Extension of an Artificial Chromosome-Based System as a Novel Delivery Strategy for CAR-T Cell Therapy of Ovarian Cancer to Human Lymphocytes
Abstract
Ovarian cancer remains one of the leading causes of cancer death among women in the United States. Unfortunately, most patients are diagnosed with advanced-stage disease, and recurrence after definitive therapy is high. Thus, new therapeutic strategies are needed to improve the lives of women with ovarian cancer. Unfortunately, recent progress in immunotherapy and adoptive cellular therapy in other malignancies have not extended to ovarian cancer treatment, and innovative strategies are urgently needed. One form of adoptive cellular therapy that uses modified T-cells derived from the patient represents one such approach. A major limitation to this engineered T-cell strategy is suppression by the tumor microenvironment after these treatments have been administered. One way to overcome this limitation is to modify these engineered cells with protective or inflammatory proteins via expression of genes specifically designed to overcome the hostile tumor microenvironment. However, current engineering approaches limit the number of these protective genes to 2 or 3, a number insufficient to address the many suppressive factors in the tumor microenvironment. In our completed pilot grant, we pioneered a gene-delivery system capable of encoding a potentially unlimited number of therapeutic genes, and we used a 5-gene platform as a proof of principle. We were able to demonstrate successful transfer of this gene platform to human T-cells at levels sufficient for therapeutic applications. In this proposal, we plan to continue optimization of our gene delivery system to facilitate large-scale manufacturing. We also propose to increase the number of therapeutic genes to 8 and evaluate both the 4-gene and 8-gene platform for efficacy against several ovarian cancer cell lines and patient-derived organoid samples. We will select the construct with the minimum number of genes that show efficacy in validated preclinical models of ovarian cancer. We will also evaluate our engineered T-cells for safety, a key selection factor for our final cellular therapy candidate. As a precaution, we have engineered a suicide gene into our 4-gene and 8-gene platform for use as necessary to mitigate toxicity. This approach to adoptive cellular therapy represents a generational leap over currently available methods. Just as importantly, we have overcome key obstacles in transferring our gene product to T-cells, a key prerequisite step for clinical trial testing. At the conclusion of the experiments outlined in this proposal, we will have designed, validated, and evaluated the efficacy and toxicity of a novel approach to adoptive cellular therapy for ovarian cancer. We anticipate preparations for clinical trial testing once we have selected an appropriate candidate.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310683
Entities
People
- David Spriggs
Organizations
- Massachusetts General Hospital
- United States Army