title: Establishment of antitumor memory in humans using in vitro-educated CD8+ T cells.
abstract: Although advanced-stage melanoma patients have a median survival of less than a year, adoptive T cell therapy can induce durable clinical responses in some patients. Successful adoptive T cell therapy to treat cancer requires engraftment of antitumor T lymphocytes that not only retain specificity and function in vivo but also display an intrinsic capacity to survive. To date, adoptively transferred antitumor CD8(+) T lymphocytes (CTLs) have had limited life spans unless the host has been manipulated. To generate CTLs that have an intrinsic capacity to persist in vivo, we developed a human artificial antigen-presenting cell system that can educate antitumor CTLs to acquire both a central memory and an effector memory phenotype as well as the capacity to survive in culture for prolonged periods of time. We examined whether antitumor CTLs generated using this system could function and persist in patients. We showed that MART1-specific CTLs, educated and expanded using our artificial antigen-presenting cell system, could survive for prolonged periods in advanced-stage melanoma patients without previous conditioning or cytokine treatment. Moreover, these CTLs trafficked to the tumor, mediated biological and clinical responses, and established antitumor immunologic memory. Therefore, this approach may broaden the availability of adoptive cell therapy to patients both alone and in combination with other therapeutic modalities.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA. marcus_butler@dfci.harvard.edu
authors.forename: Marcus O
authors.initials: MO
authors.lastname: Butler
authors.forename: Philip
authors.initials: P
authors.lastname: Friedlander
authors.forename: Matthew I
authors.initials: MI
authors.lastname: Milstein
authors.forename: Mary M
authors.initials: MM
authors.lastname: Mooney
authors.forename: Genita
authors.initials: G
authors.lastname: Metzler
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Murray
authors.forename: Makito
authors.initials: M
authors.lastname: Tanaka
authors.forename: Alla
authors.initials: A
authors.lastname: Berezovskaya
authors.forename: Osamu
authors.initials: O
authors.lastname: Imataki
authors.forename: Linda
authors.initials: L
authors.lastname: Drury
authors.forename: Lisa
authors.initials: L
authors.lastname: Brennan
authors.forename: Marisa
authors.initials: M
authors.lastname: Flavin
authors.forename: Donna
authors.initials: D
authors.lastname: Neuberg
authors.forename: Kristen
authors.initials: K
authors.lastname: Stevenson
authors.forename: Donald
authors.initials: D
authors.lastname: Lawrence
authors.forename: F Stephen
authors.initials: FS
authors.lastname: Hodi
authors.forename: Elsa F
authors.initials: EF
authors.lastname: Velazquez
authors.forename: Michael T
authors.initials: MT
authors.lastname: Jaklitsch
authors.forename: Sara E
authors.initials: SE
authors.lastname: Russell
authors.forename: Martin
authors.initials: M
authors.lastname: Mihm
authors.forename: Lee M
authors.initials: LM
authors.lastname: Nadler
authors.forename: Naoto
authors.initials: N
authors.lastname: Hirano
mesh_terms: D019264:Adoptive Transfer; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D000938:Antigen-Presenting Cells / Q000187:drug effects / Q000276:immunology; D015703:Antigens, CD / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D060908:CTLA-4 Antigen; D002465:Cell Movement / Q000187:drug effects; D000939:Epitopes / Q000276:immunology; D005260:Female; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects / Q000276:immunology; D007156:Immunologic Memory / Q000187:drug effects / Q000276:immunology*; D019409:Interleukin-15 / Q000008:administration & dosage / Q000494:pharmacology; D007376:Interleukin-2 / Q000008:administration & dosage / Q000494:pharmacology; D058965:MART-1 Antigen / Q000276:immunology; D008297:Male; D008545:Melanoma / Q000188:drug therapy / Q000276:immunology*; D008875:Middle Aged; D010641:Phenotype; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology / Q000637:transplantation; D013997:Time Factors
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D000939:Epitopes; D019409:Interleukin-15; D007376:Interleukin-2; D058965:MART-1 Antigen