Combination Therapeutics with CAR-T Cell Therapy

Adoptive cellular immunotherapy, specifically chimeric antigen receptor T-cell (CAR-T) therapy, has recently emerged as a breakthrough treatment for multiple hematological malignancies with potential for long term cure. However, multiple hurdles remain to be overcome. Some issues are inherent to CAR-T cells, such as suboptimal expansion, rapid exhaustion, or rejection. Other problems are related to the immunosuppressive tumor microenvironment, which dampens CAR-T activity. Additionally, CAR-T cell treatment is associated with significant toxicities relating to activation of the immune system, most notably cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Multiple strategies are currently underway to increase CAR-T efficacy and decrease toxicity. Some of those strategies involve creating optimized stand-alone CAR-T cell products, while other strategies involve combining existing CAR-T therapies with other treatment modalities. In this chapter, we will focus on combination strategies that are currently being used and/or are under exploration. We will first discuss strategies used to increase CAR-T effectiveness through combination with immunomodulatory agents, cancer-directed therapies, tumor antigen expression enhancers, or HCT. We will then discuss strategies aimed at decreasing CAR-T toxicity through combination with other immunomodulatory agents. All current clinical trials exploring these strategies will also be discussed.