lewis-y-antigen and Leukemia--Myeloid--Acute

In a phase I study of autologous chimeric antigen receptor (CAR) anti-LeY T-cell therapy of acute myeloid leukemia (AML), we examined the safety and postinfusion persistence of adoptively transferred T cells. Following fludarabine-containing preconditioning, four patients received up to 1.3 × 109 total T cells, of which 14-38% expressed the CAR. Grade 3 or 4 toxicity was not observed. One patient achieved a cytogenetic remission whereas another with active leukemia had a reduction in peripheral blood (PB) blasts and a third showed a protracted remission. Using an aliquot of In111-labeled CAR T cells, we demonstrated trafficking to the bone marrow (BM) in those patients with the greatest clinical benefit. Furthermore, in a patient with leukemia cutis, CAR T cells infiltrated proven sites of disease. Serial PCR of PB and BM for the LeY transgene demonstrated that infused CAR T cells persisted for up to 10 months. Our study supports the feasibility and safety of CAR-T-cell therapy in high-risk AML, and demonstrates durable in vivo persistence.

Topics: Aged; Bone Marrow; Female; Humans; Immunotherapy, Adoptive; Leukemia, Myeloid, Acute; Lewis Blood Group Antigens; Male; Middle Aged; Receptors, Antigen, T-Cell; Remission Induction; T-Lymphocytes; Transplantation Conditioning; Vidarabine

Topics: Female; Humans; Immunotherapy, Adoptive; Leukemia, Myeloid, Acute; Lewis Blood Group Antigens; Male; Receptors, Antigen, T-Cell; T-Lymphocytes

We have evaluated the carbohydrate antigen Lewis(Y) (Le(Y)) as a potential target for T-cell immunotherapy of hematological neoplasias. Analysis of 81 primary bone marrow samples revealed moderate Le(Y) expression on plasma cells of myeloma patients and myeloblasts of patients with acute myeloid leukemia (AML) (52 and 46% of cases, respectively). We developed a retroviral vector construct encoding a chimeric T-cell receptor that recognizes the Le(Y) antigen in a major histocompatibility complex-independent manner and delivers co-stimulatory signals to achieve T-cell activation. We have shown efficient transduction of peripheral blood-derived T cells with this construct, resulting in antigen-restricted interferon-gamma secretion and cell lysis of Le(Y)-expressing tumor cells. In vivo activity of gene-modified T cells was demonstrated in the delayed growth of myeloma xenografts in NOD/SCID mice, which prolonged survival. Therefore, targeting Le(Y)-positive malignant cells with T cells expressing a chimeric receptor recognizing Le(Y) was effective both in vitro and in a myeloma mouse model. Consequently, we plan to use T cells manufactured under Good Manufacturing Practice conditions in a phase I immunotherapy study for patients with Le(Y)-positive myeloma or AML.

Topics: Animals; Female; Genetic Therapy; Genetic Vectors; Humans; Immunotherapy, Adoptive; Interferon-gamma; Leukemia, Myeloid, Acute; Lewis Blood Group Antigens; Lymphocyte Activation; Male; Mice; Mice, Inbred NOD; Mice, SCID; Multiple Myeloma; Receptors, Antigen, T-Cell; Retroviridae; T-Lymphocytes; Transduction, Genetic