A patient's own T cells can be modified using gene therapy technology to express receptors, termed chimeric antigen receptors or CARs, which allow these immune T cells to recognize proteins on the tumor cell surface and in turn allow these CAR modified T cells to recognize and kill the patient's own tumor cells. To this end, the ability to generate patient T cells to recognize ovarian cancer cells is a promising and novel approach to treating very poor prognosis patients with advanced or relapsed ovarian carcinomas. The rationale for using patient T cells modified to recognize tumor cells is based on clinical observations demonstrating a correlation between tumor progression and the presence of the patient's own endogenous T cells within the tumor which suggests that a patient's own immune response to the cancer has clinical benefit. Therefore it is reasonable to propose that if we could generate in the laboratory a large population of tumor specific T cells, upon reinfusion, these T cells should be able to significantly kill off a large number of these ovarian cancer tumor cells. To this end, application of this approach requires that we identify a T cell target on the surface of the ovarian cancer tumor cell and subsequently generate a CAR which recognizes this target. MUC-16ecto is a novel identified target derived from MUC-16, a glycoprotein expressed on a majority of ovarian carcinomas, which is significantly retained on the tumor cell surface, making this an attractive target for genetically modified CAR T cells. To this end, we have recently generated just such a CAR, termed 4H11-28z, which recognizes the MUC-16ecto target over-expressed on most peritoneal and ovarian cancer tumor cells. However, while the generation of these tumor specific CAR T cells in the laboratory is required for this immune-based approach to ovarian cancer, it alone is not likely to be sufficient to obtain optimal anti-tumor effects when treating patients. Specifically, successful clinical application of this T cell therapy approach will require further modifications ogf the T cell to overcome tumor mediated immune suppression of these tumor targeted CAR T cells. To this end, we have generated and validated a tri-cistronic gamma-retrovial vector containing the 4H11-28z CAR specific to the retained MUC-16ecto antigen as well as genes encoding for the pro-inflammatory flexi IL-12 (fIL- 12)cytokine designed to enhance CAR T cell antitumor efficacy, modulation of the immunosuppressive tumor microenvironment and recruitment of the endogenous anti-tumor response. Additionally CAR T cells will be modified to express a truncated epidermal growth factor receptor (EGFRt) which will be utilized as a suicide vector for elimination of these CAR T cells with the EGFR specific MAb cetuximab in the context of unforeseen toxicities.
In Aim 1 of this project we will conduct a phase I dose escalation clinical trial treating relapsed MUC- 16ecto+ peritoneal/ovarian tumors with 4H11-28z/fIL-12/EGFRt autologous T cells. We will assess safety and tolerability of this therapy and as secondary endpoints we will assess response to therapy as well as the impact of therapy on CAR T cell persistence and modulation of the ovarian tumor microenvironment.
In Aim 2 of this project we will validate the clinical relevance of an immune competent orthotopic murine model of ovarian cancer based on clinical trial outcomes in Aim 1 and further investigate whether the additional therapy through checkpoint blockade with a PD-1 targeted an antibody may enhance the anti-tumor efficacy of CAR T cells and will further explore a clinically relevant approach to in vivo CAR T cell imaging. Collectively we anticipate that positive outcomes of the pre-clinical studies proposed in Aim 2 of the project (enhanced antitumor efficacy with PD-1 checkpoint blockade, as well as meaningful imagining of CAR T cells utilizing clinically applicable approaches) will be applied to the ongoing clinical trial proposed in Aim 1 of this application through an ammendment of the clinical protocol proposing to treat additional cohorts of patients.
Most patients with relapsed ovarian cancers have a very poor prognosis. For this reason novel approaches to treat this disease are needed. Immune based therapies of cancer, including treatment with patient T cells genetically modified to express tumor antigen targeted chimeric antigen receptors (CARs) as well as immune checkpoint blockade of T cell inhibitory receptors such as PD-1 and CTLA-4 with monoclonal antibodies, was recently hailed by Science as the scientific breakthrough of the year in 2013. In this project we plan to utilize these afore mentioned immunotherapy approaches as well as CAR T cell directed secretion of the IL-12 cytokine to modulate the immune suppressive tumor environment in order to step-wise translate an optimal approach to treating this disease in the clinical setting as well as optimally understanding the immune-based mechanisms behind improved anti-tumor outcomes. Overall, we anticipate that the aims of this project will markedly enhance our understanding the tumor immunology of ovarian cancers, improve our ability to utilize the immune system to treat this otherwise predominantly lethal disease, and further recognize that the insights gained from this work will likely be extrapolated to immune-based therapies of other solid tumor malignancies.
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| Hectors, Stefanie J; Wagner, Mathilde; Bane, Octavia et al. (2017) Quantification of hepatocellular carcinoma heterogeneity with multiparametric magnetic resonance imaging. Sci Rep 7:2452 |
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| 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 |
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