The long-term goal of Project 1 (C. Rooney and L. Wang) is to improve the expansion and persistence of adoptively transferred tumor-specific T cells using two novel approaches. (1) Incorporation of a third- generation chimeric antigen receptor (CAR) for GD2 containing intracellular signaling domains for CD28 and OX40 is hypothesized to enhance and sustain T- cell responses intratumorally, while providing resistance to inhibitory ligands elaborated within the tumor microenvironment. (ii) An extratumoral proliferative boost should be attained by engrafting the GD2.CAR onto T cells specific for the varicella-zoster virus (VZV), for which there exists a potent live-attenuated booster vaccine that increases the in vivo proliferation of VZV-specific T cells via their TCRs. These broad concepts will be explored in a clinical trial of GD2.CAR-engrafted VZV-specific T cells for the treatment of patients with advanced GD2-positive sarcomas ( A i m s 1 and 2). Because this will be a "first-in-man" study, the transduced T cells will also incorporate an inducible safety switch based on dimerization of the caspase-9 molecule, which was validated in a recent clinical trial against graft-vs.-host disease. Unfortunately, the youngest pediatric sarcoma patients will be VZV-negative, making it difficult to generate VZV-specific autologous T cells and to justify vaccination of these seronegative patients with a live-attenuated virus. Hence, Aim 3 will evaluate in a preclinical model a cellular vaccine against GD2 that should provide extratumoral stimulation via the CAR. This effort will rely on the JF neuroblastoma (NB) cell line, which has been extensively tested as a cellular vaccine for NB. GD2 is strongly expressed by JF cells and can be presented to GD2,CAR-positive T cells both directly by the JFNB cells and indirectly by local antigen- presenting cells. Genetic modification of JFNB cells to express cytokines, such as ILI 5 and GM-CSF, that enhance T-cell proliferation and recruit and activate dendritic cells should promote extratumoral proliferation of the CAR-positive T cells in ananalogous way to stimulation of the native T cell receptor by VZV. In part therefore our project uses concepts developed in Project 3 and provides potential ways of increasing the safety and efficacy of projects 2 and 3 (the iC9 safety gene) and Project 4 (the DNR for TGFbeta).
Progress in the development of T-cell therapy for advanced sarcomas and other high-risk solid tumors has been slowed by the weak expression or absence of targetable tumor antigens and poor performance of infused T cells . Project 1 seeks to address this problem by combining improved antigen receptor capabilities with a novel vaccination strategy to ensure adequate T-cell stimulation, both within and outside the tumor site.
|DeRenzo, Christopher; Gottschalk, Stephen (2014) Genetically modified T-cell therapy for osteosarcoma. Adv Exp Med Biol 804:323-40|
|Rouce, Rayne H; Louis, Chrystal U; Heslop, Helen E (2014) Epstein-Barr virus lymphoproliferative disease after hematopoietic stem cell transplant. Curr Opin Hematol 21:476-81|
|Perna, Serena K; Pagliara, Daria; Mahendravada, Aruna et al. (2014) Interleukin-7 mediates selective expansion of tumor-redirected cytotoxic T lymphocytes (CTLs) without enhancement of regulatory T-cell inhibition. Clin Cancer Res 20:131-9|
|Leen, Ann M; Heslop, Helen E; Brenner, Malcolm K (2014) Antiviral T-cell therapy. Immunol Rev 258:12-29|
|Zhou, Xiaoou; Di Stasi, Antonio; Tey, Siok-Keen et al. (2014) Long-term outcome after haploidentical stem cell transplant and infusion of T cells expressing the inducible caspase 9 safety transgene. Blood 123:3895-905|
|Chia, Whay-Kuang; Teo, Marissa; Wang, Who-Whong et al. (2014) Adoptive T-cell transfer and chemotherapy in the first-line treatment of metastatic and/or locally recurrent nasopharyngeal carcinoma. Mol Ther 22:132-9|
|Anurathapan, Usanarat; Leen, Ann M; Brenner, Malcolm K et al. (2014) Engineered T cells for cancer treatment. Cytotherapy 16:713-33|
|Anurathapan, Usanarat; Chan, Robert C; Hindi, Hakeem F et al. (2014) Kinetics of tumor destruction by chimeric antigen receptor-modified T cells. Mol Ther 22:623-33|
|Heslop, Helen E (2014) Combining drugs and biologics to treat nasopharyngeal cancer. Mol Ther 22:8-9|
|Lee, Daniel W; Gardner, Rebecca; Porter, David L et al. (2014) Current concepts in the diagnosis and management of cytokine release syndrome. Blood 124:188-95|
Showing the most recent 10 out of 114 publications