Adoptive transfer of TCR-engineered T cells is a potent therapy, able to induce clinical responses in different human malignancies. Nevertheless, treatment toxicities may occur and, in particular for solid tumors, responses may be variable and often not durable. To address these challenges, it is imperative to carefully select target antigens and to immunologically interrogate the corresponding tumors when designing optimal T cell therapies. Here, we review recent advances, covering both omics- and laboratory tools that can enable the selection of optimal T cell epitopes and TCRs as well as the identification of dominant immune evasive mechanisms within tumor tissues. Furthermore, we discuss how these techniques may aid in a rational design of effective combinatorial adoptive T cell therapies.
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