The generation of specific anti-tumor immune effectors (antibodies and T-cells) is a necessary condition for clinical efficacy of cancer vaccines;however, the efficacy of these effectors, and perhaps even their generation by vaccination, may be opposed by any of several immunosuppressive mechanisms that have been found in tumor microenvironments and in the peripheral blood of cancer patients. In a recently completed randomized, double-blind, controlled, multicenter phase III clinical trial, patient-specific tumor-derived idiotype (Id) protein was conjugated with a carrier protein (keyhole-limpet hemocyanin, KLH) and administered together with an adjuvant (granulocyte-macrophage colony stimulating factor, GM-CSF) to patients with advanced stage, previously untreated follicular lymphoma (FL), in complete remission following standard induction chemotherapy. Vaccination with Id-KLHCSF significantly prolonged disease-free survival (DFS), compared with the control group that received a non-specific immune stimulant (KLHCSF). The objective of this proposal is to identify predictors of clinical outcome after therapeutic idiotype vaccination in patients with FL, and use them to identify mechanisms affecting vaccine efficacy. Predictors will be found by correlating DFS with the results of immunologic and genomic studies on cryopreserved pre- and post vaccine serum and peripheral blood mononuclear cells, and viable tumor biopsy samples obtained at initial diagnosis, available from all treated patients from both arms of this trial. We propose four Specific Aims: 1) determine whether the induction of antitumor humoral and/or cellular immune responses correlates favorably with clinical outcome following idiotype vaccination in FL, 2) determine whether the state of the immune system prior to vaccination and the cellular elements in the tumor microenvironment affect the induction of antitumor immune responses and clinical outcome following Id vaccination in FL, 3) determine whether the gene expression profiles of neoplastic and/or non-neoplastic cells in the tumor microenvironment at diagnosis predict clinical outcome following idiotype vaccination in FL, and 4) determine whether immune-response related gene polymorphisms predict clinical outcome following idiotype vaccination in FL.
The overall goal of this project is to provide a deeper understanding of the interaction between the immune system and cancer cells, and suggest potential targets to improve results in future cancer vaccine trials. The proposed studies are likely to have substantial impact on the development of the cancer vaccine field in general and lymphoma vaccines in particular.
|Sathyanarayanan, Vishwanath; Neelapu, Sattva S (2015) Cancer immunotherapy: Strategies for personalization and combinatorial approaches. Mol Oncol 9:2043-53|
|Nastoupil, Loretta J; Neelapu, Sattva S (2015) Novel immunologic approaches in lymphoma: unleashing the brakes on the immune system. Curr Oncol Rep 17:30|
|Westin, Jason R; Chu, Fuliang; Zhang, Min et al. (2014) Safety and activity of PD1 blockade by pidilizumab in combination with rituximab in patients with relapsed follicular lymphoma: a single group, open-label, phase 2 trial. Lancet Oncol 15:69-77|
|Voo, Kui Shin; Foglietta, Myriam; Percivalle, Elena et al. (2014) Selective targeting of Toll-like receptors and OX40 inhibit regulatory T-cell function in follicular lymphoma. Int J Cancer 135:2834-46|
|Neelapu, Sattva S; Kwak, Larry W (2014) Rush hour traffic: directing T cells to tumor. J Natl Cancer Inst 106:|
|Rawal, Seema; Chu, Fuliang; Zhang, Min et al. (2013) Cross talk between follicular Th cells and tumor cells in human follicular lymphoma promotes immune evasion in the tumor microenvironment. J Immunol 190:6681-93|