Oral Presentation Advances in Neuroblastoma Research Congress 2016

Preclinical assessment of CD171-directed CAR T cell adoptive therapy for childhood neuroblastoma: CE7 epitope target safety and product manufacturing feasibility (#101)

Annette Kuenkele 1 , Julie Park 2 , Laura Finn 3 , Agne Taraseviciute 2 , Carolina Berger 4 , Olivia Finney 5 , Christopher Brown 5 , Stephanie Mgebroff 5 , Adam Johnson 5 , Michael Jensen 5
  1. Charité Berlin, Berlin, Germany
  2. Department of Pediatrics, Seattle Children’s Hospital, University of Washington, Seattle, WA, USA
  3. Department of Medicine, University of Washington, Seattle, WA, USA
  4. Fred Hutchinson Cancer Research Center, Seattle, WA, USA
  5. Ben Towne Center Childhood Cancer Research, Seattle Children’s Research Institute, Seattle, WA, USA

Background: The identification and vetting of cell surface tumor restricted epitopes for chimeric antigen receptor (CAR) redirected T cell immunotherapy is the subject of intensive investigation. We have focused on CD171 (L1-CAM), an abundant cell surface molecule on neuroblastomas, and, specifically, on the glycosylation dependent tumor-specific epitope recognized by the CE7 monoclonal antibody.

Methods: CD171 expression was assessed by IHC using CE7 mAb in tumor microarrays of primary, metastatic, and recurrent neuroblastoma, as well as human and rhesus macaque tissue arrays. The safety of targeting the CE7 epitope of CD171 with CE7-CAR T cells was evaluated in a pre-clinical rhesus macaque trial on the basis of CD171 homology and CE7 cross reactivity. The feasibility of generating bioactive CAR T cells from heavily pretreated pediatric patients with recurrent/refractory disease was assessed.

Results: CD171 is uniformly and abundantly expressed by neuroblastoma tumor specimens obtained at diagnoses and relapse independent of patient clinical risk group. CD171 expression in normal tissues is similar in humans and rhesus macaques. Infusion of up to 100x106 CE7-CAR+ CTLs in rhesus macaques revealed no signs of specific on-target off-tumor toxicity. Manufacturing of lentivirally transduced CD4+ and CD8+ CE7-CAR T cell products under GMP was successful in 4 out of 5 consecutively enrolled neuroblastoma patients in a phase I study. All four CE7-CAR T cell products demonstrated in vitro and in vivo anti-tumor activity.

Conclusion: Our preclinical assessment of the CE7 epitope on CD171 supports it’s utility and safety as a CAR T cell target for neuroblastoma immunotherapy.