Adoptive Immunotherapy with Antigen-Specific T Cells Expressing a Native TCR

Although T cells genetically modified with chimeric antigen receptors became the first immune effector product to obtain FDA approval, T-cell products that recognize their antigenic targets through their native receptors have also produced encouraging responses. For instance, T cells recognizing immunogenic viral antigens are effective when infused in immunosuppressed patients. A large number of tumor antigens are also expressed on nonviral tumors, but these antigens are less immunogenic. Many tumors can evade a transferred immune response by producing variants, which have lost the targeted antigens, or inhibitory molecules that recruit suppressive cells, impeding persistence and function of immune effectors. Nevertheless, infusion of antigen-specific T cells has been well-tolerated, and clinical responses have been consistently associated with immune activity against tumor antigens and epitope spreading. To overcome some of the obstacles mentioned above, current research is focused on defining ex vivo culture conditions that promote in vivo persistence and activity of infused antigen-specific T cells. Combinations with immune checkpoint inhibitors or epigenetic modifiers to improve T-cell activity are also being evaluated in the clinic. Antigen-specific T cells may also be manufactured to overcome tumor evasion mechanisms by targeting multiple antigens and engineered to be resistant to inhibitory factors, such as TGFβ, or to produce the cytokines that are essential for T-cell expansion and sustained antitumor activity. Here, we discuss the use of T cells specific to tumor antigens through their native receptors and strategies under investigation to improve antitumor responses.