POST TRANSPLANT T CELL RECONSTITUTION IN NEUROBLASTOMA

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DESCRIPTION (provided by applicant): Our long-term goal is to develop combined immunotherapy and biologic therapies to improve the survival of patients with high-risk neuroblastoma. Neuroblastoma (NB) is the most common extracranial solid tumor of childhood, with a poor long-term survival rate. In an effort to improve these results, we recently performed trial to determine the feasibility of tandem high-dose chemotherapy with autologous stem cell rescue. We found an encouraging 3-year EFS of 58%, however impaired immune reconstitution constituted the major morbidity of this treatment regimen. In this trial we propose to assess the feasibility of cellular immune reconstitution in patients following tandem transplantation. We will carefully assess the effect of infusion of co-stimulated expanded autologous T cells (T cell augmentation; TCA) on immune recovery, establishing the infrastructure to engineer autologous therapeutic cellular neuroblastoma vaccines. In response to PAR-03-005, the SPECIFIC AIMS of this proposal are to: (1) Conduct a two-part clinical trial to study the feasibility of post-transplant TCA in pediatric patients with high-risk NB and test the impact of TCA on immune reconstitution. In the first part, we will complete the ongoing pilot study of TCA in high-risk NBL in 12 patients. In the second part we will perform a randomized phase II trial of TCA in additional 24 patients, testing the impact of TCA on CD4 reconstitution and conjugate vaccine response. We will determine (a) the rate of tumor contamination in ex vivo expanded T cell populations; (b) whether adoptive transfers increase the rate of T cell recovery and vaccine response; (c) clinical toxicity; and (d) the EFS in this high-risk group of patients. (2) (A) Determine the pace and quality of T cell reconstitution for patients undergoing SCR and T cell augmentation by measuring: (i) peripheral blood T lymphocyte subsets via flow cytometry, (ii) CD4+ T lymphocyte receptor repertoire via spectratyping, (iii) clinical DTH reactions to recall antigen, and (iv) response to a conjugate vaccine. (B) Use these parameters to compare patients receiving T cell augmentation vs. standard SCR. (3) Assess (i) anti-NB immunity for patients undergoing SCR and TCA and (ii) assess survivin as a potential tumor antigen in NB. Assays used will include: IFN- gamma production in ELISPOT assays to targets loaded with tumor RNA, surviving RNA, or control RNA, survivin-specific cytotoxic T lymphocytes via peptide/MHC tetramers in HLA-A2+ patients, and CTL response to targets loaded with tumor, survivin, or control RNA.