Immunotransplant

Historically, the effect of vaccines -particularly against pathogens- has been assessed by measurement of their induction of a B-cell-mediated -or humoral- immune response, i.e. the production of pathogen-specific antibodies. In the study of both infectious diseases and cancer, a majority of potential immune targets are only expressed intra-cellularly, and are thus inaccessible to antibody-mediated elimination. T-cell mediated immunity, by contrast, has the potential to recognize targets expressed either extra- or intra-cellularly and has therefore been studied extensively for treatment of these diseases.

A number of pre-clinical and clinical studies have demonstrated that vaccines against pathogens, bystander (non-pathogenic) proteins, tumor-associated antigens, or whole tumor cells, can induce specific T-cell mediated immune responses.^{[1][2][3][4][5][6]} A number of approaches have been considered to amplify T cell mediated immune responses(e.g. IL-2, CTLA-4, IL-7, CD137), and some of these have shown clinical efficacy in eliminating particular types of cancer, most notably melanoma and renal cell carcinoma.

The use of immunotransplant to enhance T cell-mediated immune responses, derive from studies of T cell homeostasis. The total cohort of T cells in an organism maintain homeostasis – a consistent total number of T cells in the peripheral blood. Transient elevations in peripheral blood T cell counts cause the whole population to diminish, transient depletions cause the whole population to proliferate, generally maintaining a roughly total T cell count. The latter situation –lymphodepletion– has been studied extensively and the proliferation of mature T cells upon transfer into the lymphopenic host is referred to as “lymphodepletion-induced” or “homeostatic” proliferation.^[7] It has been shown that homeostatic proliferation induces not only quantitative changes in T cell cohorts, but qualitative changes as well, such as increased function and the development of a memory-cell phenotype.^[8] The mechanism of these changes has been shown to be primarily due to upregulation of a group of cytokines including IL-7 and IL-15 induced by lymphodepletion. Additionally, lymphodepletion is a non-selective method of eliminating several known regulatory, or immunosuppressive, subsets of immune cells, such as regulatory T cells.^[9]

These observations have prompted several clinical studies of infusing pathogen- or tumor-specific T cells into lymphodepleted patients. A group at the National Cancer Institute demonstrated remarkable efficacy by infusing melanoma-specific T cells (obtained by growing tumor-infiltrating T cells ex vivo) into melanoma patients treated with lymphodepleting chemotherapy. In a series of studies (to 2005) of this approach, up to 70% of treated patients were shown to have regressions of their tumors, many of which had been considerable in size and refractory to other therapies.^[10][11] These findings compare favorably with standard-of-care therapies for melanoma which generally lead to tumor regressions in only ~10-12% of patients.^{[citation needed]}