Cytokines as an important player in the context of CAR-T cell therapy for cancer: Their role in tumor immunomodulation, manufacture, and clinical implications

Abstract

CAR-T cell therapies have been recognized as one of the most advanced and efficient strategies to treat patients with hematologic malignancies. However, similar results have not been observed for the treatment of solid tumors. One of the explanations is the fact that tumors have extremely hostile microenvironments for the infiltration and effector activity of T-cells, mainly due to the presence of highly suppressive cytokines, hypoxia, and reactive oxygen species. Taking advantage of cytokines functionally, new fourth-generation CAR constructs have been developed to target tumor cells and additionally release cytokines that can contribute to the cytotoxicity of T-cells. The manufacturing process, including the use of cytokines in the expansion and differentiation of T cells, is also discussed. Finally, the clinical aspects and the influence of cytokines on the clinical condition of patients, such as cytokine release syndrome, who receive treatment with CAR-T cells are addressed. Therefore, this review aims to highlight how important cytokines are as one of the major players of cell therapy.

Advancements in cancer immunotherapies targeting CD20: from pioneering monoclonal antibodies to chimeric antigen receptor-modified T cells

“…Tumor cells and immunosuppressive cells in the tumor microenvironment, e.g. myeloid-derived suppressive cells (MDSCs), tumor-associated macrophages (TAMs), and regulatory T cells (Tregs), can secrete suppressive cytokines that inhibit the activity of effector cells (T cells, NK cells, phagocytes), thereby reducing the effectiveness of immunotherapy ( 170 , 171 ). It has also been shown that some proteins secreted by the tumor may have a suppressive effect, including galectin-1, which inhibited CD20 mAb-induced phagocytosis in the lymphoma microenvironment ( 172 ).…”

Unlocking the Potential of Therapy-Induced Cytokine Responses: Illuminating New Pathways in Cancer Precision Medicine

“…They also described some strategies to overcome the immunosuppressive cytokines, such as dominant-negative receptors, inverted cytokine receptors, and T-cells redirected for universal cytokine killing (TRUCKs). They summarized the preclinical and clinical studies that have used different cytokines, such as IL-12, IL-15, IL-18, IL-21, IL-22, and IL-23, in combination with CAR-T cells [ 76 ]. In another recent review, the authors discussed the potential of cytokines as therapeutics for immune-related disorders.…”

Therapeutic Vaccination in Head and Neck Squamous Cell Carcinoma—A Review

“…On the other hand, TCR-T and CAR-T therapies are being explored by several authors in HNSCC, and the preliminary results are encouraging, both in terms of safety and clinical efficacy [ 163 ]. The isolated peripheral T cells can be genetically engineered to target several known tumor antigens of HNSCC, including, EGFR, MAGE-A4, MUC1, CD 70, and HER2, and the ACT with these agents has demonstrated a durable clinical response in early clinical studies [ 163 , 164 , 165 ]. Interestingly, an ongoing phase II trial (NCT04847466) is evaluating the effectiveness of irradiated PD-L1 CAR-NK cells in subjects with R/M gastric cancer or HNSCC in combination with pembrolizumab and N-803.…”