Abstract
The genetically engineered Chimeric Antigen Receptor bearing T-cell (CAR T cell) therapy has been emerged as the new paradigm of cancer immunotherapy. However, recent studies have reported an increase in the number of relapsed haematological malignancies. This review provides newer insights into how the efficacy of CAR T cells might be increased by the application of new genome editing technologies, monitoring the complexity of tumor types and T cells sub-types. Next, tumor mutation burden along with tumormicroenvironment and epigenetic mechanisms of CAR T cell as well as tumor cell may play a vital role to tackle the cancer resistance mechanisms. These studies highlight the need to consider traditional cancer therapy in conjunction with CAR T cell therapy for relapsed or cases unresponsive to treatment. Of note, this therapy is highly expensive and requires multi-skill for successful implementation, which results in reduction of its accessibility/affordability to the patients. Here, we also propose a model for cost minimization of CAR T cell therapy by a collaboration of academia, hospitals and industry.
Highlights
Understanding of the intricate relationship between the immune system and the tumor cells has provided the accelerated development of cancer treatment such as rejuvenation of host immunity, training the immune cells against the cancer cells, removing the exhaustions of immune cells against tumor antigens etc.Turning on immune cell against the cancer cell either through antibodies mediated therapeutics or re-infusion of trained immune cells into the cancer patient are excellent examples of cancer immunotherapy [1, 2, 3]
Extensive research employing immune cells in cancer treatment has led to the development of antibodies based immunotherapies [2], allogeneic stem cell transplantation [4] and Chimeric Antigen Receptors (CARs) T cell therapy [5]
Successful CAR T cell therapy has been developed by careful considerations of crucial factors such as Selection of cancers where it can act optimally; Identification of appropriate tumor antigen(s); Selection of gene constructs to design chimeric receptors; Selection of immune cells for engineering the receptors against tumor antigen; Selection of other determinants of efficacy against cancer cells such as affinity of CAR for tumor antigen(s); selection of appropriate growth factors in the development of CAR T cells; and potential toxicities associated with the therapy including cytokine release syndrome and neurotoxicity
Summary
Understanding of the intricate relationship between the immune system and the tumor cells has provided the accelerated development of cancer treatment such as rejuvenation of host immunity, training the immune cells against the cancer cells, removing the exhaustions of immune cells against tumor antigens etc. Extensive research employing immune cells in cancer treatment has led to the development of antibodies based immunotherapies [2], allogeneic stem cell transplantation [4] and Chimeric Antigen Receptors (CARs) T cell therapy [5]. We have discussed the main keys of CAR T cells focussing on ‘how to improvise it to minimize failures and relapses’ for a better outcome. This includes the discussion on the effect of tumor mutation burden (TMB), tumor microenvironment (TME), role of epigenetic mechanisms and possible combination therapies. We propose a triangular collaboration among hospital, academia and industry which may further improve the quality and affordability of this cellular therapy, especially for economically developing nations
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