With the goal of improving adoptive cell therapy (ACT) for ovarian cancer, Friese et al. evaluated the impact of CTLA-4 blockade on yield and potency of tumor-reactive TILs. Adding anti-CTLA-4 to the initial TIL culture of ovarian tumor fragments from 14 patients, and/or during the subsequent rapid expansion phase, resulted in greater numbers of CD8+ TEM cells with increased tumor reactivity, compared to standard TIL culture (IL-2 only). Early CTLA-4 blockade did not alter T cell activation, exhaustion and co-stimulatory markers, or the TCR repertoire, suggesting CTLA-4 blockade during initial TIL expansion could improve ACT.
Contributed by Katherine Turner
Adoptive cell therapy (ACT) with autologous tumor-infiltrating lymphocytes (TILs) can induce durable complete tumor regression in patients with advanced melanoma. Efforts are currently underway to expand this treatment modality to other cancer types. In the microenvironment of ovarian cancer, the engagement of co-inhibitory immune checkpoint molecules such as CTLA-4 can lead to the inactivation of TILs. Thus, approaches that directly manipulate co-inhibitory pathways within the tumor microenvironment might improve the expansion of tumor-reactive TILs. The initial expansion of TILs for ACT from tumor fragments provides a window of opportunity to manipulate an intact tumor microenvironment and improve CD8(+) T-cell output and TIL tumor reactivity. To exploit this, we used a CTLA-4-blocking antibody, added during the initial TIL culture, and found that the blockade of CTLA-4 favored the propagation of CD8(+) TILs from ovarian tumor fragments. Interestingly, adding the CTLA-4 blocking antibody in the initial phase of the TIL culture resulted in more potent anti-tumor TILs in comparison to standard TIL cultures. This phenotype was preserved during the rapid expansion phase. Thus, targeting CTLA-4 within the intact tumor microenvironment of tumor fragments enriches tumor-reactive TILs and may improve clinical outcome of TIL-based ACT in ovarian cancer.