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Background
Clinical application of adoptiv
e T c
ell th
erapy has b
een hind
er
ed by an inability to g
en
erat
e ad
equat
e numb
ers of nontol
eriz
ed, functionally activ
e, tumor-sp
ecific T c
ells, which can p
ersist in vivo. In ord
er to addr
ess this, w
e evaluat
ed th
e impact of int
erl
eukin (IL)-12 signaling during tumor-sp
ecific CD8
+ T c
ell priming in t
erms of p
ersist
enc
e and antitumor
efficacy using an
establish
ed B16 m
elanoma tumor adoptiv
e th
erapy mod
el.
Study Design
B6 mice were injected subcutaneously with B16 melanoma tumor cells. On day 12 of tumor growth, mice were preconditioned with cyclophosphamide (4mg dose, intraperitoneally), and 1 day later were treated by adoptive transfer of tumor-specific pmel-1 CD8+ T cells primed ex vivo 3 days earlier with both IL-12 and antigen (hGP10025-33 peptide) or antigen only. Tumors were measured biweekly, and infused donor T cells were analyzed for persistence, localization to the tumor, phenotype, and effector function.
Results
Adoptive transfer of tumor-specific CD8+ T cells primed with IL-12 was significantly more effective in reducing tumor burden in mice preconditioned with cyclophosphamide compared with transfer of T cells primed without IL-12. This enhanced antitumor response was associated with increased frequencies of infused T cells in the periphery and tumor as well as elevated expression of effector molecules including granzyme B and interferon-¦Ã (IFN¦Ã).
Conclusions
Our findings demonstrate that ex vivo priming of tumor-specific CD8+ T cells with IL-12 dramatically improves their in vivo persistence and therapeutic ability on transfer to tumor-bearing mice. These findings can be directly applied as novel clinical trial strategies.