Developing effective therapies for patients with epithelial ovarian cancer (EOC) represents an unmet need. Pre-clinical data suggests a strong role for immunosurveillance as a mechanism of preventing recurrence in (EOC). Exploring the potential for a multi-antigen induced immune effector response to change outcome for patients is warranted. We seek to determine whether immune checkpoint blockade will augment multi-antigen vaccination to improve clinical outcomes in patients with EOC. We will begin by evaluating multi-antigen vaccination with WT-1 analog peptide and NY-ESO-1 overlapping peptide vaccine with POLY-ICLC (+ montanide) in the presence or absence of PD-1 blockade. Based on pre-clinical testing to be completed in project 1, we will then evaluate whether the addition of MUC16 OLP versus 55 mer will further enhance the efficacy of the combinatorial strategy of multi-antigen vaccination and checkpoint blockade. We postulate that antigen-specific immune responses, T cell activation/exhaustion, and immune suppression mechanisms including Treg and myeloid-derived suppressor cells (MDSCs) in blood and tumor tissue will be favorably modulated after vaccination and immunologic checkpoint blockade in EOC. We hypothesize that by analyzing broad antigen-specific responses and by characterizing the activated/exhausted T cells and immune suppressor cells, especially in tumor tissues, we will be able to understand the immunologic response in EOC patients and to define immunologic signatures predicting clinical response. Therefore, in our second aim, we will utilize comprehensive immune analysis to define antigen specific immune response (including epitope spreading to known and previously unrecognized antigens), T cell activation/exhaustion phenotype and tumor suppression mechanisms including regulatory T cells and myeloid derived suppressor cells in order to define optimal combinatorial approaches. Samples will be analyzed pre-immunization and post immunization +/- PD-1 blockade. By focusing on antigen discovery, we suggest that such efforts to determine the specificity and reactivity of autoantibodies occurring during ovarian cancer should help define a comprehensive repertoire of immune responses from the serum of cancer patients with diagnostic and/or prognostic value. Following the completion of the trials defining the safety and immunogenicity (Year 3), we will embark on a randomized phase II trial in the second and third remission setting using a multi-center approach. This parallels our previous work evaluating carbohydrate antigen based vaccines which were taken from the phase I setting to a multi valent construct with sufficient immunogenicity and safety data to warrant ongoing randomized testing to assess efficacy.
PROJECT RELEVANCE/NARRATIVE Ovarian Cancer remains a leading cause of death for women who suffer from gynecologic cancer. With surgery and chemotherapy treatment, many patients enter a clinical remission but the majority of patients relapse. Standard chemotherapy treatments are only effective for a short time in controlling disease that return which ultimately becomes resistant t treatment. New and effective treatments are critically needed. There is evidence that the immune system plays an important role in maintaining remission and the manipulation of the immune response may improve outcomes. This project importantly looks at the effectiveness of vaccinations which target the immune system against common antigens expressed on ovarian cancer cells. It then evaluates whether adding the newer classes of agents which interfere with immune checkpoint blockade (which ?remove the brakes?) and strengthen the immune response over that can be found with vaccines alone. The hope is that the stronger immune response which involves cytotoxic (known as ?killer?) T cells can destroy remaining tumor cells. The project includes a robust monitoring effort where blood and tissue is collected to understand the immune response and learn which vaccine combinations are most effective at activating the immune system. After the best vaccine combination is identified, a randomized clinical trial is proposed to see if the enhanced immune response improves the outcome for women with ovarian cancer.
| Cornetta, Kenneth; Duffy, Lisa; Feldman, Steven A et al. (2018) Screening Clinical Cell Products for Replication Competent Retrovirus: The National Gene Vector Biorepository Experience. Mol Ther Methods Clin Dev 10:371-378 |
| Rafiq, Sarwish; Yeku, Oladapo O; Jackson, Hollie J et al. (2018) Targeted delivery of a PD-1-blocking scFv by CAR-T cells enhances anti-tumor efficacy in vivo. Nat Biotechnol 36:847-856 |
| Avanzi, Mauro P; Yeku, Oladapo; Li, Xinghuo et al. (2018) Engineered Tumor-Targeted T Cells Mediate Enhanced Anti-Tumor Efficacy Both Directly and through Activation of the Endogenous Immune System. Cell Rep 23:2130-2141 |
| Knorr, David A; Dahan, Rony; Ravetch, Jeffrey V (2018) Toxicity of an Fc-engineered anti-CD40 antibody is abrogated by intratumoral injection and results in durable antitumor immunity. Proc Natl Acad Sci U S A 115:11048-11053 |
| Bournazos, Stylianos; Ravetch, Jeffrey V (2017) Fc? Receptor Function and the Design of Vaccination Strategies. Immunity 47:224-233 |
| Hectors, Stefanie J; Wagner, Mathilde; Bane, Octavia et al. (2017) Quantification of hepatocellular carcinoma heterogeneity with multiparametric magnetic resonance imaging. Sci Rep 7:2452 |
| Yeku, Oladapo; Li, Xinghuo; Brentjens, Renier J (2017) Adoptive T-Cell Therapy for Solid Tumors. Am Soc Clin Oncol Educ Book 37:193-204 |
| Szender, J Brian; Papanicolau-Sengos, Antonios; Eng, Kevin H et al. (2017) NY-ESO-1 expression predicts an aggressive phenotype of ovarian cancer. Gynecol Oncol 145:420-425 |
| Rao, Thapi Dharma; Fernández-Tejada, Alberto; Axelrod, Abram et al. (2017) Antibodies Against Specific MUC16 Glycosylation Sites Inhibit Ovarian Cancer Growth. ACS Chem Biol 12:2085-2096 |
| Bournazos, Stylianos; Wang, Taia T; Dahan, Rony et al. (2017) Signaling by Antibodies: Recent Progress. Annu Rev Immunol 35:285-311 |
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