The most common malignant primary brain tumor, glioblastoma (GBM), remains uniformly fatal despite surgical resection, incapacitating radiation therapy, and myelodepleting temozolomide (TMZ) chemotherapy. Adjuvant immunotherapy promises to induce robust tumor-specific immune responses that eliminate neoplastic cells with unparalleled specificity, but TMZ-induced lymphopenia would be expected to curtail the induction and persistence of productive antitumor immune responses. However, following periods of lymphopenia, such as those induced by TMZ, there is a homeostatic proliferation of remaining lymphocytes. Thus, T-cells that predominate during this recovery period have a competitive advantage and may become disproportionately over-represented in the recovering lymphocyte population. We and others have identified this as an opportunity to enhance the preferential expansion and maintenance of ex vivo expanded and adoptively transferred anti-tumor T-cells. While high-dose IL-2 has been utilized in most human clinical trials of adoptive immunotherapy for maintenance and expansion of transferred lymphocytes, recent studies in murine models have demonstrated capacity to achieve T cell maintenance and anti-tumor efficacy using in vivo vaccination in the absence of exogenous cytokine supplementation. Given the documented neurotoxicity of IL-2 in patients with GBM, the capacity to facilitate in vivo engraftment of tumor-specific lymphocytes using concomitant vaccination is of paramount interest. Furthermore, our preliminary data demonstrate that vaccines given during the recovery from TMZ-induced lymphopenia result in dramatically enhanced humoral responses and antigen- specific T-cell frequencies in mice and humans. Although our preliminary data uses T-cells from mice with transgenic T-cell receptors to evaluate the combination of vaccine and adoptive immunotherapy in the context of TMZ, such approaches are not easily translated into human studies. Dendritic cells (DCs) loaded with the total antigenic content of tumor cells in the form of RNA (TTRNA), however, provide an innovative strategy that we and others have safely and successfully to expand tumor-specific lymphocytes against a broad repertoire of tumor antigens. Our OVERALL GOAL then is to evaluate the combination of adoptive cellular therapy and TTRNA-loaded DC vaccines during recovery from serial lymphodepletion with TMZ in a murine brain tumor model prior to clinical studies in humans.
Treatment for brain tumors represents the most expensive medical therapy per quality-adjusted life-year saved currently provided in the United States, and brain tumors remain the most common cause of cancer death among children and account for more deaths in adults than melanoma. Vaccines are an attractive adjuvant approach to therapy for these tumors, but are thwarted by the chemotherapy used for these tumors that kills lymphocytes that might respond to these vaccines. This effect of the chemotherapy, however, actually helps maintain anti-tumor lymphocytes infused immediately after the chemotherapy so we will evaluate the combined efficacy of vaccines and transferred antitumor lymphocytes in this proposal.
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| Sanchez-Perez, Luis A; Choi, Bryan D; Archer, Gary E et al. (2013) Myeloablative temozolomide enhances CD8? T-cell responses to vaccine and is required for efficacy against brain tumors in mice. PLoS One 8:e59082 |
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