CAR‑T cell combination therapy: the nextrevolution in cancer treatment

Introduction: In recent decades, the advent of immune-basedtherapies, most notably Chimeric antigen receptor (CAR)-T celltherapy has revolutionized cancer treatment. The promising resultsof numerous studies indicate that CAR-T cell therapy hashad a remarkable ability and successful performance in treatinghematological malignancies. However, the heterogeneity andimmunosuppressive tumor microenvironment (TME) of solidtumors have challenged the effectiveness of these anti-tumorfighters by creating various barriers.Materials and Methods: This systematic review was conductedto outline comprehensive studies published in PubMed, Scopus,Science Direct and Google Scholar databases from ۲۰۰۳ toOctober ۲۰۲۲ by using ۵ keywords. ۲۸۷ articles were screenedand ۹۷ were totally included.Result: Numerous studies have shown that the use of CARTcell therapy in combination with other cancer treatmentshave led to the synergistic effect of these therapies together. Inthis regard, chemotherapy and radiotherapy both cause tumorcell degradation and increase the activity of CAR-T cells andother immune cells by applying apoptosis on tumor cells andreleasing DAMPs from them. On the other hand, they stimulatethe production of inflammatory cytokines and inhibit theimmunosuppressive cells and factors in TME. Oncolytic virusesincrease the infiltration and efficacy of CAR-T cells intumor sites through the production of RANTES, CXCL۱۱,and IL-۱۵. Also, they play a substantial role in DC maturationand M۱ macrophage polarization. Besides, utilizing the cellularand molecular cancer vaccines is another practical strategythat helps CAR-T cells target tumor cells precisely and enhancetheir anti-tumor cytotoxicity. BiTEs contribute to establishingclose relationships between effector cells and tumor cells byengaging two different antigens. Checkpoint inhibitors, whichhave recently received much attention in treating cancers, have also shown promising results in combination with CAR-T celltherapy. In this context, the use of blocking antibodies, drugantagonists, dominant-negative receptors (DNR), and knockingout mechanisms such as CRISPR/Cas۹ and shRNA to suppressthe inhibitory checkpoints like PD-۱/ PDL-۱ as well as administratingthe costimulatory molecules like CD۲۸ and ۴-۱BB,in combination with CAR-T cell would be promised in cancertreatment. Inverted cytokine receptors (ICRs) such as ۴/۷ ICRand ۴/۲۱ ICR or administration of IL-۲, IL-۱۲, and IL-۱۵ cytokines,would be other potent combination therapy with CARTcells. Immunomodulatory factors are other anti-cancer agentsthat can be applied in combination with CAR-T cells, includingGSIS as an inhibitor of GS, mir-۱۵۵ as an IDO inhibitor, Lenidomideas an enhancer of inflammatory cytokines and inhibitorof anti-inflammatory cytokines as well as other factors such asdecitabine, SMACs, HDACi, etc.Conclusion: Consequently, the synergistic effects of differenttreatments in their combined use can be more successful in degradingtumor cells and helping to regress the disease comparedto monotherapy approaches.

کلیدواژه ها:

CAR-T cell therapy ، immunotherapy ، hematologicalmalignancies ، combination therapy ، solid tumors