Gene-Edited Interleukin CAR-T Cells Therapy in the Treatment of Malignancies: Present and Future

Abstract

In recent years, chimeric antigen receptor T cells (CAR-T cells) have been faced with the problems of weak proliferation and poor persistence in the treatment of some malignancies. Researchers have been trying to perfect the function of CAR-T by genetically modifying its structure. In addition to the participation of T cell receptor (TCR) and costimulatory signals, immune cytokines also exert a decisive role in the activation and proliferation of T cells. Therefore, genetic engineering strategies were used to generate cytokines to enhance tumor killing function of CAR-T cells. When CAR-T cells are in contact with target tumor tissue, the proliferation ability and persistence of T cells can be improved by structurally or inductively releasing immunoregulatory molecules to the tumor region. There are a large number of CAR-T cells studies on gene-edited cytokines, and the most common cytokines involved are interleukins (IL-7, IL-12, IL-15, IL-18, IL-21, IL-23). Methods for the construction of gene-edited interleukin CAR-T cells include co-expression of single interleukin, two interleukin, interleukin combined with other cytokines, interleukin receptors, interleukin subunits, and fusion inverted cytokine receptors (ICR). Preclinical and clinical trials have yielded positive results, and many more are under way. By reading a large number of literatures, we summarized the functional characteristics of some members of the interleukin family related to tumor immunotherapy, and described the research status of gene-edited interleukin CAR-T cells in the treatment of malignant tumors. The objective is to explore the optimized strategy of gene edited interleukin-CAR-T cell function.

TCR-T Immunotherapy: The Challenges and Solutions

“…Similar to CRS related to monoclonal antibody therapy, CRS related to adoptive T cell therapy is closely associated with increases in IL-6 and TNF-α levels, accompanied by increases in IL-2, granulocyte macrophage colony stimulating factor (GM-CSF), IL-5, IL-8 and IL-10 ( 75 – 78 ). IL-6, the central mediator of CRS toxicity ( 79 ), has been shown to play important roles in the activation, expansion, survival and polarization of T cells ( 80 ), and to promote the expression of T cell adhesion factor ( 81 ). In addition, IL-6 has also been found to regulate the surface expression of Fas receptor by upregulating anti-apoptotic factors through STAT3, thus inhibiting T cell apoptosis ( 82 , 83 ).…”

Advances in CAR-T Cell Genetic Engineering Strategies to Overcome Hurdles in Solid Tumors Treatment

“…Some of them hace been addressed in the Treg section (see section 2.2.2 on Tregs). For an extensive review on gene-edited interleukin CAR-T cells published recently, see Zhang et al (268).…”

“…For an extensive review on gene-edited interleukin CAR-T cells published recently, see Zhang et al. ( 268 ).…”

Emerging Approaches for Solid Tumor Treatment Using CAR-T Cell Therapy

“…ILs can also reverse immunosuppressive TMEs, which may be advantageous for treating solid tumors. Thus, novel IL secreting systems or inverted cytokine receptor (ICR) have been incorporated in CAR-T cells, which was reviewed in Zhang et al [130]. CAR-T cells targeting prostate stem cell antigen (PSCA) were further engineered to improve T cell persistence and expansion, via co-expression of TGF-β receptor-41BB and IL-4 receptor-IL7 receptor signaling domain (also called 4/7 ICR) [131].…”