CAR T therapy, or chimeric antigen receptor T-cell therapy, has revolutionized the treatment of some blood cancers, allowing patients with relapsed or refractory disease to live longer and better lives. However, cellular treatment has not been as effective in clinical trials for individuals with solid tumors, due in part to a lack of tumor targets that are not expressed in essential tissues.
Moffitt Cancer Center researchers have identified a novel potential target for CAR T cells called OR2H1 that slows development in lung and ovarian cancers, according to a recent study published in Molecular Cancer Therapeutics, a publication of the American Association for Cancer Research.
The genetic modification of the patient’s T cells is the cornerstone of CAR T-cell therapy. Their cells are harvested via an apheresis procedure and delivered to a lab where they are genetically engineered to carry a T cell receptor gene that identifies a particular marker on cancer cells. Before being sent straight to the hospital to be injected back into the patients, the transformed T cells, now known as CAR T cells, are stimulated to proliferate and multiply.
The CAR T cells’ receptor functions as a GPS, locating their particular marker on the surface of cancer cells. CAR T treatments are now licensed to treat lymphoma, leukemia, and multiple myeloma patients, but there are no approved CAR T treatments for solid cancers.
Researchers at Moffitt are working to uncover tumor markers that might make CAR T a viable treatment option for patients with solid tumors. The objective is to discover a marker that is produced on tumor cells but not normal cells in order to limit the risk of side effects. Dr Jose Conejo-Garcia and research colleagues concentrated their search on a class of proteins known as olfactory receptors, which are produced in the nose and have a role in smell perception.
Scientists observed that the protein OR2H1 is expressed in a range of solid tumors, ranging from 4% of colon cancer samples to 69% of gall bladder cancer samples, during lab trials. Importantly, OR2H1 was discovered only in the testis out of all the normal tissues studied, suggesting that treatments that target OR2H1 would have little effect on normal cells.
The researchers next developed CAR T cells that were only able to recognize the OR2H1 protein. The OR2H1 CAR T cells were able to destroy OR2H1-expressing lung and ovarian cancer cells but had no impact on healthy cells.
In immunodeficient mice treated with human tumors, the OR2H1 CAR T cells demonstrated anti-tumor activities in vivo. Tumor inhibition was seen in lung and ovarian cancer mouse models with variable amounts of OR2H1, as well as chemotherapy-resistant ovarian cancer cells.
OR2H1 may be an effective target for CAR T treatments in solid tumors, according to their findings. The researchers believe that the results of these first studies will lead to the creation of OR2H1 CAR T cells for a wide range of solid tumor patients.
Our work demonstrates the applicability of this therapy to a wide variety of patients, given the expression of OR2H1 in a subset of solid tumors across multiple histologies, including high-grade serous ovarian cancers, lung carcinoma, cholangiocarcinoma, prostate cancer and ovarian cancers of multiple other histologies. Targeting a molecule that is not expressed in vital tissues would allow us to further engineer T cells to overcome immunosuppression at tumor beds, if needed.”
Jose Conejo-Garcia, MD, PhD, Chair, Department of Immunology, Moffitt Cancer Center
Martin, A. L., et al. (2022) Olfactory Receptor OR2H1 is an effective target for CAR T cells in human epithelial tumors. Molecular Cancer Therapeutics. doi.org/10.1158/1535-7163.MCT-21-0872.