Modulation of Radiation Doses and Chimeric Antigen Receptor T Cells: A Promising New Weapon in Solid Tumors-A Narrative Review

Abstract

Tumor behavior is determined by its interaction with the tumor microenvironment (TME). Chimeric antigen receptor (CART) cell therapy represents a new form of cellular immunotherapy (IT). Immune cells present a different sensitivity to radiation therapy (RT). RT can affect tumor cells both modifying the TME and inducing DNA damage, with different effects depending on the low and high doses delivered, and can favor the expression of CART cells. CART cells are patients' T cells genetically engineered to recognize surface structure and to eradicate cancer cells. High-dose radiation therapy (HDRT, >10-20 Gy/fractions) converts immunologically "cold" tumors into "hot" ones by inducing necrosis and massive inflammation and death. LDRT (low-dose radiation therapy, >5-10 Gy/fractions) increases the expansion of CART cells and leads to non-immunogenetic death. An innovative approach, defined as the LATTICE technique, combines a high dose in higher FDG- uptake areas and a low dose to the tumor periphery. The association of RT and immune checkpoint inhibitors increases tumor immunogenicity and immune response both in irradiated and non-irradiated sites. The aim of this narrative review is to clarify the knowledge, to date, on CART cell therapy and its possible association with radiation therapy in solid tumors.

Keywords: CART; immunotherapy; radiotherapy; solid tumor; tumor microenvironment.

Figure 1

Effect of differentiated doses on tumor cells. High doses of radiation therapy lead to immunogenic cell death through both DAMPs, ATP, calreticulin, HMGB1, and TLR4 production, and the associated tumor antigens. This process results in the maturation of dendritic cells and the activation of T cells. Low doses of radiation therapy lead to non-immunogenic cell death through macrophage polarization (M2 → M1) and recruitment of CD4+ cells and NK cells. LDRT reduces ROS and maintains blood vessel integrity, allowing the movement of CART cells and cell effectors across the vascular endothelium into the tumor tissue. Tumor cells and activated T cells express on a surface immune checkpoint (IC). The link between the IC and the corresponding ligand inhibits T cells from killing tumor cells. The use of immune checkpoint inhibitors (ICIs) allows TC cells to kill tumor cells. The link IC–ICI blocks T reg activity. CARTs can bind antigen-associated tumors (TAAs) and induce tumor cell death. T cell exhaustion is one of the limitations of CART effects. The use of ICIs can elicit a durable response; LDRT increases the expansion of infused CART. HDRT increases immunosuppressive cells.