title: Early memory phenotypes drive T cell proliferation in patients with pediatric malignancies.
abstract: Engineered T cell therapies have begun to demonstrate impressive clinical responses in patients with B cell malignancies. Despite this efficacy, many patients are unable to receive T cell therapy because of failure of in vitro expansion, a necessary component of cell manufacture and a predictor of in vivo activity. To evaluate the biology underlying these functional differences, we investigated T cell expansion potential and memory phenotype during chemotherapy in pediatric patients with acute lymphoblastic leukemia (ALL) and non-Hodgkin lymphoma (NHL). We found that patients with T cell populations enriched for early lineage cells expanded better in vitro and that patients with ALL had higher numbers of these cells with a corresponding enhancement in expansion as compared to cells from patients with NHL. We further demonstrated that early lineage cells were selectively depleted by cyclophosphamide and cytarabine chemotherapy and that culture with interleukin-7 (IL-7) and IL-15 enriched select early lineage cells and rescued T cell expansion capability. Thus, early lineage cells are essential to T cell fitness for expansion, and enrichment of this population either by timing of T cell collection or culture method can increase the number of patients eligible to receive highly active engineered cellular therapies.
authors.affiliation: Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. nathan.singh@uphs.upenn.edu.
authors.forename: Nathan
authors.initials: N
authors.lastname: Singh
authors.affiliation: Division of Oncology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Perazzelli
authors.affiliation: Division of Oncology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
authors.forename: Stephan A
authors.initials: SA
authors.lastname: Grupp
authors.affiliation: Division of Oncology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Barrett
mesh_terms: D000293:Adolescent; D019070:Cell Lineage / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007156:Immunologic Memory / Q000187:drug effects; D007223:Infant; D019409:Interleukin-15 / Q000494:pharmacology; D015851:Interleukin-7 / Q000494:pharmacology; D008297:Male; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy / Q000276:immunology*; D010641:Phenotype; D013601:T-Lymphocytes / Q000187:drug effects / Q000473:pathology*
chemical_list: D019409:Interleukin-15; D015851:Interleukin-7