Colette Bilynsky
CAR-T cell therapy is widely available in the United States, with 6 FDA-approved formulations, and has been previously discussed on Oncobites. However, a new clinical trial using the CAR (chimeric antigen receptor) technology is underway, but using macrophages instead of T-Cells in the hope of treating more types of cancer. But let’s take a step back and review what traditional CAR-T cell therapy is. T-cells are a type of immune cell that help protect the body from disease. Cytotoxic T cells (or Killer T cells) operate as the assassins of the immune system, hunting down pathogens. CAR-T cells therapy uses the T-cells natural ability to kill pathogens and cells, but adds the CAR protein which helps the T-cells specifically find the cancer cells. T-cells are taken from the patient and genetically modified to have the CAR protein. These cells are then given back to the patient. This kind of targeted treatment strategy works well for cancers like leukemia and lymphoma, or cancers that mostly live in the blood. CAR-T cells though have a major drawback: they are not effective at targeting solid tumors.
Solid tumors make up about 90% of adult human cancers (colorectal, lung, or breast cancers for example). What makes them challenging for CAR-T cells to treat is that the tumor microenvironment itself tries to prevent T-cells from infiltrating the tumor. The tumor microenvironment is what we call all of the parts within a tumor including the different cell types, extracellular matrix (proteins and minerals outside of the cells that create a structure), and signaling molecules (like hormones, cytokines, or growth factors). When taken together, these factors often work together to make an environment that T cells have trouble penetrating.
But macrophages are already present within solid tumors, making up a large portion of the tumor volume. They also can be part of the reason that T cells have trouble infiltrating solid tumors. Macrophages respond to signals in the part of the body they are residing, and “polarize” along a spectrum to best respond to what the body needs. Macrophages respond to infections or viruses by polarizing towards a M1, or pro-inflammatory, pole. This allows them to recruit and activate other immune cells to help stop the infection. At the other end of the spectrum is the M2, or anti-inflammatory, pole. These M2 macrophages help wounds heal and prevent other immune cells from activating. Cancer cells influence the macrophages within the tumor to be M2, which suppresses the activity of other immune cells, preventing them from attacking the cancer.
Researchers have been investigating utilizing the CAR technology on macrophages to make CAR-Macrophage therapies. The macrophages from the patient are modified in two ways for CAR-M therapy. Firstly, they are changed to have a sustained M1 (pro-inflammatory and anti-cancer) phenotype. Second, they are given CAR which allows them to target and kill the cancer cells by essentially “eating” them. The CAR-M were shown to be effective in animal models, and are now being tested in a phase I clinical trial led by Dr. Kim A. Reiss at Penn Medicine in conjunction with Carisma Therapeutics. This clinical trial aims to test the safety of the CAR-M therapy in treating HER2+ solid tumors. HER2+ tumors can be breast, bladder, pancreatic, ovarian, and stomach cancers. Some preliminary data from the study was presented at the SITC (Society for Immunotherapy of Cancer) conference at the end of 2021. The CAR-macrophages were found to be able to penetrate and change the environment of solid tumors, which are some promising initial results, as this is what the CAR-T therapies have struggled to achieve.
Furthermore, the FDA has given this CAR-M therapy a Fast Track designation. The Fast Track program is intended to quicken the review of treatments that have the potential to treat a serious unmet need. This would help the treatment become available to patients more rapidly upon successful completion of its clinical trials.
As a researcher focusing on how macrophages affect cancer progression and treatment, I will be excitedly watching the progression of this clinical trial. This CAR-M therapy has the potential to dramatically improve solid tumor treatment, affecting a huge portion of cancer patients.
Edited by Susan Egbert
Sources:
1. CAR Macrophage Trial Endorses Cell Therapy for Solid Tumors. https://www.pennmedicine.org/news/news-releases/2022/january/first-in-human-trial-with-car-macrophages-shows-the-cell-therapy-safe-feasible-for-solid-tumors.
2. Solid Tumor Research – US. https://www.thermofisher.com/us/en/home/life-science/cancer-research/solid-tumor-research.html.
3. Carisma Therapeutics Inc. A Phase 1, First in Human Study of Adenovirally Transduced Autologous Macrophages Engineered to Contain an Anti-HER2 Chimeric Antigen Receptor in Subjects With HER2 Overexpressing Solid Tumors. https://clinicaltrials.gov/ct2/show/NCT04660929 (2022).
4. Ayscue, S. Carisma Therapeutics Announces U.S. Food and Drug Administration Grants Fast Track Designation to CT-0508 for the Treatment of Patients with Solid Tumors. Carisma Therapeutics https://carismatx.com/carisma-therapeutics-announces-u-s-food-and-drug-administration-grants-fast-track-designation-to-ct-0508-for-the-treatment-of-patients-with-solid-tumors/ (2021).
5. CAR T Cells: Engineering Immune Cells to Treat Cancer – NCI. https://www.cancer.gov/about-cancer/treatment/research/car-t-cells (2013).
6. Klichinsky, M., Ruella, M., Shestova, O. et al. Human chimeric antigen receptor macrophages for cancer immunotherapy. Nat Biotechnol 38, 947–953 (2020). https://doi.org/10.1038/s41587-020-0462-y
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