TY - JOUR
T1 - Establishment of antitumor memory in humans using in vitro-educated CD8+ T cells
AU - Butler, Marcus O.
AU - Friedlander, Philip
AU - Milstein, Matthew I.
AU - Mooney, Mary M.
AU - Metzler, Genita
AU - Murray, Andrew P.
AU - Tanaka, Makito
AU - Berezovskaya, Alla
AU - Imataki, Osamu
AU - Drury, Linda
AU - Brennan, Lisa
AU - Flavin, Marisa
AU - Neuberg, Donna
AU - Stevenson, Kristen
AU - Lawrence, Donald
AU - Hodi, F. Stephen
AU - Velazquez, Elsa F.
AU - Jaklitsch, Michael T.
AU - Russell, Sara E.
AU - Mihm, Martin
AU - Nadler, Lee M.
AU - Hirano, Naoto
PY - 2011/4/27
Y1 - 2011/4/27
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=79955373860&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=79955373860&partnerID=8YFLogxK
U2 - 10.1126/scitranslmed.3002207
DO - 10.1126/scitranslmed.3002207
M3 - Article
C2 - 21525398
AN - SCOPUS:79955373860
SN - 1946-6234
VL - 3
JO - Science Translational Medicine
JF - Science Translational Medicine
IS - 80
M1 - 80ra34
ER -