Macrophage-targeting CAR T cells


Immunotherapy is revolutionizing the treatment of many cancers. However, most patients with solid tumors do not respond to current immunotherapy agents. Among the factors involved in resistance to therapy are the tumor-associated macrophages (TAM). TAMs are one of the most abundant cell types in the tumor microenvironment of solid tumors and adopt specific molecular states associated with poor clinical outcome. TAMs contribute to the suppression of antitumor immune responses and support tumor growth through a variety of mechanisms, including promoting angiogenesis, providing an immunosuppressive environment, helping to create a barrier that excludes effector T cells from the tumor core, capturing tumor antigens and preventing cross-presentation by cDC1, and promoting tumor invasiveness and metastasis. A new approach to cancer immunotherapy that uses one type of immune cell to kill another—rather than directly attacking the cancer—provokes a robust anti-tumor immune response that shrinks ovarian, lung, and pancreatic tumors in preclinical disease models, according to researchers at the Icahn School of Medicine at Mount Sinai in New York. The findings led by Professor Brian Brown were published in the peer-reviewed journal Cancer Immunology Research.

The study involved a twist on a type of therapy that uses immune cells known as CAR T cells. CAR T cells in current clinical use are engineered 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 the 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 became activated and killed the tumor macrophage.

Treatment of mice bearing ovarian, lung, and pancreatic tumors with these macrophage-targeting CAR T cells reduced the number of tumor macrophages, shrunk the tumors, and extended their survival. The killing of tumor macrophages allowed the mouse’s own T cells to access and kill the cancer cells. The investigators further demonstrated that this anti-tumor immunity was driven by release of the cytokine interferon-gamma from the CAR T cells.

The authors initial goal was just to use the CAR T cells to kill the immunosuppressive macrophages, but they discovered they were also boosting tumor immunity by releasing  powerful immune-boosting molecule. Shifting the sights of CARs from cancer cells to tumor macrophages potentially addresses another key barrier to the successful elimination of solid tumors with CAR T cells. There are very few proteins found exclusively on cancer cells and not on healthy tissues that can be used to target cancer cells in solid tumors directly without damaging the healthy tissue.

The macrophages found in tumors that suppress immunity are very similar across different types of cancer and very different from macrophages in healthy tissues. This has led to an interest in macrophage-depleting agents for cancer therapy, but approaches developed to date have had limited success in clinical trials.

The research team molecular studies of human tumors have revealed macrophage subsets present in human tumors and not in normal tissues and are similar across tumors and across patients. So macrophage-targeting CAR T cells could be a broad way to target different types of solid tumors and improve immunotherapy.  In summary, the authors have shown that targeting of macrophages using CAR T cells can achieve antitumor efficacy as a monotherapy in different models of solid organ tumors, bypassing the need for expression of CAR targets on tumor cells. This approach has promising features to become a new tool in the cancer immunotherapy repertoire, making it possible to deliver CAR T cells and IFNγ into solid tumors in a tumor antigen-agnostic manner.  Next, the authors are working on tumor macrophage-specific CAR and generating humanized versions of the genetic instructions, so that they can be introduced into cancer patients’ own T cells.

Macrophage-targeting CAR T cells - Medicine Innovates

About the author

Brian D Brown, PhD
PROFESSOR | Genetics and Genomic Sciences
Icahn School of Medicine at Mount Sinai

Dr. Brian Brown is an immunologist and molecular biologist whose research has a strong focus on biotechnology and therapeutics. His training began with his doctoral studies in Canada and his work to establish ways to overcome the immune response hindering gene therapy. He subsequently did his postdoctoral studies in Italy where he helped develop a new platform for controlling gene expression, which has led to improvements in experimental treatments for genetic disease, cancer, and viral infection. Dr. Brown’s lab is now working to identify the factors that control immunity and tolerance, and translate these findings in to strategies that can be used to turn the immune system against cancer or viruses.  In 2008 Dr. Brown joined the faculty of Mount Sinai he was promoted to full Professor with tenure in 2018.  In 2016 he became the Associate Director of Mount Sinai’s Precision Immunology Institute (PrIISM) and in 2021 he was named Director of the Icahn Genomics Institute (IGI).


Alfonso R. Sánchez-Paulete; Jaime Mateus-Tique; Gurkan Mollaoglu; Sebastian R. Nielsen; Adam Marks; Ashwitha Lakshmi; Jalal A. Khan; C. Matthias Wilk; Luisanna Pia; Alessia Baccarini; Miriam Merad; Brian D. Brown, Targeting Macrophages with CAR T Cells Delays Solid Tumor Progression and Enhances Antitumor Immunity, Cancer Immunology Research (2022). DOI: 10.1158/2326-6066.CIR-21-1075

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