused on refining the therapy, specifically optimizing the delivery and release of interleukin-12 within tumors in mouse models. This work aims to maximize therapeutic impact while ensuring patient safety as the approach moves toward potential human clinical trials. A clinical trial investigating nadunolimab, another immunotherapy, in combination with immune-checkpoint inhibitor therapy for metastatic microsatellite stable (MSS) colorectal cancer is currently ongoing at Mount Sinai Tisch Cancer Center, according to a recent report.
The study, titled “Armored macrophage-targeted CAR-T cells reset and reprogram the tumor microenvironment and control metastatic cancer growth,” involved contributions from Jaime Mateus-Tique, Ashwitha Lakshmi, Bhavya Singh, Rhea Iyer, Alfonso R. Sánchez-Paulete, Chiara Falcomata, Matthew Lin, Gvantsa Pantsulaia, Alexander Tepper, Trung Nguyen, Angelo Amabile, Gurkan Mollaoglu, Luisanna Pia, Divya Chhamalwan, Jessica Le Berichel, Hunter Potak, Marco Colonna, Alessia Baccarini, Joshua Brody, Miriam Merad, and Brian D. Brown. The research was supported by grants from the National Institutes of Health (U01CA28408, R01CA254104), the Alliance for Cancer Gene Therapy, the Feldman Family Foundation, and the Applebaum Foundation.