Challenges and new technologies in adoptive cell therapy

Abstract

Adoptive cell therapies (ACTs) have existed for decades. From the initial infusion of tumor-infiltrating lymphocytes to the subsequent specific enhanced T cell receptor (TCR)-T and chimeric antigen receptor (CAR)-T cell therapies, many novel strategies for cancer treatment have been developed. Owing to its promising outcomes, CAR-T cell therapy has revolutionized the field of ACTs, particularly for hematologic malignancies. Despite these advances, CAR-T cell therapy still has limitations in both autologous and allogeneic settings, including practicality and toxicity issues. To overcome these challenges, researchers have focused on the application of CAR engineering technology to other types of immune cell engineering. Consequently, several new cell therapies based on CAR technology have been developed, including CAR-NK, CAR-macrophage, CAR-γδT, and CAR-NKT. In this review, we describe the development, advantages, and possible challenges of the aforementioned ACTs and discuss current strategies aimed at maximizing the therapeutic potential of ACTs. We also provide an overview of the various gene transduction strategies employed in immunotherapy given their importance in immune cell engineering. Furthermore, we discuss the possibility that strategies capable of creating a positive feedback immune circuit, as healthy immune systems do, could address the flaw of a single type of ACT, and thus serve as key players in future cancer immunotherapy.

Higher TIGIT+ γδ TCM cells may predict poor prognosis in younger adult patients with non-acute promyelocytic AML

“…T-cell immunotherapy has been increasingly investigated in AML ( 16 ). Nevertheless, the redirection of pan CD3+ T cells to target leukemia blasts has demonstrated limited efficacy in clinical trials and is often accompanied with severe toxicity in patients with AML due to T-cell immune dysfunction ( 17 , 34 ). In vitro and mouse model studies have shown the cytotoxic effects of γδ T cells on AML cells ( 35 ).…”

“…As a minor subset of lymphocytes, human γδ T cells account for approximately 2%–10% of CD3+ T cells in PB and exhibit non-major histocompatibility complex (non-MHC)-restricted recognition of tumor antigens ( 14 , 15 ). Upon activation in the periphery, γδ T cells exhibit remarkably diverse effector functions associated with immune response and a potent cytotoxic activity via elevated levels of CD107a expression and interferon (IFN)-γ cytokine production, granzyme B, and perforin secretion ( 16 , 17 ). Previously, we highlighted γδ T-cell-based immunotherapy as a highly promising strategy in cancer immunotherapy ( 18 ).…”

Modulation of the tumor microenvironment and mechanism of immunotherapy-based drug resistance in breast cancer

“…However, engineered immune cell application also involves several limitations. Unavailability of suitable target, low antigen density, loss of antitumor activity due to exhaustion and poor infiltration possess challenges in CAR-T therapy [ 108 ]. Moreover, this therapy exhibits several adverse effects due to targeting antigens present in the normal tissues [ 109 ].…”

“…C-reactive protein along with various inflammatory cytokines are also elevated [ 111 ]. CAR-NK and CAR-M also exhibit several issues like limited proliferation capacity, insufficient infiltration, limited availibility, etc [ 108 ].…”

Chimeric antigen receptor-natural killer cell therapy: current advancements and strategies to overcome challenges

“…Adoptive cell therapy (ACT) is a promising immunotherapy targeting cancer cells by transferring specialized or engineered immune cells which are endowed with tumor-killing ability into a cancer patient ( 1 ). Among current ACTs implemented, chimeric antigen receptor (CAR) therapy becomes increasingly significant as T cells engineered with CAR (CAR-T) have shown clinical success in hematological malignancies in clinical settings owing to their remarkable anticancer abilities.…”