2. CAR-T with License to Kill Solid Tumors in Search of a Winning Strategy

Doi:10.3390/ijms20081903

Artificial receptors designed for adoptive immunotherapy require dual functions: antigen recognition and the ability to activate lytic machinery of reprogrammed effector T cells. In this way, CAR-T cells pass their cell killing action to cancer cells expressing the target tumor antigen, thereby bypassing the restriction of HLA-restricted antigen recognition. Evolving technologies have proposed a range of soluble and cellular "immunological weapons" to kill tumor cells; they include monoclonal antibodies that recognize tumor-associated antigens on the surface of tumor cells and expression on the surface of tumor-specific T cells. The immune cell checkpoint inhibits the receptor. To maintain the quality, intensity and duration of signals delivered by genetically engineered T cells, a series of powerful chimeric antigen receptors (CARs) have been designed to specifically target tumor cells while minimizing off-target toxicity. Cellular immune weapons have shown significant effects in curing leukemia, but have shown limited efficacy and persistence in the treatment of solid tumors. The general experience with immunological checkpoint inhibitors and CAR-T cell immunotherapy has identified a range of variables, weaknesses, and advantages that affect the clinical outcomes of neoplastic disease.

In a new review-type paper, researchers from the First University of Rome and the University of Rome in the United States outlined these aspects in order to identify current "missing strategies" to combat epithelial cancer. Related papers were published in the April 2019 issue of the International Journal of Molecular Sciences, titled "CAR-T with License to Kill Solid Tumors in Search of a Winning Strategy."

The design of CAR has unlimited potential, and sufficient observation may contribute to future CAR design, whether it is its extracellular domain or its intracellular domain. The intracellular domain is designed to maintain a less differentiated T cell phenotype with enhanced ability and decreased tendency to fail. Transcriptomic analysis of patients with chronic lymphocytic leukemia who have been successfully treated with CAR-T cells revealed a universal activation pattern of IL-6/STAT3 signaling pathway through IL-6, IL-17, IL-22, IL-31 and CCL20. This provides rationality for the design of novel intracellular domains that are capable of maintaining and maximizing T cell function to promote clinically potent memory T cell proliferation.

Loss of antigen, or simply its downregulation, has spurred the development of CARs that target more than one antigen. In "Universal CAR," CD16-CR appears to provide the most reliable method for treating solid tumors with CAR-T because it combines T cell redirection with the therapeutic activity of mAb, which may rapidly alter the target antigen when new tumor phenotype appears and possibly utilize the IgG produced by the B cell against the tumor antigen.

Another aspect that needs to be considered is how to maximize the activity of CAR-T cells in an unfriendly inhibitory tumor microenvironment. Encouraging results come from IDO inhibitors (fludarabine and cyclophosphamide), which have been shown to enhance the efficacy of CAR-T cells against CD19 B cell leukemia and are currently being evaluated in clinical trials. If verified, this preliminary information will provide a good reason to combine the two immunotherapies.

The final consideration is the generic CAR and immune checkpoint inhibitors. Although it is still speculative, the genetically engineered CD16-CR-expressing T cells are redirected to tumor cells by blocking the monoclonal antibody to the immunological checkpoint PD-L1, which is at least in selected cancer types. The combined use of immunological checkpoint inhibitors and CAR-T cell therapy provides further possibilities. This will have the advantage of maximizing T cell reactivity by blocking SHP2-mediated dephosphorylation of the proximal TCR signaling protein, while in T cells against PD-L1+ cancer cells after CD16-CR transduction Triggering activity similar to ADCC (antibody dependent cell-mediated cytotoxicity, antibody-dependent cell-mediated cytotoxicity), but no one has done any experiments in this regard.

To be continued in Part Three…