Tcf-1 protects anti-tumor TCR-engineered CD8 T-cells from GzmB mediated self-destruction.

Background: T-cell longevity is undermined by antigen-driven differentiation programs that render cells prone to attrition through several mechanisms. CD8 T cells that express the Tcf-1 transcription factor have undergone limited differentiation and exhibit stem-cell-like replenishment functions that facilitate persistence. We engineered human CD8 T cells to constitutively express Tcf-1 and a TCR specific for the NY-ESO-1 cancer-associated antigen.

CXCR6 by increasing retention of memory CD8 T cells in the ovarian tumor microenvironment promotes immunosurveillance and control of ovarian cancer.

Purpose: Resident memory CD8 T cells, owing to their ability to reside and persist in peripheral tissues, impart adaptive sentinel activity and amplify local immune response, and have beneficial implications for tumor surveillance and control. The current study aimed to clarify the less known chemotactic mechanisms that govern the localization, retention, and residency of memory CD8 T cells in the ovarian tumor microenvironment.

Experimental Design: RNA and protein expressions of chemokine receptors in CD8 resident memory T cells in human ovarian tumor-infiltrating CD8 T cells and their association with survival were analyzed.

A prime/boost vaccine platform efficiently identifies CD27 agonism and depletion of myeloid-derived suppressor cells as therapies that rationally combine with checkpoint blockade in ovarian cancer.

Cancer immunotherapies have generated remarkable clinical responses for some patients with advanced/metastatic disease, prompting exploration of rational combination therapies to bolster anti-tumor immunity in patients with limited response or those who experience tumor progression following an initial response to immunotherapy. In contrast to other tumor indications, objective response rates to single-agent PD-1/PD-L1 blockade in ovarian cancer are limited, suggesting a need to identify combinatorial approaches that lead to tumor regression in a setting where checkpoint blockade alone is ineffective. Using a pre-clinical model of aggressive intraperitoneal ovarian cancer, we have previously reported on a heterologous prime/boost cancer vaccine that elicits robust anti-tumor immunity, prolongs survival of tumor-bearing mice, and which is further improved when combined with checkpoint blockade.

Fidelity of human ovarian cancer patient-derived xenografts in a partially humanized mouse model for preclinical testing of immunotherapies.

Background: Immune checkpoint blockers (ICBs) have been approved by the Food and Drug Administration to be used alone in front-line therapies or in combination with other regimens for certain advanced cancers. Since ICB only works in a subset of patients and has limited efficacy in treating ovarian cancer (OVC), developing preclinical models that help to understand which patients may derive benefit from ICB would be of tremendous benefit in OVC.

Methods: Here, we generated preclinical human OVC models from freshly resected tumors, which include six patient-derived xenografts (PDXs) from six different patient tumors, three transplantable OVC PD spheroid lines (PD-sphs), and 3 cell lines (PD-CLs).