Feng et al. engineered CD4-directed CAR T cells to secrete an IL-15/IL-15Rα complex. This modification led to effective lysis of CD4-expressing tumor cell lines in vitro and superior tumor control and survival extension in NSG mice, compared to CD4 CAR T cells alone. In a phase I trial of three patients with relapsed/refractory T cell lymphoma, treatment was safe and led to regression of tumors, significant reduction of leukemic T cells (either CD3-CD4+ or CD3+CD4+), Tregs, and normal CD4+ T cells (which recovered), and persistent expansion of CD8+ T cells and NK cells.
Contributed by Alex Najibi
ABSTRACT: T-cell lymphomas are aggressive lymphomas that often resist current therapy options or present with relapsed disease, making the development of more effective treatment regimens clinically important. Previously, we have shown that CD4 CAR can effectively target T-cell malignancies in preclinical studies. As IL-15 has been shown to strengthen the anti-tumor response, we have modified CD4 CAR to secrete an IL-15/IL-15sushi complex. These CD4-IL15/IL15sushi CAR T cells and NK92 cells efficiently eliminated CD4+ leukemic cell lines in co-culture assays. Additionally, CD4-IL15/IL15sushi CAR out-performed CD4 CAR in in vivo models, demonstrating a benefit to IL-15/IL-15sushi inclusion. In a Phase I clinical trial, CD4-IL15/IL15sushi CAR T cells were tested for safety in three patients with different T-cell lymphomas. Infusion of CD4-IL15/IL15sushi CAR T cells was well-tolerated by the patients without significant adverse effects and led to the remission of their lymphomas. Additionally, infusion led to the depletion of CD4+ Treg cells and expansion of CD3+CD8+ T cells and NK cells. These results suggest that CD4-IL15/IL15sushi CAR T cells may be a safe and effective treatment for patients with relapsed or refractory T-cell lymphomas, where new treatment options are needed.
Author Info: (1) Department of Hematology, Peking University Shenzhen Hospital, Shenzhen, China. (2) Department of Hematology, Peking University Shenzhen Hospital, Shenzhen, China. (3) iCell Ge
Author Info: (1) Department of Hematology, Peking University Shenzhen Hospital, Shenzhen, China. (2) Department of Hematology, Peking University Shenzhen Hospital, Shenzhen, China. (3) iCell Gene Therapeutics LLC, Research & Development Division, Long Island High Technology Incubator, Stony Brook, NY, United States. (4) Department of Hematology, Peking University Shenzhen Hospital, Shenzhen, China. (5) Department of Hematology, Peking University Shenzhen Hospital, Shenzhen, China. (6) Department of Hematology, Peking University Shenzhen Hospital, Shenzhen, China. (7) Department of Hematology, Peking University Shenzhen Hospital, Shenzhen, China. (8) Department of Hematology, Peking University Third Hospital, Beijing, China. (9) Department of Nuclear Medicine, Peking University Third Hospital, Beijing, China. (10) iCell Gene Therapeutics LLC, Research & Development Division, Long Island High Technology Incubator, Stony Brook, NY, United States. (11) iCell Gene Therapeutics LLC, Research & Development Division, Long Island High Technology Incubator, Stony Brook, NY, United States. (12) iCell Gene Therapeutics LLC, Research & Development Division, Long Island High Technology Incubator, Stony Brook, NY, United States. (13) iCell Gene Therapeutics LLC, Research & Development Division, Long Island High Technology Incubator, Stony Brook, NY, United States. (14) iCell Gene Therapeutics LLC, Research & Development Division, Long Island High Technology Incubator, Stony Brook, NY, United States. (15) Department of Hematology, Peking University Shenzhen Hospital, Shenzhen, China.
