Kunle Odunsi, MD, PhD, is Director of the University of Comprehensive Cancer Center (UCCCC), and Dean for Oncology, the AbbVie Distinguished Service Professor of Obstetrics and Gynecology, Biological Sciences Division at the University of Chicago.
Dr. Odunsi's lab focuses on understanding immune mechanisms at play in the tumor microenvironment (TME) and translates that understanding into clinical trials for ovarian cancer. In the TME, the immune system and tumor cells battle back and forth, and our lab is working to optimize conditions so that the immune system wins and tumor cells are cleared.
The Odunsi Lab is oriented toward clinical translation objectives, and the projects span from basic science to preclinical models, pre-clinical IND-enabling toxicity studies, clinical research, and clinical trials.
- Immunological mechanisms in anti-tumor responses in the tumor microenvironment
- Immunotherapy in gynecological cancer clinical trials
- Pre-clinical and clinical development of tumor antigen targeted therapies
- Mechanisms of immune recognition and localized immunosuppression in human ovarian cancer tumor microenvironments.
Currently, Dr. Odunsi is Principal Investigator of the Roswell Park/University of Chicago Specialized Program of Research Excellence (SPORE) in Ovarian Cancer (P50CA159981). Other funding sources for the Odunsi Lab include the US Department of Defense, the National Institutes of Health, and the National Cancer Institute.
Metabolic adaptation of ovarian tumors in patients treated with an IDO1 inhibitor constrains antitumor immune responses
To uncover underlying mechanisms associated with failure of indoleamine 2,3-dioxygenase 1 (IDO1) blockade in clinical trials, we conducted a pilot clinical study in 17 patients with newly diagnosed advanced high-grade serous ovarian cancer. Patients were treated with the IDO1 inhibitor epacadostat, and immunologic, transcriptomic, and metabolomic characterization of the tumor microenvironment was undertaken in baseline and posttreatment tumor biopsies. We demonstrated that A2a and A2b purinergic receptor antagonists rescued NAD+-mediated suppression of T cell proliferation and function. Combining IDO1 inhibition and A2a/A2b receptor blockade improved survival and boosted the antitumor immune signature in mice with IDO1 overexpressing ovarian cancer.
Tcf-1 protects anti-tumor TCR-engineered CD8 + T-cells from GzmB mediated self-destruction
T-cell longevity is undermined by antigen-driven differentiation programs that render cells prone to attrition. CD8 + T cells that express the Tcf-1 transcription factor have undergone limited differentiation and exhibit stem-cell-like 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. Co-engineered cells were assessed for potential for adoptive cellular immunotherapy. Constitutive TCF-1B expression protected T cells from apoptosis associated with elicitation of effector function and promoted stem cell-like characteristics. Our study presents constitutive Tcf-1B expression as a potential means to impart therapeutic T cells with attributes of persistence for durable anti-tumor activity.
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
In contrast to other tumors, objective response rates to single-agent PD-1/PD-L1 blockade in ovarian cancer are limited. Using a pre-clinical model of aggressive ovarian cancer, we previously reported on a prime/boost cancer vaccine that elicits robust anti-tumor immunity, prolongs survival of tumor-bearing mice, and further improved when combined with checkpoint blockade. Using whole tumor transcriptomic data, we identified candidate therapeutic targets. In the context of a highly effective cancer vaccine, CD27 agonism or antibody-mediated depletion of granulocytic cells each modestly increased tumor control following vaccination, with anti-PD-1 therapy further improving efficacy. These findings support the use of immunotherapies with well-defined mechanisms(s) of action as a valuable platform for identifying candidate combination approaches.
Efficacy and Safety of Pembrolizumab in Combination With Bevacizumab and Oral Metronomic Cyclophosphamide in the Treatment of Recurrent Ovarian Cancer: A Phase 2 Nonrandomized Clinical Trial
This clinical trial focused on immune checkpoint inhibitors augmented by combination therapy with bevacizumab and metronomic cyclophosphamide in patients with recurrent ovarian cancer. In this single-arm, phase 2 nonrandomized clinical trial, 40 patients with platinum-sensitive or platinum-resistant ovarian cancer received pembrolizumab with bevacizumab every 3 weeks and oral cyclophosphamide daily. The objective response rate was 47.5% with a median progression-free survival of 10.0 months, and this regimen was well tolerated with good quality of life during treatment. These findings suggest that the combination of pembrolizumab with bevacizumab and metronomic cyclophosphamide has clinical activity with a favorable toxicity profile in treatment of recurrent ovarian cancer.