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Last Updated: 10/10/18

Ovarian Cancer SPORE

Roswell Park Cancer Institute — University of Pittsburgh Cancer Institute

OVERALL SPORE PI
Kunle Odunsi, M.D., Ph.D.

Co-Principal Investigators
Kirsten Moysich, Ph.D.
Roswell Park Cancer Institute
Robert Edwards, M.D.
University of Pittsburgh Cancer Institute

Principal Investigator Contact Information

Kunle O. Odunsi, M.D., PhD
Professor
Gynecologic, Oncology & Immunology
Roswell Park Cancer Institute
Elm and Carltons Street
Buffalo, NY 14263
Phone: (716) 845-3497
Fax: (716) 845-7608
Email: kunle.odunsi@roswellpark.org

Overall Abstract

The overall goal of the University of the Roswell Park Cancer Institute (RPCI) and University of Pittsburgh (UPCI) Ovarian Cancer SPORE is to reduce the morbidity and mortality of ovarian cancer through innovative translational research. It includes four individual research projects, four supportive cores, and research and career development programs. This proposal brings together basic and applied investigators to conduct innovative and diverse translational investigations aimed at risk stratification, treatment of primary and recurrent ovarian cancer, and prevention of relapse in patients in remission. The four projects have been carefully designed to have significant potential to change clinical practice paradigms in ovarian cancer within five years. The theme of the program uniquely reflects immune based approaches in the etiology, prognosis and treatment of patients with ovarian cancer. The proposed projects will: 1) Test a novel therapeutic strategy to break indoleamine 2,3-dioxygenase (IDO)-mediated immune tolerance in ovarian cancer, while inducing anti-tumor-specific immunity in patients in second remission (Project 1); 2) Test a combinatorial strategy of mTOR inhibiton and IL-21 for ex-vivo conditioning of antigen stimulated CD8+ T cells for effector and memory functional attributes; and test whether the ex vivo generated cells produce durable immunity against ovarian tumor in a clinical trial (Project 2); 3) Test whether autologous tumor-loaded type-1-polarized dendritic cells (aDC1s) will generate CTLs capable of recognizing ovarian cancer in either MHC class Irestricted- or MHC class I-unrestricted fashion; when used both as a vaccine and for adoptive T cell therapy (Project 3); Determine the predictive significance of myeloid derived suppressor cells (MDSCs), which have strong immunosuppressive properties in the long term survival of ovarian cancer patients (Project 4). Each project addresses at least one of the translational areas outlined in the SPORE guidelines and together, the program addresses the translational pathways defined by the Translational Research Working Group. Four Cores will support these projects: Administration, Biospecimen, Biostatistics and Medical Informatics, Immune Monitoring. The Developmental Research Progam will support a pathway for continued identification and support of diverse research that could replace or improve current projects, and a Career Development Program will recruit and support candidates committed to training in translational research in ovarian cancer. The Developmental Research Program and the Career Developmental Program will provide a framework to mentor young investigators to develop careers in ovarian cancer translational research, and to fertilize testing of high risk, potentially paradigm changing projects with translational potential.

Project 1: Inhibition of Indole-amine 2,3 Dioxygenase to Enhance Ovarian Tumor Immunity

Project Co-Leaders:
Kunle Odunsi, MD, PhD
Alex Olawaiye, MD
Protul Shirkant, PhD

The long range goal of our studies is to generate durable CD8+ T cell responses against epithelial ovarian cancer (EOC) for extending remission rates. We have demonstrated a role for the immunoregulatory enzyme, indoleamine 2,3 dioxygenase (IDO) in restricting effector CD8+ expansion and augmenting expansion of CD4+CD25+FOXP3+ Treg cells in human and murine ovarian cancer. In turn, we have shown that Treg cells suppress polyfunctional high avidity effector T cells derived from vaccinated patients. Consequently, we hypothesize that blockade of IDO activity by a novel IDO inhibitor, INCB024360 will (i) abrogate differentiation of CD4+ T cells into Treg cells, (ii) reverse IDO mediated arrest of T cell proliferation, (iii) unmask vaccine induced high avidity polyfunctional effector CD8+ T cells and thereby potentiate vaccine efficacy against EOC in a clinical trial. To test our hypotheses, we propose: SA1: To test whether the combinatorial regimen of IDO inhibition and rCNP-NY-ESO-1/TRICOM immunization is safe, and produces clinical efficacy in a phase I/IIb trial; SA2: To test whether INCB024360 mediated IDO blockade favors generation of high avidity polyfunctional effector CD8+ T cells; SA3: To determine the impact of IDO blockade on vaccine induced CD4+ T cell response for high avidity CD8+ Effector/Memory generation. The experimental plan is designed to test whether vaccine efficacy will be enhanced by blocking IDO mediated immune tolerance in a clinical trial. Mechanistically, because our phase II study design is randomized with a 2X2 factorial design, we will be able to delineate the impact of IDO blockade on promoting vaccine induced T cell clonal expansion and effector/memory differentiation, and whether this is mediated by relieving inhibition of high avidity polyfunctional antigen specific T cells by Tregs. The successful completion of our proposed studies will result in the generation of critical data that will facilitate Phase III evaluation of IDO blockade to relieve Treg mediated immune tolerance, promote conditions that favor durable host immunity and prolong disease free survival in ovarian cancer patients.

