Author(s): Katarzyna Urbanska aff1 , Daniel J Powell aff1 aff2
adoptive T-cell therapy; chimeric antigen receptor; gene engineering; immunotherapy; ovarian cancer; TCR; TILs
Despite recent advances in targeted therapies, epithelial ovarian cancer (EOC) remains the most lethal form of gynecologic malignancy. Thus, improving the clinical outcome of patients will require reinvestment in research development and further clinical investigation. T-cell accumulation in EOC is prognostic for survival and recent advances in adoptive T-cell therapy now provide a renewed opportunity to specifically modulate T-cell number and activity in EOC and mediate tumor regression. Here, we discuss the application of adoptive T-cell transfer based immunotherapy and its prospects for the treatment of EOC.
Evidence of the role of the immune system in human EOC comes from epidemiologic and clinical data demonstrating the presence of CD3+ tumor-infiltrating T lymphocytes (TILs) and its association with favorable prognosis and longer survival [1 ]. Patients whose tumors contained TILs had 5-year overall survival rate of 38%, whereas patients whose tumors lacked TILs only had a rate of 4.5%. Additionally, the 5-year progression-free survival rates for patients whose tumors harbored or lacked TILs were 31.0 and 8.7%, respectively. Follow-up studies revealed that the prognostic value is strongest for CD8+ cytotoxic T lymphocytes that are localized within the epithelial component of tumors, rather than the associated stroma, and that other factors associated with cytotoxic T-lymphocyte activity are also associated with increased survival, e.g., IFN[gamma], IFNR, TNF[alpha] and MHC class I. By contrast, regulatory T cells, which suppress immune responses and maintain tolerance to self-antigens, are associated with decreased survival [ 2 ]. The functional phenotype and composition of TIL subsets further supports the notion that immune activation is associated with improved survival [ 3 ]. For instance, CD8+ CD103+ T cells with an effector memory phenotype are present in large numbers in some high-grade serous ovarian cancers and are correlated with survival, without the need to discriminate their epithelial versus stromal location [ 4 ]. These provoking findings provide the basis for therapeutic applications that dramatically bolster the number and functional activity of endogenous immune cells in high-grade serous ovarian cancer.
Current immunotherapies for EOC fall into three broad categories: broad-acting immune checkpoint inhibitors and cytokines; therapeutic vaccines and the focus of this editorial, adoptive lymphocyte transfer. The infusion of T lymphocytes, referred to as adoptive cell therapy (ACT), has the potential to enhance antitumor immunity, augment vaccine efficacy and eradicate tumor, as observed in some tumor types. Adoptive transfer of TILs requires the isolation of T cells from fresh patient biopsy specimens and the progressive expansion of tumor-specific T cells ex vivo . Early studies have identified methods to yield polyclonal tumor-reactive T cells from tumors or ascites. In addition to TILs being present in ovarian cancer, the tumor cells themselves express individualized mutated self-proteins [5 ] and shared tumor associated-antigens, such as HER2/Neu, folate receptor alpha, mesothelin, NY-ESO-1, WT1 and TAG-72, which can serve as targets for humoral and cellular immune responses. Together, the characteristics of tumor cells and...