Immune T cells can be functionally defined in terms of their cytokine secretion profile: CD4+, Th1 and CD8+, Tc1 cells primarily secrete IL-2 and IFN-g, whereas CD4+, Th2 and CD8+, Tc2 cells primarily secrete IL-4, IL-5, IL-10, and IL-13. These Th1/Tc1 (type I) and Th2/Tc2 (type II) subsets are cross-regulatory in vivo: in the setting of murine allogeneic bone marrow transplantation, we have found that type I cells initiate graft-versus-host disease (GVHD), whereas type II cells mediate reduced GVHD and inhibit type I-mediated GVHD. In murine models, we have also found that graft-versus-leukemia (GVL) and graft-versus-tumor (GVT) effects against breast cancer cells are primarily mediated through type I immunity. Although type II cells may be therapeutic for indolent malignancy or minimal residual disease, it is likely that type I immunity will be required to cure more aggressive or advanced disease. As such, we are currently evaluating methods to utilize type I immunity in the allogeneic transplantation setting, including a strategy that administers a T cell replete allograft (type I immunity) that is supplemented by additional donor CD4+, Th2 cells. In an initial clinical trial involving n=28 Th2 cell recipients, we established a dose of Th2 cells that promoted both type I and type II immunity and was associated with significant anti-tumor responses in patients with refractory hematologic malignancy; however, GVHD remained a limiting factor to this approach. In light of this information, we have developed a second generation approach to Th2 cell therapy that involves Th2 cell generation in vitro in the presence of the immune suppression drug rapamcyin. Rapamycin generated murine Th2 cells (Th2.rapa) have an enhanced capacity to promote type II immunity and to prevent GVHD; in pre-clinical human studies, we identified that Th2.rapa cells are greatly enriched for the Th2 cytokine phenotype. Based on these results, a clinical trial utilizing Th2.rapa cells is being evaluated for GVHD prevention (protocol 04-C-0055). In addition to this Th2 cell allograft augmentation strategy, we are also evaluating the use of purified CD4+Th2 and CD8+Tc2 cells in transplants involving purified hematopoietic stem cells. The focus here is to perform a """"""""T cell exchange"""""""", whereby the T cells contained within mobilized stem cell populations are replaced the the in vitro expanded Th2/Tc2 cells. In murine studies, we have found that the Th2/Tc2 population can effectively prevent graft rejection, mediate a modest GVT effect, and is associated with greatly reduced GVHD. This Th2/Tc2 strategy may have particular application for HLA mis-matched transplantation, and hopefully therefore improve transplantation therapy for the approximate 75% of cancer patients that lack an HLA matched sibling.
Showing the most recent 10 out of 14 publications