Project 2: Rapamycin and IL-21 conditioned CD8+ T cells for adoptive cellular therapy of ovarian cancer

Project Co-Leaders:
Protul Shrikant, PhD
Kunle Odunsi, MD

Immunotherapy is an attractive option to extend remission rates in ovarian cancer. The use of adoptive cell transfer (ACT) of ex vivo generated tumor-antigen specific effector/memory CD8+ T cells circumvents the regulatory environment present in ovarian cancer patients and can mediate durable immunity. However, strategies to ex vivo generate effector/memory CD8+ T cells have not been described and the application of ACT to treat ovarian tumor remains untested. Based on our reported findings and new evidence generated by using both murine and human T cells, we hypothesize that the gamma chain cytokine; IL-21 in combination with mTOR inhibitor; rapamycin, will ex vivo generate tumor-antigen specific effector/memory CD8+ T cells that enable durable immunity to ovarian cancer patients by ACT. We have designed two specific aims to test the hypothesis and generate information that can support a phase 2 trial. First, to determine the combinatorial dose of Rapamycin and IL-21 that optimally produces human WT1 specific effector/memory CD8+ T cells with high replicative potential for adoptive cellular therapy and second to evaluate in a Phase I study, the safety, in vivo persistence and anti-tumor efficacy of IL-21/ Rapamycin conditioned WT-1 specific CD8+ T cells adoptively transferred to patients with advanced ovarian cancer. The completion of this study will identify a new strategy to generate antigen-specific CD8+ T cells for effector/memory function and test their efficacy in  ACT, it is likely to establish a new approach to treat ovarian cancer.

Project 3: MHC-Restricted and MHC-Non-Restricted Targeting of Ovarian Cancer by aDC1-induced CTLs

Project Co-Leaders:
Robert Edwards, MD
Pawel Kalinski, MD, PhD

Genomic instability of ovarian cancer (OvCa) cells and the resulting frequent loss or reduction of HLA expression and function facilitate immune avoidance of this aggressive cancer. The goal of this Project is to develop an effective mode of immunotherapy capable of targeting both MHC-positive and MHC-negative variants of OvCa and counteracting local immune suppression, known to contribute to poor prognosis in OvCa patients. We observed that type-1-polarized DCs (aDC1s), a novel type of DCs developed by our group, effectively cross-present OvCa-related antigens and induce high numbers of MHC class I-restricted CTLs capable of recognizing defined OvCa-related antigenic epitopes. However aDC1-induced CTLs also express elevated levels of NK receptors, NKG2D- and DNAM1. Such “NK cell-like” (n)CTLs recognize OvCa cells in both MHC class I-restricted- and MHC class I-unrestricted fashion. IFNg produced by aDC1- activated nCTLs has a strong positive impact on OvCa microenvironment, suppressing the chemokines that attract undesirable Treg cells and MDSCs and enhancing the production of the chemokines that attract additional effector cells. Based on these preliminary data, we hypothesize that autologous tumor-loaded aDC1s used both as vaccines and as ex-vivo inducers of OvCa-specific CTLs for adoptive T cell transfer in OvCa can be useful in the immunotherapy of patients treated with primary chemotherapy (which may sensitize tumor cells for the NKG2D- and DNAM-1-mediated recognition). We will test the hypothesis that local adoptive transfer of ex-vivo-sensitized (n)CTLs will amplify the effects of systemic vaccination against OvCa, by promoting direct elimination of residual tumor cells and the attraction of additional (vaccination-induced) T cells. In Specific Aim 1, we will evaluate the mechanisms involved in the induction of OvCa specific NKG2Dhigh/DNAM-1high (n)CTLs by aDC1s and the mechanisms of their TCR-dependent and TCR independent recognition and killing of OvCa cells. In Specific Aim 2, we will evaluate the regulation of the NK cell-type receptors ligands (MICA/B, ULBP1-6, PVR/CD155 and Nectin-2/CD112) on OvCa cells by chemotherapy, CTL/NK-produced cytokines and additional clinically-applicable biologic agents, and will evaluate the potential for additional sensitization of OvCa cells for (n)CTL-mediated killing. In Specific Aim 3, we will evaluate in phase I clinical trial (24 high-risk patients with advanced primary OvCa) the feasibility and safety of combined immunotherapy of advanced OvCa involving vaccination with autologous tumor loaded aDC1s and intraperitoneal adoptive transfer of increasing numbers ex-vivo-induced OvCa-specific (n)CTLs, in the context of systemic and intraperitoneal chemotherapy.

