For years, chimeric antigen receptor (CAR) T-cell therapy has been successfully used in treating blood cancers (e.g., leukemia, lymphoma, myeloma) but, unfortunately, had been unable to replicate the results in solid tumors. This was the case until Innovative Cellular Therapeutics, a Shanghai-based biotechnology company involved in cell therapy research and development, came up with a potential CAR T-cell technology that claims to effectively reduce tumor size in patients with colorectal and thyroid cancer.
Exploring the Limitations of CAR T-Cells
While T-cells are tasked with the extremely important role of protecting the body against pathogens and cancer cells, they usually come short of fulfilling their role upon encountering solid tumors. This happens due to several reasons, which include (1) the lack of cancer-specific targets, (2) the T-cells’ limited ability to penetrate and survive in solid tumor sites, and (3) the presence of immunosuppressive factors within the hostile solid tumor microenvironment.
To circumvent these limitations, several technological advances have been made to reinforce the ability of T-cells in fighting cancer cells. One such technology, specifically known as the adoptive cell transfer (or ACT), involves the ex vivo enhancement and proliferation of tumor-specific cells and re-infusing them to the patient to target and eliminate cancer cells.
ACT can be conducted by (1) expanding tumor-infiltrating lymphocytes (TILs) from the tumor site or (2) obtaining non-therapeutic endogenous lymphocytes from the peripheral blood and making them tumor-specific through genetic redirection with a chimeric antigen receptor (CAR) or T-cell receptor (TCR).
CARs usually consist of an endodomain with one, two, or three signaling domains, a hinge, a transmembrane domain, and a single-chain variable fragment (scFv) ectodomain capable of targeting an antigen of choice. Theoretically, T-cells with specificity against a target antigen can promote long-term immunity through genetic redirection. However, different types of tumors provide different results.
CAR T-cell therapy demonstrated overwhelming success in treating hematologic malignancies such as acute lymphoblastic leukemia, chronic lymphocytic leukemia, and diffuse large B cell lymphoma. While remissions can be quite impressive (up to 90% in some cases), CAR T-cell therapy for solid tumors cannot boast of the same success since it is still in its infancy stages.
CAR T-Cells and Solid Tumors: Addressing the Challenges
To date, TIL has been more effective in treating solid tumors, but some exciting advances are brewing up in the area of CAR therapy. Fourth-generation CAR constructs with enhanced migration, efficacy, and immunosuppression resistance are currently being developed for the treatment of solid tumors. One notable development in this space is ICT’s CoupledCAR platform technology.
CoupledCAR is a novel technology designed to induce more potent anti-tumor responses by enhancing the proliferation, migration ability, and resistance of T-cells against immunosuppression. With these enhancements, T-cells are expected to infiltrate tumor sites with greater efficacy. In fact, clinical data from two studies conducted in China indicated that this technology shows great promise in reducing tumor size in patients with thyroid and colorectal cancer.
Based on the results of the clinical trial, two patients with advanced thyroid cancer exhibited significant cancer size reduction a few months after the therapy. One patient showed a marked reduction in the size of his thoracic paratracheal nodules and lymph node metastasis, while the other patient experienced a 73.5% volume reduction in her lung tumor two months after the therapy.
Another two patients with colorectal cancer, both of whom received chemotherapy and underwent surgery to remove the tumor, experienced similar results. The first patient, a 55-year-old man, showed a 45% reduction in tumor size in the first month of receiving the therapy, while the tumor that metastasized in the left lung of the second patient was reduced by 75%.
While it may be too early to tell, recent developments indicate that CAR T-cell therapy can be an effective treatment for solid tumors.