Integration of a novel solid tumor immunotherapy platform: CAR T cells, targeted radiotherapy and cytokine therapy

Responses of solid tumors to immunotherapy and cell-based therapies have remained limited. The UW Carbone Cancer Center was the first Wisconsin site to test chimeric antigen receptor (CAR) T cells, a personalized “living drug” genetically engineered to recognize and kill B-cell leukemia in children.

However, success of CAR-T cells against any solid tumors has been limited to isolated case reports and responses have only been transient. Barriers include an immunosuppressive tumor microenvironment (TME) and lack of appropriate cytokine stimulation to promote CAR-T cell persistence/function/memory. Local radiation to a single tumor can overcome these CAR-T impediments, but is not feasible in the face of multiple sites of metastases. Targeted Radionuclide Therapy (TRT) safely delivers systemic irradiation selectively to all sites of solid tumors, inducing release of tumor-antigens to sensitize immune cells (aka “in situ vaccine”) while eliminating immunosuppressive cell subsets within the TME. This proposal, for the first time, brings together experts in CAR T cells (Capitini, Saha), TRT (Hernandez, Weichert) and in situ vaccination (Morris, Sondel), to develop a novel platform to leverage TRT and cytokine therapy to improve the CAR-T response of an important pediatric solid tumor, neuroblastoma. Preliminary data demonstrate that neuroblastoma can be specifically targeted by GD2-CAR-T cells. TRT is selectively taken up by GD2+ tumors and can facilitate an in situ vaccine effect resulting in control of tumor. The addition of a novel interleukin-2 receptor agonist, bempegaldesleukin, can enhance the anti-tumor effects of TRT further.

This project will develop the combination of CAR-T cells, TRT and bempegaldesleukin in mice bearing metastatic GD2+ neuroblastoma to determine the safety, anti-tumor efficacy and impact on the TME and CAR T cell persistence, in order to justify subsequent clinical testing here at UW. Outcomes will lead to grant submissions to NIH and St. Baldrick’s foundation as well as several manuscripts.

 

PRINCIPAL INVESTIGATOR

Christian Capitini, associate professor of pediatrics

 

CO-PRINCIPAL INVESTIGATORS

Reinier Hernandez, assistant professor of medical physics

Paul Sondel, professor of pediatrics

 

CO-INVESTIGATORS

Zachary Morris, assistant professor of human oncology

Kris Saha, associate professor of biomedical engineering

Jamey Weichert, professor of radiology