A Novel STAT3 Antisense Oligonucleotide-Based Immunotherapy for Renal Cell Carcinoma
Abstract
Renal cell carcinoma (RCC) is the most common type of kidney cancer. Despite significant clinical achievement in treating RCC using new immunotherapies that restore activity of some immune cells, such as T cells, the response rates are still relatively low at ~40%. This is likely a result of the overwhelming immunosuppressive effect of the tumor microenvironment on T cells. Therefore, we postulate a treatment modality combining ICIs targeting T cells with STAT3 targeting in myeloid-derived suppressor cells will be required to overcome this immunosuppression and restore antitumor responses. We have previously shown that STAT3, a protein regulator activated in cancer cells and in immune cells, is responsible for putting the brakes on T cell activity in various types of tumors. In our preliminary results, we have also shown high STAT3 and its downstream target Arginase-I expression in patients with RCC being treated with combinations ICIs anti-STAT3 and anti-CTLA-4. Therefore, the proposed study will specifically investigate associations between STAT3 signaling in the clinical responses of patients to immune checkpoint inhibitors. Importantly, we will also assess whether a novel treatment developed in our lab, which blocks STAT3 production and releases the brakes on T cells in the tumor microenvironment, can induce antitumor effects against kidney cancers in mice and potentially benefit RCC patients. Our plan is (1) to examine potential reasons why RCC patients do not respond to treatment and (2) to determine the efficacy of our novel inhibitor together with immune checkpoint inhibitors against kidney tumors in mice. The multidisciplinary research plan of this training grant will support my plans to collaborate with leading cancer immunotherapy and kidney cancer investigators. The proposal provides a unique opportunity to gain training in oncology, molecular biology, immunology and develop close collaboration with clinicians and scientists. We anticipate that it will take approximately 2 years to complete the analysis of RCC patients samples from the ongoing clinical trial and 3 years to complete the preclinical studies in mice run in parallel. Ultimately, our aim is to help patients with RCC, by removing existing brakes on their immune system that prevent them from benefiting from current therapies and then activating their immune system to fight their own cancers.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210402
Entities
People
- Marice Alcantara
Organizations
- Beckman Research Institute of City of Hope
- United States Army