Journal Article

IL-12-secreting CD19-targeted cord blood-derived T cells for the immunotherapy of B-cell acute lymphoblastic leukemia

Giralt, S A, Brentjens, R J, Barker, J N, Purdon, T J, Pegram, H J, Curran, K J, van Leeuwen, D G

2015

Overview

Disease relapse or progression is a major cause of death following umbilical cord blood (UCB) transplantation (UCBT) in patients with high-risk, relapsed or refractory acute lymphoblastic leukemia (ALL). Adoptive transfer of donor-derived T cells modified to express a tumor-targeted chimeric antigen receptor (CAR) may eradicate persistent disease after transplantation. Such therapy has not been available to UCBT recipients, however, due to the low numbers of available UCB T cells and the limited capacity for ex vivo expansion of cytolytic cells. We have developed a novel strategy to expand UCB T cells to clinically relevant numbers in the context of exogenous cytokines. UCB-derived T cells cultured with interleukin (IL)-12 and IL-15 generated >150-fold expansion with a unique central memory/effector phenotype. Moreover, UCB T cells were modified to both express the CD19-specific CAR, 1928z, and secrete IL-12. 1928z/IL-12 UCB T cells retained a central memory-effector phenotype and had increased antitumor efficacy in vitro. Furthermore, adoptive transfer of 1928z/IL-12 UCB T cells resulted in significantly enhanced survival of CD19 + tumor-bearing SCID-Beige mice. Clinical translation of CAR-modified UCB T cells could augment the graft-versus-leukemia effect after UCBT and thus further improve disease-free survival of transplant patients with B-cell ALL.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/154/51/1844 / 692/699/67/1059/2325 / 692/699/67/1990/283/2125 / 692/699/67/1990/291/1621/1915 / Acute lymphoblastic leukemia / Acute lymphocytic leukemia / Adoptive transfer / Animals / Anticancer properties / Antigens / Antigens, CD19 - metabolism / Antitumor activity / B-Lymphocytes - cytology / Blood / Cancer Research / Care and treatment / CD19 antigen / Cell Line, Tumor / Chimeric antigen receptors / Cord blood / Critical Care Medicine / Cytokines / Cytokines - metabolism / Development and progression / Disease Progression / Disease-Free Survival / Fetal blood / Fetal Blood - cytology / Flow Cytometry / Genetic aspects / Graft-versus-leukemia reaction / Health aspects / Hematology / Humans / Immunologic Memory / Immunotherapy / Immunotherapy - methods / Intensive / Interleukin 12 / Interleukin 15 / Interleukin-12 - immunology / Interleukin-12 - metabolism / Interleukin-15 - immunology / Interleukins / Internal Medicine / Leukemia / Lymphatic leukemia / Lymphocytes / Lymphocytes B / Lymphocytes T / Medicine / Medicine & Public Health / Memory cells / Methods / Mice / Mice, SCID / Oncology / original-article / Patient outcomes / Phenotype / Phenotypes / Precursor Cell Lymphoblastic Leukemia-Lymphoma - immunology / Precursor Cell Lymphoblastic Leukemia-Lymphoma - therapy / Recurrence / Survival / T-Lymphocytes - cytology / T-Lymphocytes - immunology / Transgenes / Transplantation / Transplants & implants / Umbilical cord