Childhood Cancer

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Enhancing the therapeutic efficacy of chimeric antigen receptor T cells for acute myeloid leukemia

Institution: 
Washington University
Researcher(s): 
Miriam Kim, MD
Grant Type: 
Young Investigator Grants
Year Awarded: 
2019
Type of Childhood Cancer: 
Acute Myeloid Leukemia (AML)
Project Description: 

Background: T cells can be genetically engineered to target a specific cell surface marker that is present on cancer cells, and this form of therapy, termed chimeric antigen receptor (CAR) T cells, has been highly successful in the treatment of pediatric acute lymphoblastic leukemia (ALL). We propose to adapt CAR T cell therapy to meet the unmet needs of children with acute myeloid leukemia (AML), a disease with suboptimal clinical outcomes.

Project Goal: We have generated CAR T cells against myeloid antigens such as CD33 and CLL-1. To maximize therapeutic efficacy, we propose to develop dual-targeting CAR T cells with activity against both CD33 and CLL-1 expressing tumor cells, and evaluate their anti-tumor efficacy and also their ability to prevent antigen-negative escape using in vivo mouse xenograft models. We will also use a novel long-acting IL-7 hybrid fusion cytokine (NT-I7) to enhance the expansion and persistence of CAR T cell activity in vivo, and evaluate whether this combination can generate long-term immunologic memory against tumor cells. By performing these studies, we hope to generate a potent CAR construct that in the future can be used clinically to mediate long-term disease-free survival in children with AML.

Project Update 2023: We have developed dual antigen targeting CAR T cells to improve the breadth and the depth of disease targeting in AML, as compared to single antigen targeting CAR T cells. We have investigated a variety of formats to target two antigens and identified the optimal dual-targeting CAR construct that exhibits strong anti-tumor activity against tumor cell lines expressing both antigens. Additionally, this dual CAR also has activity against a mixed cell population containing cells expressing only single antigens. We are also investigating the addition of cytokine stimulation to CAR T cells to enhance their activity. We found that IL-7 stimulation can markedly increase the expansion of human CAR T cells in immunodeficient mice. This long-acting IL-7 reagent is currently being investigated in a phase I clinical trial as an adjunctive therapy for patients with B cell lymphoma receiving CD19-targeting CAR T cell therapy.

Co-funded by: 
Northwestern Mutual Foundation