According to researchers from the Icahn School of Medicine at Mount Sinai in New York. The results were published on October 11, 2022 in the journal Cancer immunology research [https://doi.org/10.1158/2326-6066.CIR-21-1075].
The study involved a variation of a type of therapy that uses immune cells called CAR T cells. CAR T cells currently in clinical use are designed to recognize cancer cells directly and have successfully treated several blood cancers. But there have been challenges that prevent their effective use in many solid tumors.
Most solid tumors are heavily infiltrated by a different type of immune cell called macrophages. Macrophages help tumors grow by blocking the entry of T cells into tumor tissue, which prevents CAR T cells and the patient’s own T cells from destroying cancer cells.
To tackle this immune suppression at the source, the researchers engineered T cells to make a ‘chimeric antigen receptor’ (CAR) that recognizes a molecule on the surface of macrophages. When these CAR T cells encountered a tumor macrophage, the CAR T cell activated and killed the tumor macrophage.
Treatment of mice with ovarian, lung and pancreatic tumors with these macrophage-targeting CAR T cells reduced the number of tumor macrophages, shrunk the tumors and prolonged their survival.
Figure 1: Mice with lung cancer were treated with macrophage-targeting CAR T cells, resulting in reduced tumor macrophage counts (right side), shrunken tumors, and prolonged survival.
Credit: Jamie Mateus-Tique, Icahn Mount Sinai
Destroying the tumor macrophages allowed the mouse’s own T cells to access and kill the cancer cells. The researchers further demonstrated that this anti-tumor immunity was induced by the release of the cytokine interferon-gamma – a molecule involved in the regulation of inflammatory responses – by CAR T cells.
“Our original goal was simply to use CAR T cells to kill immunosuppressive macrophages, but we found that they also boost tumor immunity by releasing this potent immune-boosting molecule,” said lead author Brian Brown, PhD, Director of Icahn Genomics. Institute and Associate Director of the Marc and Jennifer Lipschultz Institute for Precision Immunology (PrIISM) at Icahn Mount Sinai. “It was a one-two punch from that treatment alone.”
Shifting the focus of CARs from cancer cells to tumor macrophages potentially addresses another key barrier to successful elimination of solid tumors with CAR T cells. There are very few proteins found exclusively on cancer cells and not on healthy tissue that can be used to directly target cancer cells in solid tumors without damaging healthy tissue.
Macrophages found in tumors that suppress immunity are very similar in different types of cancer and very different from macrophages in healthy tissue.
This has led to interest in macrophage depleting agents for the treatment of cancer, but approaches developed to date have had limited success in clinical trials.
“Our molecular studies of human tumors have revealed subsets of macrophages present in human tumors and not in normal tissues and are similar from tumor to tumor and patient to patient. Thus, macrophage-targeting CAR T cells could be a broad way to target different types of solid tumors and improve immunotherapy,” said Miriam Merad, MD, PhD, study co-lead author and director of PrIISM.
Next, researchers work on tumor macrophage-specific CAR and generate humanized versions of the genetic instructions, so they can be introduced into cancer patients’ own T cells.
The article is titled “Targeting macrophages with CAR T cells delays solid tumor progression and enhances anti-tumor immunity”.
Additional co-authors are Alfonso R. Sánchez-Paulete, PhD, Jaime Mateus-Tique, Gurkan Mollaoglu, PhD, , Sebastian R. Nielsen, PhD, Adam Marks, Ashwitha Lakshmi, Jalal A. Khan, MD, PhD, C. Matthias Wilk, MD, Luisanna Pia, Alessia Baccarini, PhD, all of Icahn Mount Sinai.
BDB was supported by the NIH (R01CA257195) and a grant from the Alliance for Cancer Gene Therapy. MM was supported by the NIH (R01CA254104). A grant from the Applebaum Foundation also supported the project. ARSP was supported by a grant from Fundación Alfonso Martín Escudero (Spain).
About Icahn School of Medicine at Mount Sinai
The Icahn School of Medicine at Mount Sinai is internationally recognized for its outstanding research, education, and clinical care programs. It is the sole academic partner of the eight member hospitals* of the Mount Sinai Health System, one of the largest academic health systems in the United States, providing care to a large and diverse patient population.
Ranked 14th nationally in National Institutes of Health (NIH) funding and among the 99th percentile in research dollars per researcher by the Association of American Medical Colleges, Icahn Mount Sinai has a talented, productive, and thriving faculty. More than 3,000 full-time scientists, educators, and clinicians work across 34 academic departments and 35 multidisciplinary institutes, a structure that facilitates tremendous collaboration and synergy. Our focus on translational research and therapeutics is evident in areas as diverse as genomics/big data, virology, neuroscience, cardiology, geriatrics, as well as gastrointestinal and liver disease.
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Icahn Mount Sinai’s commitment to groundbreaking science and clinical care is reinforced by academic affiliations that complement and supplement the school’s programs.
Through the Mount Sinai Innovation Partners (MSIP), the health system facilitates the real-world application and commercialization of medical breakthroughs made at Mount Sinai. Additionally, MSIP develops research partnerships with industry leaders such as Merck & Co., AstraZeneca, Novo Nordisk and others.
The Icahn School of Medicine at Mount Sinai is located in New York City, on the border between the Upper East Side and East Harlem, and classroom instruction takes place on a campus facing Central Park. The location of Icahn Mount Sinai provides many opportunities to interact with and care for diverse communities. The learning extends far beyond the boundaries of our physical campus, to the eight Mount Sinai Health System hospitals, our academic affiliates, and around the world.
* Mount Sinai Health System member hospitals: The Mount Sinai Hospital; Mount Sinai Beth Israel; Mount Sinai Brooklyn; Mount Sinai Morningside; the queens of Mount Sinai; Mount Sinai South Nassau; West Mount Sinai; and New York Eye and Ear Infirmary of Mount Sinai.
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