Abstract IA24: Translating fundamental immunobiology into adoptive T-cell therapy for ovarian cancer

Abstract

Abstract In nearly half of all high-grade serous cancers, tumor-infiltrating T lymphocytes (TILs) invade and accumulate in tumor epithelial islets. These immunologically “hot” cancers are prognostic for patient survival and provide a strong rationale for immune-based treatment strategies that mobilize and enhance endogenous immune responses. In other cancers, such as melanoma and HPV-associated cervical cancer, TILs with autologous tumor reactivity can be isolated from resected tumors and expanded ex vivo for reinfusion to the patient in a process called adoptive immunotherapy. Adoptive immunotherapy using TILs in patients with these cancers frequently results in durable complete responses. In ovarian cancer patients, responses to TIL therapy have been less dramatic due in part to technical difficulties in identifying and expanding the tumor-reactive subset of TILs. In an effort to improve TIL therapy, we identified a surface biomarker of naturally occurring tumor reactive TILs in ovarian cancer and showed in preclinical models systems that these cells mediate enhanced TIL killing of autologous tumor cells ex vivo and in vivo, paving the way for more effective TIL therapy. Mass cytometry analysis revealed a complex network of immune inhibitory molecules expressed by tumor-reactive TILs that act in unison to dampen antitumor immunity, and for which clinical-grade blocking antibodies exist, rationalizing the use of TIL therapy in combination with immune checkpoint inhibitors for ovarian cancer. Facilitating adoptive T-cell therapy in the subset of patients with immunologically “cold” ovarian cancers relies upon the de novo induction of T cell antitumor reactivity. One approach relies on the stimulation of nonreactive endogenous immune cells with tumor antigens. Use of lysates generated from the patient’s own tumor provides the opportunity to vaccinate against shared antigens as well as patient-specific mutational antigens. In this prime-and-boost approach, a patient can first be vaccinated against patient-specific antigens to induce antitumor immunity, and the vaccine-primed T cells then harvested and expanded to high numbers outside of the body before reinfusion into the patient. The feasibility and safety of this approach has now been established in ovarian cancer with evidence of biologic activity. In the era of synthetic biology, “off-the-shelf” tumor-reactive T cells can now be generated de novo through the use of gene engineering. Using advanced gene-transfer systems and sophisticated cell-cultivation technologies, patients’ T cells are endowed with antigen-specificity and a capacity for enhanced antigen-dependent proliferation, activity, and survival, based on principles of fundamental immunology. In this way, engineered T cells can overcome issues of HLA loss by tumor cells as well as T-cell exhaustion. In preclinical xenograft models, gene-modified T cells exert antigen-specific killing of human ovarian cancer. Gene-engineered T cells are the subject of our ongoing clinical trials and pave a new route toward adoptive immunotherapy, which renders ovarian cancers immunologically “hot.” Citation Format: Daniel J. Powell, Jr. Translating fundamental immunobiology into adoptive T-cell therapy for ovarian cancer. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr IA24.