Less yin, more yang: confronting the barriers to cancer immunotherapy.

Clinical trials involving T cell-based immunotherapy for the treatment of human cancer have shown limited degrees of success. In cancer vaccine trials conducted at multiple centers worldwide, immunization has often resulted in the robust elicitation of T cells that specifically recognize antigens expressed on the surface of tumor cells. However, to date, objective clinical responses resulting from these approaches have remained relatively rare. By contrast, adoptive transfer of laboratory-expanded T cells into patients has had more success, producing impressive clinical regressions in a subset of advanced metastatic melanoma patients. The failure of activated T cells to consistently induce clinical responses in many other patients has pushed us toward a deeper understanding of natural immunoregulatory mechanisms that are directly responsible for diminishing tumor-specific T-cell activation, migration, and effector function in vivo. Such immunosuppressive factors likely evolved to prevent autoimmunity, but are frequently co-opted by tumors to evade tumor-specific immune responses. With this knowledge, it now becomes imperative to develop specific clinical interventions capable of eliminating tumor-specific immunosuppression, with the goal of shifting the balance to favor effector T-cell function and tumor cell killing.

Single epitope mucosal vaccine delivered via immuno-stimulating complexes induces low level of immunity against simian-HIV.

The difficulty in developing an effective vaccine to contain the HIV/AIDS epidemic coupled with the fact that primary HIV-1 infection typically occurs via mucosal sites has increased emphasis on vaccine approaches that protect at mucosal surfaces. In this study we employed HIV and simian-HIV (SHIV)-derived T helper (Th) and cytotoxic T lymphocyte (CTL) single epitopes incorporated into immuno-stimulating complexes (ISCOM) as a candidate immunogens. Immunized rhesus macaques (Macaca mulatta) were challenged with CCR5-tropic SHIV(SF162p4). On the day of challenge, low levels of virus-neutralizing antibodies (Ab) and CTLs were detected in ISCOM-immunized macaques. Greater than 10(5) viral RNA copies per ml of plasma in 2/5 immunized and 3/4 control macaques were detected within 3 weeks post-challenge. Depletion of CD4+ T cells from gut-associated lymphoid tissues (GALT) was observed by post-challenge day (PCD) 14 in all macaques regardless immunization. Nonetheless, lower viral loads and relatively better preservation of peripheral CD4+ T cells following the SHIV infection was observed in ISCOM-immunized macaques. We predict that if coadministered with additional epitopes and/or more efficacious mucosal delivery system or route, HIV/SIV-derived peptide vaccines may have potential to elicit heterologous protection.