Project 4: Myeloid Derived Suppressor Cells in Ovarian Carcinogenesis

Project Co-Leaders:
Shashi Lele, MD
Francesmary Modugno, PhD

We propose a comprehensive genetic and molecular epidemiological investigation of the role of Myeloid Derived Suppressor Cells (MDSCs) in ovarian cancer prognosis. These cells have been shown to be associated with defective dendritic cell function and suppression of CD4+ and CD8+ T cell response via multiple mechanisms. This is a highly significant project for risk classification for prognosis, and identification of factors that may interfere with the efficacy of immunotherapeutic treatment approaches in ovarian cancer patients. To achieve this objective we propose three innovative aims that allow the first comprehensive investigation of MDSC in ovarian carcinogenesis in a well-designed epidemiologic framework. In Specific Aim 1, we will benefit from our strong collaborative ties with the Ovarian Cancer Association Consortium, which will allow us access to a very large cohort of over 13,000 of ovarian cancer patients in which we will measure the relationship between single nucleotide polymorphisms (SNPs) in genes hypothesized to be associated with MDSC activity and ovarian cancer outcomes (survival and recurrence). This is the first study to consider the association between SNPs in genes believed relevant to modulating MDSC levels and cancer prognosis in general and ovarian cancer prognosis in particular. In Specific Aim 2, we will assess the association between clinical characteristics and short-term outcomes with MDSC frequencies in tumor and blood samples prior to and post treatment in 320 serous ovarian cancer patients. Lastly in Aim 3 we test for association of significant SNPs (Aim 1) with MDSC levels in blood and tumor tissue from patients with ovarian cancer to help determine if MDSC levels are possibly driving the significant associations of SNPs with clinical outcomes seen in Aim 1. Importantly, from this information we will build a clinical instrument using predictive models in order to identify patients susceptible to poor outcomes. Together these three aims allow for a comprehensive investigation of the roles of phenotypic expression and genetic variation in an important immune pathway relevant to susceptibility to poor clinical characteristics at diagnosis and outcomes in ovarian cancer.

Core A: Administration Core

Core Co-Directors:
Kunle Odunsi, MD, PhD
Francesmary Modugno, PhD
Kirsten Moysich, PhD
Robert Edwards, MD

The goal of Administration Core is to ensure that translational goals of the RPCI-UPCI Ovarian Cancer SPORE are met and that resources are used effectively. The Administration Core will provide leadership, direction and administrative services for the purposes of enhancing research productivity and maintaining a stimulating translational research environment for ovarian cancer. The Administration Core will provide a platform to assure integration of diverse scientific disciplines into a unified multidisciplinary approach for achieving excellence in translational research in ovarian cancer. The Administration Core will be organized to meet 4 primary objectives, the provision of 1) Leadership; 2) Administrative Management; 3) Data and Communications Management; and 4) Scientific Management. The Leadership objective will be met by an MD-PhD team with many years of experience leading large, complex, multi-institutional research efforts in ovarian cancer. The Administrative Management objective will be met through proper adherence to the financial commitments and scientific support made by RPCI and UPCI, responsible project management by the Program Manager and by strong administrative support. The Data and Communications Management objective will be met by the creation of a Central Database that will be used to track all research subjects and specimens, house all data generated, and facilitate data analysis, and a website accessible by the RPCIUPCI Ovarian Cancer SPORE investigators, investigators from other NCI Ovarian Cancer SPORE grants, research subjects, and the general public. The Scientific Management objective will be met by close supervision of the RPCI-UPCI Ovarian Cancer SPORE by the Executive Committee, and Internal and External Advisory Boards. The Administration Core will foster the exchange of ideas and promote collaboration through its interactions with the Individual Research Project Leaders, Developmental Research Program Project Leaders, Career Developmental Program Project Leaders, Core Directors and all members of the research groups. Importantly, the Administration Core will monitor timelines and ensure that the translational objectives are met for all SPORE projects. The Administration Core will have direct responsibility for organization and facilitation of annual reviews of the Individual Research Projects, Developmental Research Program projects, Career Developmental Program projects, Tissue Core, Biostatistics and Bioinformatics Core, and the Immune Analysis Core by the Internal and External Advisory Boards and organization of an annual scientific retreat.

