Regression of established
tumors can be induced by adoptive immunotherapy (AIT) with
tumor draining lymph node (DLN) lymphocytes activated with
bryostatin and
ionomycin (B/I). We hypothesized that B/I-activated T cells cultured in
IL-7 +
IL-15 might proliferate and survive in culture better than cells cultured in
IL-2, and that these cells would have equal or greater anti-
tumor activity in vivo.
Tumor antigen-sensitized DLN lymphocytes from either wild-type or
T cell receptor transgenic mice were harvested, activated with B/I, and expanded in culture with either
IL-2,
IL-7 +
IL-15 or a regimen of alternating
cytokines. Cell yields, proliferation, apoptosis, phenotypes, and in vitro responses to
tumor antigen were compared for cells grown in different
cytokines. These T cells were also tested for anti-
tumor activity against
melanoma lung
metastases established by prior i.v. injection of
B16 melanoma cells.
IL-7 +
IL-15 or alternating
cytokines resulted in much faster and prolonged proliferation and much less apoptosis of B/I-activated T cells than culturing the same cells in
IL-2. This resulted in approximately tenfold greater yields of viable cells. Culture in
IL-7 +
IL-15 yielded higher proportions of CD8+ T cells and a higher proportion of cells with a central memory phenotype. Despite this, T cells grown in
IL-7 +
IL-15 had higher IFN-gamma release responses to
tumor antigen than cells grown in
IL-2. Adoptive transfer of B/I-activated T cells grown in
IL-7 +
IL-15 or the alternating regimen had equal or greater efficacy on a "per-cell" basis against
melanoma metastases. Activation of
tumor antigen-sensitized T cells with B/I and culture in
IL-7 +
IL-15 is a promising modification of standard regimens for production of T cells for use in adoptive immunotherapy of
cancer.