Currently, patients with treatment-refractory follicular lymphoma, the most common sub-type of non-Hodgkin's lymphoma, have a poor chance of disease-free survival and this group needs to be treated with innovative approaches. Adoptive transfer of ex vivo-expanded autologous T cells rendered specific for CD19 is a method proposed to augment tumor-specific immune responses in these patients in order to improve disease control. The specificity for CD19 is derived from a chimeric immunoreceptor expressed on the cell surface of genetically modified T cells that combines antibody recognition of CD19 with the effector-function of activated T cells. A phase I clinical trial is proposed for relapsed/recurrent follicular lymphoma based on the introduction of a CD19-specific chimeric immunoreceptor to render CD8+ and CD4+ T cells capable of targeting CD19+ lymphoma cells in an MHC-independent manner and be deleted by ganciclovir as a result of the co-expression of a bifunctional hygromycinlthymidine kinase (HyTK) selection/suicide gene. Following fludarabine-based lympho-depleting therapy, research participants will receive low-dose recombinant human interleukin-2 (rhlL-2) and an intra-patient dose escalation of autologous CD19R+HyTK+ T cells, expanded in vitro in compliance with current good manufacturing practice. This study will answer questions regarding the safety and feasibility of infusing CD19-specific HyTK+ T cells (specific aim #1), as well as determining the in vivo persistence (specific aim #2) and immunogenicity of the genetically modified T cells (specific aim #3) and will investigate the antitumor efficacy and lymph node-homing properties of the CD19-specific T cells (specific aim #4). The data collected from this clinical trial will facilitate the design of second-generation adoptive immunotherapy protocols, not just for follicular lymphoma, but other B-lineage malignancies.
The specific aims of this application are: (1) To determine the feasibility and safety of adoptively transferred autologous CD19R+HyTK+ T cells in research participants with recurrent/refractory follicular lymphoma (2) To determine the persistence of adoptively transferred autologous CD19R+HyTK+ T cells in research participants after lympho-depleting therapy. (3) To determine the immune response against adoptively transferred autologous CD19R+HyTK+ T cells in research participants after lympho-depleting therapy (4) To determine the efficacy of adoptively transferred autologous CD19R+HyTK+ T cells and low-dose rhlL-2 in research participants after lympho-depleting therapy.
| Park, Julie R; Digiusto, David L; Slovak, Marilyn et al. (2007) Adoptive transfer of chimeric antigen receptor re-directed cytolytic T lymphocyte clones in patients with neuroblastoma. Mol Ther 15:825-33 |
