title: Synergy of brief activation of CD8 T-cells in the presence of IL-12 and adoptive transfer into lymphopenic hosts promotes tumor clearance and anti-tumor memory.
abstract: Adoptive T-cell therapy holds great promise for the treatment of metastatic melanoma. However, prohibitive costs associated with current technology required for culture and expansion of tumor-reactive T-cells, the need for intense preconditioning regimens to induce lymphopenia, and the unpredictable anti-tumor effect of adoptively transferred T-cells remain significant impediments for its clinical implementation. Here we report a simplified combinatorial approach that involves short activation of CD8(+) T cells in the presence of IL-12 followed by adoptive transfer into tumor bearing animals after a single injection of cyclophosphamide. This approach resulted in complete eradication of B16 melanoma, and the establishment of long term immunological memory capable of fully protecting mice after a second B16 melanoma challenge. The activated donor cells were unique because they simultaneously exhibited traits for cytotoxic effector function, central memory-like, homing, and senescence. After tumor eradication and within three months after transfer, CD8+ cells exhibited a conventional memory CTL phenotype. Moreover, these memory CTLs acquired functional attributes characteristic of memory stem cells, including the ability to resist chemotherapy-induced toxicity. Our results suggest that short-term T-cell receptor signaling in the presence of IL-12 promotes promiscuous qualities in naïve CTL which - upon transfer into lymphopenic hosts- are sufficient to eradicate tumors and generate life-long tumor-specific memory.
authors.affiliation: Department of Medicine, Division of Hematology/Oncology, Sylvester Cancer Center, University of Miami, Miami, FL33136, USA.
authors.forename: C Marcela
authors.initials: CM
authors.lastname: Díaz-Montero
authors.forename: Osama
authors.initials: O
authors.lastname: Naga
authors.forename: Abdel-Aziz A
authors.initials: AA
authors.lastname: Zidan
authors.forename: Mohamed L
authors.initials: ML
authors.lastname: Salem
authors.forename: Maria
authors.initials: M
authors.lastname: Pallin
authors.forename: Anita
authors.initials: A
authors.lastname: Parmigiani
authors.forename: Gail
authors.initials: G
authors.lastname: Walker
authors.forename: Eric
authors.initials: E
authors.lastname: Wieder
authors.forename: Krishna
authors.initials: K
authors.lastname: Komanduri
authors.forename: David J
authors.initials: DJ
authors.lastname: Cole
authors.forename: Alberto J
authors.initials: AJ
authors.lastname: Montero
authors.forename: Mathias G
authors.initials: MG
authors.lastname: Lichtenheld