CAR-Based Strategies beyond T Lymphocytes: Integrative Opportunities for Cancer Adoptive Immunotherapy

Abstract

Chimeric antigen receptor (CAR)-engineered T lymphocytes (CAR Ts) produced impressive clinical results against selected hematological malignancies, but the extension of CAR T cell therapy to the challenging field of solid tumors has not, so far, replicated similar clinical outcomes. Many efforts are currently dedicated to improve the efficacy and safety of CAR-based adoptive immunotherapies, including application against solid tumors. A promising approach is CAR engineering of immune effectors different from αβT lymphocytes. Herein we reviewed biological features, therapeutic potential, and safety of alternative effectors to conventional CAR T cells: γδT, natural killer (NK), NKT, or cytokine-induced killer (CIK) cells. The intrinsic CAR-independent antitumor activities, safety profile, and ex vivo expansibility of these alternative immune effectors may favorably contribute to the clinical development of CAR strategies. The proper biological features of innate immune response effectors may represent an added value in tumor settings with heterogeneous CAR target expression, limiting the risk of tumor clonal escape. All these properties bring out CAR engineering of alternative immune effectors as a promising integrative option to be explored in future clinical studies.

CSPG4-Specific CAR.CIK Lymphocytes as a Novel Therapy for the Treatment of Multiple Soft-Tissue Sarcoma Histotypes

“…The latter finding is consistent with previous data underscoring the importance of antigen density to define a therapeutic window for antigens that are expressed, although at low levels, also by normal tissues (54,55). Author Manuscript Published OnlineFirst on September 8, 2020; DOI: 10.1158/1078-0432.CCR-20-0357 (12). Here, rather than exploring different immune cell subsets, we propose that T cells with enhanced cytokine-activation during the ex vivo expansion such as CAR-engineered CIK may represent a valid cellular platform for the treatment of STS.…”

“…Adoptive immunotherapy with T lymphocytes redirected by tumor antigen (TA)-specific chimeric antigen receptors (CAR) is one of the most effective therapy in B-cell malignancies (8)(9)(10). However, application of CAR.T cells to solid tumors remains challenging (11)(12)(13)(14)(15). Here, we have tested the ability of cytokine-inducedkiller T-lymphocytes (CIK) engineered with a TA-specific CAR to target tumor cells obtained by multiple STS hystotypes in vitro and in vivo.…”

What Can Gamma Delta T Cells Contribute to an HIV Cure?

“…HCMV seropositivity is typically associated with substantial clonal expansion within the Vδ1 population, and differentiation toward a terminally differentiated (CD27-CD45RA+) phenotype (Davey et al, 2017;van Der Heiden et al, 2020). In contrast to Vδ2 cells, the Vδ1 cell population is significantly expanded during HIV infection and ART (De Paoli et al, 1991;De Maria et al, 1992;Rossol et al, 1998;Wesch et al, 1998;Poles et al, 2003;Poggi et al, 2004;Fausther-Bovendo et al, 2008;Li et al, 2014;Cimini et al, 2015;Olson et al, 2018;Chevalier et al, 2019), the implications of which are largely unknown (Juno and Eriksson, 2019).…”

“…A major disadvantage to current αβ T cell-based chimeric antigen receptor (CAR)-T cell therapies is the potential for serious and/or fatal side effects, including cytokine release syndrome (van Den Berg et al, 2015), off-target effects due to antigen cross-reactivity (Linette et al, 2013), or transgenic TCR mispairing with endogenous TCR (Zhang et al, 2004). Several studies suggest that γδT-based immunotherapy is less likely to result in cytokine release syndrome (CRS) or off-target effects than αβ T cells (Harrer et al, 2017;Pauza et al, 2018;Rotolo et al, 2019). Indeed, expanded γδ T cells can mediate potent cytotoxicity but simultaneously produce lower levels of cytokines than αβ T cells (Harrer et al, 2017).…”

“…Given the utility of both ADCC-based and direct recognition of HIV-infected T cells in cure strategies, mixed γδT expansion may be a potent method by which to generate effector γδT cells. More complex approaches could also engineer such cells to express a CAR, providing an additional mechanism by which to recognize infected cells (Rotolo et al, 2019).…”