Mount Sinai Researchers Reprogram Immune Cells to Fight Metastatic Cancer
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A groundbreaking immunotherapy developed at the Icahn School of Medicine at Mount Sinai is taking a novel approach to combating metastatic cancer, focusing not on directly attacking cancer cells, but on dismantling their protective shield. Published in the January 22 online issue of Cancer Cell, the research demonstrates promising results in preclinical models of aggressive ovarian and lung cancers, offering a potential new avenue for treating advanced solid tumors that have proven resistant to existing therapies.
A New Strategy for ‘Walled Fortress’ Tumors
Conventional immunotherapies often struggle to penetrate the defenses erected by tumors, which suppress immune activity in their immediate surroundings. As one researcher explained, “What we call a tumor is really cancer cells surrounded by cells that feed and protect them. It’s a walled fortress.” Previous attempts to overcome this barrier have been hampered by the inability to bypass these “guards.” The Mount Sinai team’s innovative strategy, inspired by the Trojan horse, circumvents this issue by targeting the cells protecting the cancer – tumor-associated macrophages.
These macrophages, normally functioning as early responders in healthy tissue to fight infection and repair damage, are reprogrammed within tumors to suppress immune responses, fuel cancer growth, and facilitate disease spread. The Mount Sinai team designed a therapy to selectively remove these tumor-specific macrophages while leaving healthy macrophages unharmed, effectively shifting the tumor environment from immune-suppressed to immune-active.
Re-Engineering CAR T Cells for Targeted Macrophage Removal
The therapy leverages CAR T cells, engineered immune cells created from a patient’s own T cells. While traditionally designed to directly kill cancer cells, identifying suitable targets on solid tumors has been a significant challenge. To overcome this, researchers redirected the CAR T cells to recognize tumor macrophages instead.
Further enhancing the therapy, the team modified the CAR T cells to release interleukin-12, a potent immune-stimulating molecule that activates killer T cells. In experiments involving mice with metastatic lung and ovarian cancer, the results were dramatic. Treated animals experienced significantly extended lifespans, with many achieving complete remission.
Reshaping the Tumor Microenvironment for Broad Applicability
Advanced spatial genomics techniques revealed how the therapy reshaped the tumor environment, eliminating immune-suppressing cells and attracting immune cells capable of destroying cancer. This shift is particularly significant because it renders the therapy antigen-independent, meaning it doesn’t rely on identifying specific markers on cancer cells. This broadens its potential application to a wide range of cancers, including those unresponsive to traditional immunotherapy. The success observed in both lung and ovarian cancer models further underscores this potential.
“Macrophages are found in every type of tumor, sometimes outnumbering the cancer cells. They’re there because the tumor uses them as a shield,” explained a senior author of the study. “What’s so exciting is that our treatment converts these cells from protecting the cancer to killing it. We’ve turned foe into ally.”
What’s Next for This Novel Immunotherapy?
While these preclinical results are highly encouraging, researchers emphasize the need for human studies to assess the therapy’s safety and efficacy in patients. The current findings are considered a crucial proof of concept, rather than an immediate cure.
The team is currently focused on refining the approach, specifically optimizing the delivery and release of interleukin-12 within tumors in mouse models. Their goal is to maximize therapeutic impact while ensuring patient safety as they move closer to potential clinical trials. Looking ahead, researchers believe this strategy could serve as a foundation for future CAR T therapies that reshape tumors by targeting their support cells, rather than solely focusing on the cancer cells themselves.
The research was detailed in a paper titled “Armored macrophage-targeted CAR-T cells reset and reprogram the tumor microenvironment and control metastatic cancer growth.” The study was supported by NIH grants (U01CA28408, R01CA254104), the Alliance for Cancer Gene Therapy, the Feldman Family Foundation, and the Applebaum Foundation.
