Vaccination to improve the persistence of CD19CAR gene-modified T cells in relapsed pediatric acute lymphoblastic leukemia

• Published in: Leukemia Vol. 31; no. 5; pp. 1087 - 1095
• Main Authors: Rossig, C, Pule, M, Altvater, B, Saiagh, S, Wright, G, Ghorashian, S, Clifton-Hadley, L, Champion, K, Sattar, Z, Popova, B, Hackshaw, A, Smith, P, Roberts, T, Biagi, E, Dreno, B, Rousseau, R, Kailayangiri, S, Ahlmann, M, Hough, R, Kremens, B, Sauer, M G, Veys, P, Goulden, N, Cummins, M, Amrolia, P J
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.05.2017; Nature Publishing Group
• Subjects: 13; 13/31; 42; 42/44; 45/77; 631/250/251; 631/67/1059/2325; 692/308/575; 692/4028/67/2332; 692/699/67/1990/283/2125; 692/699/67/580; 692/700/565/251/1567; Acute lymphoblastic leukemia; Antigens; Antigens, CD19; B cells; Bone marrow; Cancer Research; Care and treatment; CD19 antigen; Cell therapy; Child; Child, Preschool; Childrens health; Chimera; Chimeric antigen receptors; Clinical trials; Critical Care Medicine; Cytokines; Cytotoxicity; Epstein-Barr virus; Expansion; Feasibility studies; Female; Graft versus host disease; Graft-versus-host reaction; Hematology; Herpesvirus 4, Human; Hospitals; Humans; Immunization; Immunology; Immunotherapy; Immunotherapy - methods; Immunotherapy, Adoptive; Intensive; Internal Medicine; Leukemia; Lymphatic leukemia; Lymphocytes; Lymphocytes T; Lymphocytic leukemia; Male; Medicine; Medicine & Public Health; Neurotoxicity; Oncology; original-article; Patients; Pediatrics; Precursor Cell Lymphoblastic Leukemia-Lymphoma - therapy; Receptors; Receptors, Antigen, T-Cell - genetics; Receptors, Antigen, T-Cell - immunology; Recurrence; Risk factors; Stem cell transplantation; Stem cells; T cell receptors; T cells; T-Lymphocytes, Cytotoxic - transplantation; T-Lymphocytes, Cytotoxic - virology; Vaccination; Vaccines; United States; Germany; United Kingdom > UK; France
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/leu.2017.39

Trials with second generation CD19 chimeric antigen receptors (CAR) T-cells report unprecedented responses but are associated with risk of cytokine release syndrome (CRS). Instead, we studied the use of donor Epstein–Barr virus-specific T-cells (EBV CTL) transduced with a first generation CD19CAR, relying on the endogenous T-cell receptor for proliferation. We conducted a multi-center phase I/II study of donor CD19CAR transduced EBV CTL in pediatric acute lymphoblastic leukaemia (ALL). Patients were eligible pre-emptively if they developed molecular relapse (>5 × 10 −4 ) post first stem cell transplant (SCT), or prophylactically post second SCT. An initial cohort showed poor expansion/persistence. We therefore investigated EBV-directed vaccination to enhance expansion/persistence. Eleven patients were treated. No CRS, neurotoxicity or graft versus host disease (GVHD) was observed. At 1 month, 5 patients were in CR (4 continuing, 1 de novo ), 1 PR, 3 had stable disease and 3 no response. At a median follow-up of 12 months, 10 of 11 have relapsed, 2 are alive with disease and 1 alive in CR 3 years. Although CD19CAR CTL expansion was poor, persistence was enhanced by vaccination. Median persistence was 0 (range: 0–28) days without vaccination compared to 56 (range: 0–221) days with vaccination ( P =0.06). This study demonstrates the feasibility of multi-center studies of CAR T cell therapy and the potential for enhancing persistence with vaccination.