The intent of this project is to improve the therapeutic potential of T-cell therapy targeting neuroblastoma (NB) by co-expressing a tumor-specific chimeric antigen receptor (CAR) and a cytokine receptor. NB is the most common malignant extracranial tumor of childhood, and children with high-risk disease continue to have a poor outcome despite intensive therapy. New treatment strategies are therefore required. We have recently demonstrated that adoptive transfer of Epstein-Barr-virus-specific CTLs (EBV-CTLs), genetically modified to express a chimeric antigen receptor (CAR) targeting GD2 expressed by neuroblasts, persisted in the circulation for 6 weeks and determined objective tumor responses in 4/8 patients with refractory/relapsed NB. Since it is now evident that tumor responses to CTL infusions correlate with the persistence/expansion of these CTLs, we propose a new strategy to improve the growth of adoptively transferred CAR-GD2-EBV-CTLs. Although in vivo expansion of CTLs can be accomplished in the acutely lymphodepleted host, profund lymphodepletion may be excessively toxic to the majority of refractory/resistant NB patients who have already received significant doses of chemotherapy and radiation. Moreover, the administration of high-doses of IL-2 significantly contributes in increasing the toxicity and in favoring the expansion of regulatory T cells (Tregs) that inhibit the function of anti-tumor CTLs. In contrast to IL-2, the administration of recombinant IL-7 (rIL-7) seems well tolerated and produces polyclonal expansion of naive CD4+ and CD8+ T lymphocytes, without evident increase of Tregs, suggesting that this cytokine can be used to improve the persistence/expansion of adoptively transferred CTLs. Unfortunately, IL-7 has only limited activity on ex vivo expanded tumor-directed CTLs because the expression of IL-7 receptor alpha (IL-7Ra) is rapidly down-regulated once T cells are exposed to antigen stimulation. We found that gene transfer can be used to restore functional IL-7Ra in EBV- CTLs without affecting their antigen specificity and effector function. Based on these data, we propose to evaluate in a preclinical model and then in a phase I clinical trial whether EBV-CTLs co-expressing CAR-GD2 and IL-7Ra infused into refractory/relapsed NB patients safely expand and persist in response to the administration of rIL-7, and whether such engineered CTLs have anti-tumor activity.

Public Health Relevance

We have had success in treating patients with neuroblastoma by using their own immune cells modified with a chimeric molecule that eliminate the tumor cells. In this project we intend to arm these cells to be more potent by improving their growth when infused into the patients with neuroblastoma.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA142636-05
Application #
8610145
Study Section
Clinical Oncology Study Section (CONC)
Program Officer
Timmer, William C
Project Start
2010-04-05
Project End
2015-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
5
Fiscal Year
2014
Total Cost
$266,823
Indirect Cost
$92,997
Name
Baylor College of Medicine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
Nishio, Nobuhiro; Diaconu, Iulia; Liu, Hao et al. (2014) Armed oncolytic virus enhances immune functions of chimeric antigen receptor-modified T cells in solid tumors. Cancer Res 74:5195-205
Heczey, Andras; Liu, Daofeng; Tian, Gengwen et al. (2014) Invariant NKT cells with chimeric antigen receptor provide a novel platform for safe and effective cancer immunotherapy. Blood 124:2824-33
Caruana, Ignazio; Diaconu, Iulia; Dotti, Gianpietro (2014) From monoclonal antibodies to chimeric antigen receptors for the treatment of human malignancies. Semin Oncol 41:661-6
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
Chakraborty, Rikhia; Mahendravada, Aruna; Perna, Serena K et al. (2013) Robust and cost effective expansion of human regulatory T cells highly functional in a xenograft model of graft-versus-host disease. Haematologica 98:533-7
Arber, C; Abhyankar, H; Heslop, H E et al. (2013) The immunogenicity of virus-derived 2A sequences in immunocompetent individuals. Gene Ther 20:958-62
Savoldo, Barbara; Dotti, Gianpietro (2013) Chimeric antigen receptors (CARs) from bench-to-bedside. Immunol Lett 155:40-2
Perna, Serena K; De Angelis, Biagio; Pagliara, Daria et al. (2013) Interleukin 15 provides relief to CTLs from regulatory T cell-mediated inhibition: implications for adoptive T cell-based therapies for lymphoma. Clin Cancer Res 19:106-17
Chakraborty, Rikhia; Rooney, Cliona; Dotti, Gianpietro et al. (2012) Changes in chemokine receptor expression of regulatory T cells after ex vivo culture. J Immunother 35:329-36

Showing the most recent 10 out of 12 publications