Core B: Biospecimen/Pathology Core

Core Co-Directors:
Carl Morrison, MD, DVM
Esther Elishaev, MD

The Biospecimen Core (BC) will provide essential services related to pathology for all projects of this Specialized Program of Research Excellence (SPORE). Each of the three sites (RPCI, UPCI, and Fred Hutchinson Cancer Research Center) in this SPORE will provide local services that are applicable to the project at the particular site. In addition to developing a high quality biospecimen bank, the BC will provide many other services to the SPORE investigators that include tissue microarrays, laser capture microdissection, general research histology services, immunohistochemistry, digital imaging, and pathology review of slides and images. In addition to services directly related to collection or processing of tissues, the BC will also be instrumental in testing of specimens for various markers to determine patient eligibility for the different clinical trails. The BC will directly add to the science of this ovarian SPORE by a detailed immunological annotation of ovarian tumors and the microenvironment.

Core C: Biostatistics/Medical Informatics Core

Core Co-Directors:
Alan Hutson, PhD
Carmelo Gaudioso, PhD, MD
Junko Matsuzaki, PhD

The Biostatistics and Medical Informatics Core will ensure that biostatistics, bioinformatics and medical informatics design and modeling support is available to all RPCI Prostate Cancer SPORE project leaders and core directors and their co-investigators. The Biostatistics and Medical Informatics Core is designed to provide statistical support that considers both institutional proximity and the biostatistical, bioinformatics and medical informatics needs of individual investigators. Specifically, we aim to: To assist basic, translational and clinical researchers of the RPCI Ovarian Cancer SPORE with proper formulation, refinement and execution of study objectives by applying the appropriate biostatistics and bioinformatics analyses, and providing the appropriate interpretation of their results, in terms of both strengths and limitations; To establish a robust data management system to effectively manage the Ovarian Cancer SPORE’s informatics needs in supporting multidisciplinary, multi-project, multi-institutional clinical and translational research and facilitating data sharing and information dissemination; and To notify RPCI-UPCI Ovarian Cancer SPORE investigators when data are sufficiently mature to write a manuscript, to write the statistical methods section of manuscripts and to provide expert collaborative guidance in formulating the rest of the manuscript. It is anticipated that the services of the Biostatistics and Medical Informatics Core will be extensively used by all researchers associated with the SPORE. Benefits to the Biostatistics and Medical Informatics Core include providing a consistent team dedicated to efficient and effective collaboration. Benefits towards developing the Biostatistics and Medical Informatics Core include providing a consistent team dedicated to efficient collaboration across three comprehensive cancer centers.

CORE D: Immune Monitoring Core

Core Co-Directors:
Paul Wallace, PhD
Lisa Butterfield, PhD

The primary objective of the Immune Analysis Core is to establish standardized assays of cellular and humoral immune responses for the immunotherapeutic approaches being developed and tested in Individual Research Projects 1, 2 and 3 of the RPCI Ovarian Cancer SPORE. It will be also be responsible for enumerating and characterizing myeloid derived suppressor cells (MDSCs) by flow cytometry for Research Projects 4. The Core will routinely provide Ovarian Cancer SPORE investigators with high quality, state-of the- art flow cytometry, cellular monitoring by ELISPOT, proliferation and cytotoxicity assays, and multiplex cytokine bead array. The specific aims of the Immune Analysis Core are to provide cell banking services for immune monitoring assays requiring viable mononuclear cells; provide state-of-the-art, multi-color, fluorescence activated cell sorting and analytical support for Individual Research Projects, Career Development and Developmental Research Projects. This includes high-speed sorting and multi-color analysis of cellular subsets. The core will provide state-of-the-art ELISPOT, ELISA, proliferation and cytotoxicity assays for the functional characterization of antigen-specific T cell responses and provide state-of-the-art patient sample handling and assessment of immune responses, with standardized SOPs, quality assurance, quality control and data management practices to monitor assay performance and validate data quality. In addition to these established immunoassays services, the Immune Analysis Core will be instrumental in developing new methodologies and making them available to the SPORE investigators. It also has a significant educational role, working with all SPORE investigators including PI’s, technicians and young investigators on their assay development, proper use of instrumentation and interpretation of their data.