Cytokine Modulation of Chimeric Antigen Receptor T Cells to Increase Their Safety and Efficacy

Project: Research project

Project Details

Description

Chimeric antigen receptor T cell (CART) therapy is a form of immunotherapy to attack cancer. CART cell therapy uses the patients' own immune cells (T cell) as a way to treat cancer. To make CART cells, a patient's immune cells are removed by a process called leukapheresis, then are kept in the laboratory for 1 to 2 weeks. During this time, T cells are stimulated and increase in number by several folds and are engineered using inactivated viruses to make them recognize cancer cells (these engineered cells are called CART cells). Patients receive low-dose chemotherapy to make space for the newly engineered CART cells and then their own CART cells are infused back in the body. Following their infusion, CART cells further increase in number, travel and find the cancer and kill cancer cells. In patients with blood cancers, CART cell therapy has been extremely effective and was Food and Drug Administration (FDA)-approved in 2017. Most patients respond to CART cell therapy, and about 30%-40% of them achieve long lasting remission of the cancer. However, there are major challenges for CART cell therapy, which include: (1) toxicity: patients get sick shortly after CART cell therapy, are hospitalized, and develop a syndrome of cytokine release syndrome (low blood pressure, difficulty breathing, and fevers, requiring intensive care unit), and a syndrome of neurotoxicity (confusion and loss of the ability to speak; also requiring intensive care unit). There is treatment for cytokine release syndrome but no treatment is available for neurotoxicity; (2) low efficacy: while most patients initially respond to CART cell therapy, the response lasts 1 year or longer in only about one-third of patients; (3) healthcare costs: CART cell process is extremely expensive and therefore it is not easy for every patient to access the treatment. The costs of CART cell therapy are derived from (i) the cost of the product (CART cells) due to the complex process of cell engineering, and the need for special FDA-compliant manufacturing sites, and (ii) expenses of hospitalization, involved procedures, and intensive care unit care.

We have identified a protein that CART cells make, called granulocyte-macrophage colony-stimulating factor (GM-CSF) as a major driver of toxicities after CART cell therapy. We also learned that GM-CSF activate other immune cells (monocytes). which inhibit CART cell activity. We show that in mouse models for CART cell therapy; when GM-CSF is blocked, we prevent CART cell toxicities and increase their efficacy. Based on this, we initiated a multi-center phase 2 clinical trial for the combination of CART cell therapy with the GM-CSF blocking antibody lenzilumab. We plan to enroll 36 patients on this study, and so far, two patients are treated. The goal of this clinical trial is to investigate if depleting GM-CSF will result in reduced toxicities in patients receiving CART cell therapy.

The main goal of this Department of Defense application is to study how blocking GM-CSF will prevent CART cell toxicities, improve their efficacy, and change the treatment paradigm to outpatient treatment. By reducing toxicities, patients will not need to be hospitalized or admitted to the intensive care unit, and therefore, this will decrease healthcare costs associated with CART cell therapy.

StatusActive
Effective start/end date1/1/20 → …

Funding

  • Congressionally Directed Medical Research Programs: $278,250.00

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