Immune Cell Hacking: Challenges and Clinical Approaches to Create Smarter Generations of Chimeric Antigen Receptor T Cells

Abstract

T cells equipped with chimeric antigen receptors (CAR T cells) have recently provided promising advances as a novel immunotherapeutic approach for cancer treatment. CAR T cell therapy has shown stunning results especially in B-cell malignancies; however, it has shown less success against solid tumors, which is more supposed to be related to the specific characteristics of the tumor microenvironment. In this review, we discuss the structure of the CAR, current clinical advantages from finished and ongoing trials, adverse effects, challenges and controversies, new engineering methods of CAR, and clinical considerations that are associated with CAR T cell therapy both in hematological malignancies and solid tumors. Also, we provide a comprehensive description of recently introduced modifications for designing smarter models of CAR T cells. Specific hurdles and problems that limit the optimal function of CAR T cells, especially on solid tumors, and possible solutions according to new modifications and generations of CAR T cells have been introduced here. We also provide information of the future directions on how to enhance engineering the next smarter generations of CAR T cells in order to decrease the adverse effects and increase the potency and efficacy of CAR T cells against cancer.

Immunotherapies and Combination Strategies for Immuno-Oncology

“…The process of producing CAR T cells is complicated and includes multiple steps [ 157 ]. First, white blood cells are separated from a sample of the patient’s peripheral blood along with stimulation with mAbs and/or cytokines to help isolate T cells from the sample [ 157 , 158 ]. After stimulation and expansion of T cells, genetic modification of the chimeric antigen receptor takes place.…”

The Application of CAR-T Cells in Haematological Malignancies

“…Fc-arranged domains are about 200 aa long and their organization is characterized by tertiary structures (Lee and Kim 2019). The hinge domain prevents the flexibility of the exogenous part of CAR to maintain a proper level of target recognition (Elahi et al 2018). The length of this domain partially defines CAR-binding capability, and thus the antigen-of-interest recognition (Xu et al 2018).…”

“…The architecture of the first generation of CART is rather basic since their signalling domain comprises only of the CD3ζ chain (Kowolik et al 2006). The target domain of first-generation CART can include either scFv or Fab fragments, but scFv domains are predominant (Sadelain et al 2013;Elahi et al 2018). Since first-generation CART do not incorporate any additional signalling domains, they are only able to mediate optimal cellular activation via dimerization (Bagley et al 2010).…”

“…The second generation of CART, most often used in the clinic, encompass co-stimulatory domain in addition to the first-generation properties. This combination allows the activation of a secondary signalling pathway, resulting in a higher overall efficacy (Elahi et al 2018). Consequently, the fundamental improvement characteristic of second-generation CART is combining the CD3ζ with another co-stimulatory domain, most commonly CD28 or 41BB (CD137), but there are also constructs using OX40 (CD134), CD2, CD27 or inducible T-cell co-stimulator (ICOS) (Song et al 2012;Hombach et al 2012).…”

Immuno-oncology for surgeons

“…One type of adoptive T cell transfer that is showing promise is chimeric antigen receptor (CAR) T cell therapy. The CAR is an artificial transmembrane receptor which has an antibody fragment that targets cell surface antigens on cancer cells, and an intracellular domain that activates the CD3 signalling pathway once antigen binding has occurred. As such, a CAR T cell does not require antigen presentation by an MHC class I molecule, enabling it to overcome escape mechanisms involved in the antigen presentation pathways.…”