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Rossig (Abstract)

Cellular Therapy and Transplantation (CTT), Vol. 3, No. 12
doi: 10.3205/ctt-2011-No12-abstract59

© The Authors. This abstract is provided under the following license: Creative Commons Attribution 3.0 Unported

Abstract accepted for "5th Raisa Gorbacheva Memorial Meeting Hematopoietic Stem Cell Transplantation in Children and Adults", Saint Petersburg, Russia, September 18–20, 2011

Preliminary Program

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Cellular immunotherapy of childhood cancer

Claudia Rossig

Universitätskinderklinik Münster, Pädiatrische Hämatologie und Onkologie, Münster, Germany

Correspondence: Claudia Rossig, Universitätskinderklinik Münster, Pädiatrische Hämatologie und Onkologie, Albert-Schweitzer-Str. 33 D-48149 Münster, Germany, E-mail: rossig@spam is baduni-muenster.de

Abstract

The survival of children with cancer has substantially improved during the past 30 years, now resulting in maximum cure rates of 70–80%. However, high-risk diseases, including disseminated Ewing sarcoma, rhabdomyosarcoma, neuroblastoma, and subtypes of acute leukemias have remained fatal despite intensive multimodal treatment regimens. Thus, novel treatment modalities are needed to further improve survival.

Cellular immunotherapy exploits the capacity of the immune system to effectively eliminate target cells while establishing an antigen-specific immune memory. The development of immune-based strategies for cancer is challenged by the scarcity of T-cells with high receptor avidity for tumor-specific antigens within the patient's lymphocyte repertoire, and the failure of tumor cells to present antigen to T-cells. Both obstacles can be bypassed by genetic modification of T cells with recombinant chimeric receptors (CARs) which redirect T-cells towards a tumor surface antigen independent of antigen presentation.

We have generated CARs against tumor-associated antigens relevant in childhood cancers. CAR engineered T-cells against the ganglioside antigen GD2 in neuroblastoma are currently validated in clinical phase I/II studies. More recently, we explored GD2 as an immune target in Ewing sarcoma, since primitive neuroectodermal features and a suggested mesenchymal stem cell origin in this disease are also compatible with aberrant expression of this antigen. Indeed, we found that the majority of Ewing sarcomas surface-express GD2. GD2-specific T-cells efficiently interacted with Ewing sarcoma cells, eradicated multicellular tumor spheres, and had significant in vivo activity against Ewing sarcoma xenografts. Thus, immune targeting of GD2 may be a valuable strategy for eradicating dormant/chemoresistant tumor cells in both neuroblastoma and Ewing sarcoma.

We further applied CAR transfer to target CD19-positive leukemic cells persisting after transplant in high-risk acute lymphoblastic leukemia. Preclinical studies in mouse models have demonstrated that gene-modified CD19-specific T-cells efficiently prevent engraftment of human leukemia xenografts and increase survival without significant toxicity. In a multicenter clinical trial across four European countries, we now propose to administer CD19-redirected donor T-cells to children who develop evidence of minimal residual disease after allogeneic stem cell transplantation. The approach may be of major benefit to children with high-risk acute leukemia and may provide proof of principle for targeting other malignancies using CAR transfer.

Current projects focus on the in vivo survival and functional persistence of CAR gene-modified T-cells. Moreover, more effective strategies depend on elucidation of specific mechanisms of immune escape in these malignancies. Preclinical in vitro and in vivo studies and early clinical trials will pave the way for an integration of the CAR strategy into current treatment regimens for high-risk patients.

Keywords: childhood cancer, cellular therapy, chimeric T cell receptors