CAR-T cell therapy is a type of treatment where the patient’s T cells are modified in the laboratory for attacking the cancer cells. This type of modification involves adding the gene for a special receptor that binds to a certain cancer cell protein. The special receptor is named CAR or chimeric antigen receptor. CAR-T cell therapy is primarily prevalent for treating blood cancers, with FDA approvals in B cell Acute Lymphoblastic leukemia (ALL) and Non-Hodgkin Lymphoma (NHL) for targeting CD19.
CAR-T Cell Therapy
CAR-T cell therapy uses engineered human T cells that play an immunogenic role to detect and destroy abnormally functioning cells, like cancer cell line. In a normal body, cancer cells find several ways to bypass the T cell detection, thus allowing tumors to proliferate and expand. Therefore, CAR-T cells are developed to overcome these hurdles. A sample of patient’s T cells is collected and genetically engineered by introducing chimeric antigen receptors in them that resurfaces on the cell membrane. When these cells are re-injected in the patient, these receptors supposedly help the T cells to target cancer cells throughout the body by detecting cancer-specific surface proteins.
Side Effects Of CAR-T Therapy
CAR-T therapy might cause cytokine release syndrome (CRS) that leads to fever, fatigue, low blood pressure, and breathing difficulties. Other general side effects of CAR-T cell therapy include headache, seizures, speech problems, and balance difficulties. The side effects generally start to improve gradually with proper treatment, care, and management.
Allogeneic CAR-T Cell Therapy
Currently, CAR-T cell therapy is practiced in an autologous manner, i.e., the patient’s own T cells are used to modify into CAR-T cells and used for therapeutics. This poses a limitation as this whole period tales around 20 days which is crucial for the patient suffering from cancer. Moreover, other heavy dose treatments might damage the health of the patient’s T cells even before planning to get CAR-T therapy. Therefore, allogeneic CAR-T therapy are been researched upon where immune T cells are collected from healthy donors and processed similarly to develop CAR-T cells for accelerating the time of administering to cancer patients. However, the risk of graft-vs-host disease is always a concern in these allogeneic cases and studies are ongoing to look into these limitations and risks.
All these while, we were discussing CAR-T cell therapy advancements in blood cancers but recent research is widening the therapeutic response of CAR-T cell therapy in solid tumors too. Although significant therapeutic approvals have not yet been done for CAR-T therapy in solid tumors, early-stage clinical trials have shown good results in targeting IL13Rα, HER2, and CLDN18.2.
Targeting Solid Tumors With CAR-T Cells
There has been a report of preclinical evaluation of CAR-T cell therapy by Jiang et al for targeting CLDN18.2, a stomach specific isoform of claudin-18 (CLDN18). Although CLDN18.2 can be found in non-cancerous gastric tissues, it is restricted to differentiated short-lived cells of the mucosa. Research has shown that CLDN18.2 is overexpressed in gastric, esophageal, and pancreatic cancers. In a study, monoclonal antibodies have been developed against CLDN18.2 and currently has been used in several clinical trials. The monoclonal antibody Claudiximab/IMAB362 based studies also include a Phase III study in combination with mFOLFOX6 for treating gastric cancers, adenocarcinoma and metastatic cancers that are HER2 negative and CLDN18.2 positive.
Researchers have developed lentiviral vectors encoding a variety of chimeric antigen receptors like hu8E5-28Z, hu8E5-BBZ, and hu8E5-2I-28Z, based on anti-CLDN18.2 scFv. These scFv regions were linked to the intracellular signaling domain from hCD28 or hCD137 chains via hCD8 hinge and CD28 transmembrane parts. Following the lentiviral vector development, T cells were transduced with these vectors encoding the CAR genes to generate CAR T cells specific for targeting CLDN 18.2. These cells have been found to effectively lyse CLDN18.2 positive cells in vitro whereas CLDN18.2 negative cells were unaffected, therefore showing significant target specific anti-cancerous effects of CAR-T therapy in solid tumor cases in vitro studies. After promising results in in vitro studies, researchers also went ahead within vivo research to detect the efficiency of CLDN18.2 specific CAR-T cells by conducting studies on cell line- derived and patient-derived xenograft models transfected with the CLDN18.2 gene. Studies have shown significant inhibition of tumor growth and reduction of tumor weight in these models upon conducting CAR-T cell therapy specific to CLDN18.2 overexpressed cells.
Anti-cancer therapies like CAR-T cell therapy have changed the outlook of cancer therapeutics and patients have reported significant developments with this treatment model. The future holds much more advancements in this domain and with significant studies and pre-clinical trials, CAR-T therapy for solid tumors and allogeneic Car-T cell therapy will soon be a promising anti-cancer therapeutic model.
