CAR-T cell therapy for hematological malignancies: Limitations and optimization strategies

Abstract

In the past decade, the emergence of chimeric antigen receptor (CAR) T-cell therapy has led to a cellular immunotherapy revolution against various cancers. Although CAR-T cell therapies have demonstrated remarkable efficacy for patients with certain B cell driven hematological malignancies, further studies are required to broaden the use of CAR-T cell therapy against other hematological malignancies. Moreover, treatment failure still occurs for a significant proportion of patients. CAR antigen loss on cancer cells is one of the most common reasons for cancer relapse. Additionally, immune evasion can arise due to the hostile immunosuppressive tumor microenvironment and the impaired CAR-T cells in vivo persistence. Other than direct antitumor activity, the adverse effects associated with CAR-T cell therapy are another major concern during treatment. As a newly emerged treatment approach, numerous novel preclinical studies have proposed different strategies to enhance the efficacy and attenuate CAR-T cell associated toxicity in recent years. The major obstacles that impede promising outcomes for patients with hematological malignancies during CAR-T cell therapy have been reviewed herein, along with recent advancements being made to surmount them.

CAR products from novel sources: a new avenue for the breakthrough in cancer immunotherapy

“…While this reliance restricts off-target toxicity, it also confines their effectiveness largely to CD1d + tumors. Furthermore, loss-of-antigen relapse is a common cause of failure in CAR cell therapy ( 44 ). During CAR NKT cell treatment, tumor cells might downregulate their CD1d expression.…”

“…Another primary challenge is the transient persistence of CAR NKT cells, often requiring repeat doses for sustain tumor control ( 38 ). Conventional CAR T cells benefit from design improvements, such as the tailored design of costimulatory domains, and the cytokines treatment like IL-15 ( 44 ). Similar efforts have been made for CAR NKT cells to extend their durability ( 38 , 42 ) ( Figure 1 ).…”

“…reported that the effectiveness of CEA-CAR Vγ9Vδ2 T cells was limited in duration ( 83 ). Efforts to enhance the in vivo persistence of CAR T cells include the administration of IL-15 and the modulation of intracellular signaling pathways ( 44 ). Similar strategies are now being applied to CAR γδ T cells, aiming to extend their persistence ( 87 , 89 , 94 , 99 , 100 ) ( Figure 3 ).…”

Modulation of T cell function and survival by the tumor microenvironment

“…Engineered T cells with a specific T cell receptor against the cancer testis antigen New York esophageal squamous cell carcinoma 1 (NY-ESO-1) have been used to treat solid tumors ( D'Angelo et al, 2018 ; Robbins et al, 2011 ). Chimeric antigen receptor (CAR) T cells that are engineered to recognize tumors and specific proteins ( June et al, 2018 ) have demonstrated strong clinical efficacy for hematologic cancers ( Huang and Huang, 2022 ) and can be modified to target other tumor types.…”

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“…Autologous (patient-derived) Chimeric Antigen Receptor T (CAR T) cells have widely proven their efficacy to treat certain B-cell haematological malignancies [1][2][3]. However, autologous CAR-T presented some limitations regarding both the manufacturing process and the use of T cell exhaust due to several therapy lines [4,5]. The possibility to use cells from healthy donors, referred to as "off-the-shelf" allogeneic CAR T or universal CAR T (UCART) could potentially overcome these limitations, as well as making a marked reduction in costs due to the implementation of industrialized manufacturing process.…”