CAR T Cells Administered in Combination with Lymphodepletion and PD-1 Inhibition to Patients with Neuroblastoma

Andras Heczey, Chrystal U. Louis, Barbara Savoldo, Olga Dakhova, April Durett, Bambi Grilley, Hao Liu, Mengfeng F. Wu, Zhuyong Mei, Adrian Gee, Birju Mehta, Huimin Zhang, Nadia Mahmood, Haruko Tashiro, Helen E. Heslop, Gianpietro Dotti, Cliona M. Rooney, Malcolm K. Brenner

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Abstract

Targeting disialoganglioside (GD2) on neuroblastoma (NB) with T cells expressing a first-generation chimeric antigen receptor (CAR) was safe, but the cells had poor expansion and long-term persistence. We developed a third-generation GD2-CAR (GD2-CAR3) and hypothesized that GD2-CAR3 T cells (CARTs) would be safe and effective. This phase 1 study enrolled relapsed or refractory NB patients in three cohorts. Cohort 1 received CART alone, cohort 2 received CARTs plus cyclophosphamide and fludarabine (Cy/Flu), and cohort 3 was treated with CARTs, Cy/Flu, and a programmed death-1 (PD-1) inhibitor. Eleven patients were treated with CARTs. The infusions were safe, and no dose-limiting toxicities occurred. CARTs were detectable in cohort 1, but the lymphodepletion induced by Cy/Flu increased circulating levels of the homeostatic cytokine interleukin (IL)-15 (p = 0.003) and increased CART expansion by up to 3 logs (p = 0.03). PD-1 inhibition did not further enhance expansion or persistence. Antitumor responses at 6 weeks were modest. We observed a striking expansion of CD45/CD33/CD11b/CD163+ myeloid cells (change from baseline, p = 0.0126) in all patients, which may have contributed to the modest early antitumor responses; the effect of these cells merits further study. Thus, CARTs are safe, and Cy/Flu can further increase their expansion.

LanguageEnglish (US)
Pages2214-2224
Number of pages11
JournalMolecular Therapy
Volume25
Issue number9
DOIs
StatePublished - Sep 6 2017

Fingerprint

T-Cell Antigen Receptor
Neuroblastoma
Cyclophosphamide
Antigen Receptors
T-Lymphocytes
Interleukin-15
Myeloid Cells
Cytokines
fludarabine

Keywords

  • GD2-CAR
  • immunotherapy
  • neuroblastoma

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery

Cite this

Heczey, A., Louis, C. U., Savoldo, B., Dakhova, O., Durett, A., Grilley, B., ... Brenner, M. K. (2017). CAR T Cells Administered in Combination with Lymphodepletion and PD-1 Inhibition to Patients with Neuroblastoma. Molecular Therapy, 25(9), 2214-2224. DOI: 10.1016/j.ymthe.2017.05.012

CAR T Cells Administered in Combination with Lymphodepletion and PD-1 Inhibition to Patients with Neuroblastoma. / Heczey, Andras; Louis, Chrystal U.; Savoldo, Barbara; Dakhova, Olga; Durett, April; Grilley, Bambi; Liu, Hao; Wu, Mengfeng F.; Mei, Zhuyong; Gee, Adrian; Mehta, Birju; Zhang, Huimin; Mahmood, Nadia; Tashiro, Haruko; Heslop, Helen E.; Dotti, Gianpietro; Rooney, Cliona M.; Brenner, Malcolm K.

In: Molecular Therapy, Vol. 25, No. 9, 06.09.2017, p. 2214-2224.

Research output: Contribution to journalArticle

Heczey, A, Louis, CU, Savoldo, B, Dakhova, O, Durett, A, Grilley, B, Liu, H, Wu, MF, Mei, Z, Gee, A, Mehta, B, Zhang, H, Mahmood, N, Tashiro, H, Heslop, HE, Dotti, G, Rooney, CM & Brenner, MK 2017, 'CAR T Cells Administered in Combination with Lymphodepletion and PD-1 Inhibition to Patients with Neuroblastoma' Molecular Therapy, vol. 25, no. 9, pp. 2214-2224. DOI: 10.1016/j.ymthe.2017.05.012
Heczey A, Louis CU, Savoldo B, Dakhova O, Durett A, Grilley B et al. CAR T Cells Administered in Combination with Lymphodepletion and PD-1 Inhibition to Patients with Neuroblastoma. Molecular Therapy. 2017 Sep 6;25(9):2214-2224. Available from, DOI: 10.1016/j.ymthe.2017.05.012
Heczey, Andras ; Louis, Chrystal U. ; Savoldo, Barbara ; Dakhova, Olga ; Durett, April ; Grilley, Bambi ; Liu, Hao ; Wu, Mengfeng F. ; Mei, Zhuyong ; Gee, Adrian ; Mehta, Birju ; Zhang, Huimin ; Mahmood, Nadia ; Tashiro, Haruko ; Heslop, Helen E. ; Dotti, Gianpietro ; Rooney, Cliona M. ; Brenner, Malcolm K./ CAR T Cells Administered in Combination with Lymphodepletion and PD-1 Inhibition to Patients with Neuroblastoma. In: Molecular Therapy. 2017 ; Vol. 25, No. 9. pp. 2214-2224
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