Adoptive therapy involving the ex vivo isolation and expansion of antigen-specific T cells yields the promise of tumor eradication and immunoprotection with minimal toxicity. In recent years, this modality has produced promising results for the treatment of patients with metastatic melanoma. However, factors contributing to the in vivo survival and function of transferred T cells and ultimately, tumor regression in patients, have yet to be defined and optimized. It is believed that pre-infusion conditioning and post-infusion cytokine administration contribute to the efficacy of adoptively transferred T cells. We postulate that the use of T cell clones of defined magnitude, phenotype and specificity for adoptive therapy will permit a precise and rigorous examination of the influence of immunomodulatory regimens and facilitate the identification of elements responsible for a successful strategy. We propose to identify in a Phase I, dose-finding study, a cyclophosphamide conditioning regimen pre- infusion and a dose of IL-2 post-infusion that is safe and that supports the in vivo survival and function of adoptively transferred T cells. The dosing range for cyclophosphamide that will be implemented in the Phase I study, 300 to 4,000 mg/m2, is grounded in previous clinical trials demonstrating an immunopotentiating effect of cyclophosphamide. The dose and schedule of post-infusion low-dose and high-dose IL-2 have been implicated in previous clinical trials of adoptive T cell therapy to impact T cell survival in vivo. A cyclophosphamide conditioning regimen and post-infusion IL-2 schedule identified in this initial Phase I study that is deemed to be safe and that maximizes T cell persistence will be evaluated for clinical efficacy in an extended Phase II study. of Research to Public Health (lay language): Cancers that are resistant to standard chemotherapy and radiation may be treatable using components of the immune system. We propose to use immune cells, T cells, that recognize targets on tumor cells as a means of treating patients with advanced (metastatic) melanoma. By isolating and expanding such T cells and infusing them into patients, we can track the survival and function of these cells and, we hope, identify a treatment approach that will be safe and will improve the effectiveness of melanoma-specific T cells. ? ? ?
| Goodridge, Jodie P; Lee, Ni; Burian, Aura et al. (2013) HLA-F and MHC-I open conformers cooperate in a MHC-I antigen cross-presentation pathway. J Immunol 191:1567-77 |
| Chapuis, Aude G; Thompson, John A; Margolin, Kim A et al. (2012) Transferred melanoma-specific CD8+ T cells persist, mediate tumor regression, and acquire central memory phenotype. Proc Natl Acad Sci U S A 109:4592-7 |
