Our long-range goal is to develop tumor-specific allogeneic adoptive T-cell immunotherapy in the context of non-myeloablative allogeneic hematopoietic stem cell transplantation (NST) for the treatment of non-hematologic malignancies. We have selected Human Papilloma Virus (HPV)-associated cervical cancer as a model because it constitutively expresses HPV genes E6/E7, which are appropriate targets for immunotherapy, and because, when advanced, its prognosis with conventional therapies is dismal. However, in order to ultimately design a clinical trial of HPVE6/E7-specific allogeneic T-cell therapy, we first need to a) determine whether NST alone will exert a clinically detectable anti-tumor effect, and b) determine whether lymphocytes derived from donor stem cells and exposed to host tumor in vivo will acquire HPV E6/E7-specific reactivity detectable in vitro, and whether such reactivity can be augmented in vivo. Thus, as a first step, we propose to perform a Phase II clinical trial to a) study the anti-tumor efficacy, b) document the safety, c) monitor hematopoietic engraftment and lymphoid chimerism, and d) determine by concurrent immunologic monitoring whether T cells from the normal ste cell donors can acquire HPVE6/E7-specific reactivity in vivo or in vitro, with a view to eventual (after this grant period) ex vivo generation and expansion of HPVE6/E7-specific T cells for infusion. NST will consist of low-intensity, non-myeloablative but immunosuppressive conditioning, infusion of granulocyte-colony stimulating factor (G-CSF)-mobilized allogeneic peripheral blood stem cell (PBSC), post-transplant immnosuppression and, if there is progressive disease and/or mixed lymphoid chimerism after PBSC infusion, donor lymphocyte infusion (DLI). Accordingly, our specific aims are: 1. To perform a clinical trial of allogeneic NST in patients with advanced cervical carcinoma to: a. Determine the anti-tumor efficacy, b. Determine the safety, c. Monitor donor hematopoietic and lymphoid chimerism, 2. To perform laboratory immunologic monitoring studies to determine whether: a. Donor-derived cells obtained from recipients serially after NST have acquired HPV E6/E7-specific reactivity by exposure in vivo (""""""""priming"""""""") to persisting tumor expressing these antigens, and b. Cells obtained directly from donors can acquire HPV E6/E7-specific reactivity after exposure in vitro to HPV E6/E7 synthetic peptides or recombinant proteins. The clinical and laboratory results are expected to provide a rational basis and direction for the design of subsequent trials of tumor-specific adoptive cellular immunotherapy in the context of this treatment regimen.
