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.
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.
|Geldres, Claudia; Savoldo, Barbara; Dotti, Gianpietro (2016) Chimeric antigen receptor-redirected T cells return to the bench. Semin Immunol 28:3-9|
|Xu, Yang; Chaudhury, Arindam; Zhang, Ming et al. (2016) Glycolysis determines dichotomous regulation of T cell subsets in hypoxia. J Clin Invest 126:2678-88|
|Geldres, Claudia; Savoldo, Barbara; Dotti, Gianpietro (2016) Chimeric Antigen Receptors for Cancer Immunotherapy. Methods Mol Biol 1393:75-86|
|Tian, Gengwen; Courtney, Amy N; Jena, Bipulendu et al. (2016) CD62L+ NKT cells have prolonged persistence and antitumor activity in vivo. J Clin Invest 126:2341-55|
|Caruana, Ignazio; Savoldo, Barbara; Hoyos, Valentina et al. (2015) Heparanase promotes tumor infiltration and antitumor activity of CAR-redirected T lymphocytes. Nat Med 21:524-9|
|Louis, Chrystal U; Shohet, Jason M (2015) Neuroblastoma: molecular pathogenesis and therapy. Annu Rev Med 66:49-63|
|Arber, Caroline; Feng, Xiang; Abhyankar, Harshal et al. (2015) Survivin-specific T cell receptor targets tumor but not T cells. J Clin Invest 125:157-68|
|Caruana, Ignazio; Weber, Gerrit; Ballard, Brandon C et al. (2015) K562-Derived Whole-Cell Vaccine Enhances Antitumor Responses of CAR-Redirected Virus-Specific Cytotoxic T Lymphocytes In Vivo. Clin Cancer Res 21:2952-62|
|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|
|Mazloom, Ali; Louis, Chrystal U; Nuchtern, Jed et al. (2014) Radiation therapy to the primary and postinduction chemotherapy MIBG-avid sites in high-risk neuroblastoma. Int J Radiat Oncol Biol Phys 90:858-62|
Showing the most recent 10 out of 25 publications