Activating specific cytotoxic T-cells by HIFU and systemic immunotherapy in treatment of recurrent ovarian and cervical cancer in a syngeneic animal model

Project Name: Activating specific cytotoxic T-cells by HIFU and systemic immunotherapy in treatment of recurrent ovarian and cervical cancer in a syngeneic animal model
Status: Active
Primary Site: Stanford University School of Medicine
Sponsor Organization: Focused Ultrasound Foundation
Funded Date: Jan 28, 2020
Funding Period: Jan 28, 2020 - Feb 01, 2021
Funding Program: Immunotherapy
Category: Pre-Clinical
Amount Awarded: $100,000.00

Abstract

Ovarian/cervical carcinoma are recognized as cancers with low neo-antigen load, where the tumor antigens are known to be sequestered from immune cells. We propose that HIFU induced localized hyperthermia and cavitation will render the tumor immunologically non-silent, releasing tumor neo-epitopes, while concurrent immune checkpoint blockade (anti-PD-L1) will enhance the immune response to those neoepitopes by disinhibition of cytotoxic T-cells. Thereby, both treatment modalities combined would be superior to each of them alone. Combination therapy will be tested in a syngeneic animal model with ovarian cell line OV2944-HM-1 and cervical TC-1. Survival, tumor load and clonal expansion of tumor-specific T-cells will serve as endpoints. Abscopal effect at contralateral sites will also be tested. A tumor-targeting novel antibody developed in Teng Lab will be added for achieving complete survival. Novel mAb55.5 targets a tumor-specific carbohydrate-antigen on hematologic and epithelial cancers. Preliminary results suggest mAb55.5 helps generate a proinflammatory protective anti-tumor environment. Epithelial ovarian cancer is the most lethal gynecologic malignancy due to late diagnosis and eventual drug resistance. Cervical cancer is the most common gynecologic malignancy in the world with the high mortality in developing countries. The recent advent of immunooncology has led to major improvements in the treatment of multiple cancers, but not gynecologic cancers. Success of immunotherapy is dependent on the exposure of neo-antigens to immune cells. The combined use of HIFU, checkpoint therapy, and mAb55.5 will achieve all goals needed for successful oncotherapy, neo-antigen presentation (HIFU), disinhibition of anergic T-cells (

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