Preclinical Assessment of CD171-Directed CAR T-cell Adoptive Therapy for Childhood Neuroblastoma
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Preclinical Assessment of CD171-Directed CAR T-cell Adoptive Therapy for Childhood Neuroblastoma : CE7 Epitope Target Safety and Product Manufacturing Feasibility. / Künkele, Annette; Taraseviciute, Agne; Finn, Laura S; Johnson, Adam J; Berger, Carolina; Finney, Olivia; Chang, Cindy A; Rolczynski, Lisa S; Brown, Christopher; Mgebroff, Stephanie; Berger, Michael; Park, Julie R; Jensen, Michael C.
In: CLIN CANCER RES, Vol. 23, No. 2, 15.01.2017, p. 466-477.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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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 -