Preclinical Assessment of CD171-Directed CAR T-cell Adoptive Therapy for Childhood Neuroblastoma

TY - JOUR

T1 - Preclinical Assessment of CD171-Directed CAR T-cell Adoptive Therapy for Childhood Neuroblastoma

T2 - CE7 Epitope Target Safety and Product Manufacturing Feasibility

AU - Künkele, Annette

AU - Taraseviciute, Agne

AU - Finn, Laura S

AU - Johnson, Adam J

AU - Berger, Carolina

AU - Finney, Olivia

AU - Chang, Cindy A

AU - Rolczynski, Lisa S

AU - Brown, Christopher

AU - Mgebroff, Stephanie

AU - Berger, Michael

AU - Park, Julie R

AU - Jensen, Michael C

N1 - ©2016 American Association for Cancer Research.

PY - 2017/1/15

Y1 - 2017/1/15

N2 - PURPOSE: 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.EXPERIMENTAL DESIGN: 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 preclinical 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 1 × 108/kg 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 antitumor activity.CONCLUSIONS: Our preclinical assessment of the CE7 epitope on CD171 supports its utility and safety as a CAR T-cell target for neuroblastoma immunotherapy. Clin Cancer Res; 23(2); 466-77. ©2016 AACR.

AB - PURPOSE: 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.EXPERIMENTAL DESIGN: 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 preclinical 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 1 × 108/kg 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 antitumor activity.CONCLUSIONS: Our preclinical assessment of the CE7 epitope on CD171 supports its utility and safety as a CAR T-cell target for neuroblastoma immunotherapy. Clin Cancer Res; 23(2); 466-77. ©2016 AACR.

KW - Animals

KW - Antineoplastic Agents, Immunological/administration & dosage

KW - Cell Line, Tumor

KW - Epitopes/immunology

KW - Gene Expression Regulation, Neoplastic

KW - Humans

KW - Immunotherapy, Adoptive

KW - Lentivirus/genetics

KW - Macaca mulatta

KW - Neoplasm Recurrence, Local/immunology

KW - Neural Cell Adhesion Molecule L1/genetics

KW - Neuroblastoma/immunology

KW - Receptors, Antigen, T-Cell/immunology

KW - T-Lymphocytes, Cytotoxic/immunology

U2 - 10.1158/1078-0432.CCR-16-0354

DO - 10.1158/1078-0432.CCR-16-0354

M3 - SCORING: Journal article

C2 - 27390347

VL - 23

SP - 466

EP - 477

JO - CLIN CANCER RES

JF - CLIN CANCER RES

SN - 1078-0432

IS - 2

ER -