T cell therapy with L1-CAM-targeting chimeric antigen receptors (CAR) as immune therapy for neuroblastoma patients after haploidentical stem cell transplantation.

• Applicant: Professorin Dr. Annette Künkele-Langer
• Subject Area: Pediatric and Adolescent Medicine
• Term: from 2012 to 2015
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 213787805

Adoptive therapy for cancer using genetically retargeted T cells is rapidly emerging as a promising therapeutic modality for hematological malignancies, but significant work remains for effective application to solid tumors. T-depleted haploidentical hematopoietic stem cell transplantation (haploHSCT) represents a versatile platform to facilitate adoptive T cell therapy for patients who have sustained significant damage to their immune systems through prior intensive chemo/radiotherapies, such as children with relapsed neuroblastoma. Currently 90% of children with relapsed neuroblastoma die of disease. Novel therapeutic options are urgently needed for this patient group. Biological parents are haploidentical to their children, and thus, excellent candidates for the source of hematopoietic stem cells and T cells for therapy. We propose that T-depleted haploHSCT, which induces a transient state of profound lymphopenia, is an ideal setting for adoptive transfer of parent-derived central memory T cells genetically modified to express chimeric antigen receptors for targeted recognition of neuroblastoma. Several factors must be optimized for clinical application. Our proposed project has 3 aims: i) to delineate the optimal extracellular domain format and intracellular signaling domain components of a chimeric antigen receptor (CAR) to trigger T cells by human neuroblastoma, ii) to develop genetic systems to regulate the function of CAR-redirected T cells using small molecule transgene expression control technologies and iii) to develop technologies to knock out T cell antigen receptor expression in CAR-modified T cells to eliminate alloreactivity. Safe and effective adoptive therapy has the potential to improve the prognosis for children with recurrent/refractory neuroblastoma. We predict that this project will be informative for several general features of haploHSCT/adoptive therapy for a broad array of additional pediatric solid tumors, to which CARs are being designed.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Dr. Michael Jensen