According the remarkable clinical trial results described here, we strongly believe that ACT, including TIL, CTL, TCR-T, and CAR-T transfer therapy, is the most promising “living” treatment for targeting human tumors, in which T cells are the terminator. However, there remains a need to improve the killing ability of transfer cells, while reducing the side effects of ACT, such as on-target/off-tumor toxicities, cytokine release syndrome, and, at the same time, develop an ability to harness the immune microenvironment, in order to make ACT an even more successful treatment option.

In order to prevent the on-target/off-tumor toxicities, target antigens that are only expressed on tumor cells, and not on normal tissue cells, must be selected. The tumor-specific “nonself” immunogenic neoantigens encoded by either viral genes or through somatic mutations possess the potential to induce specific anticancer immunity, including cellular and humoral immune responses. Today, numerous clinical trials demonstrate that although these “nonself” antigens initiate the antigen-specific immunoglobulin G antibodies and CD4⁺/CD8⁺ T cells response, not all of them show a clinical benefit in the response rate, progression-free survival, or overall survival [76–78].

Personalized cell therapy is the key to cure human malignant diseases. There are five steps required to reach this goal. First, cancer mutations must be identified through exome sequencing. Second, tandem minigenes or synthetic peptides of all identified mutations must be created and introduced to autologous APC. Third, mature autologous APCs coculture with T cells form peripheral blood or tumor. Fourth, tumor-reactive T cells must accumulate together through 4-1BB or OX40 positive selection. Fifth, rapid expansion of such cells in vitro must be carried out and used to treat the tumor in vivo, or a PCR of the TCR of such cells must be carried out for TCR-T treatment (Figs. 11.1 and 11.2) [26].

Moreover, there exists accumulating correlative data which suggests that directly sorting PD-1⁺ lymphocytes in peripheral blood could function as an alternative noninvasive strategy to develop neoantigen-reactive lymphocytes or TCRs to treat melanomas (Fig. 11.3) [79].

Gastric cancer tumors have been shown to exhibit a high prevalence of mutations, with many occurring with EB virus infection. Both mutation antigens and viral antigens are ideal antigen targets for gastric cancer immunotherapy. Thus, we can use the abovementioned strategies to prepare T cells in clinical ACT for gastric cancer.