Adoptive immunotherapy with haploidentical natural killer cells and Anti-GD2 monoclonal antibody m3F8 for resistant neuroblastoma: Results of a phase I study Journal Article
| Authors: | Modak, S.; Le Luduec, J. B.; Cheung, I. Y.; Goldman, D. A.; Ostrovnaya, I.; Doubrovina, E.; Basu, E.; Kushner, B. H.; Kramer, K.; Roberts, S. S.; O'Reilly, R. J.; Cheung, N. K. V.; Hsu, K. C. |
| Article Title: | Adoptive immunotherapy with haploidentical natural killer cells and Anti-GD2 monoclonal antibody m3F8 for resistant neuroblastoma: Results of a phase I study |
| Abstract: | Natural killer (NK) cell-mediated antibody-dependent toxicity is a potent mechanism of action of the anti-GD2 murine monoclonal antibody 3F8 (m3F8). Killer immunoglobulin-like receptor (KIR) and HLA genotypes modulate NK activity and are key prognostic markers in m3F8-treated patients with neuroblastoma. Endogenous NK-cells are suppressed in the setting of high tumor burden and chemotherapy. Allogeneic NK-cells however, demonstrate potent anti-neuroblastoma activity. We report on the results of a phase I clinical trial of haploidentical NK-cells plus m3F8 administered to patients with high-risk neuroblastoma after conditioning chemotherapy. The primary objective was to determine the maximum tolerated NK-cell dose (MTD). Secondary objectives included assessing anti-neuroblastoma activity and its relationship to donor-recipient KIR/HLA genotypes, NK function, and donor NK chimerism. Patients received a lymphodepleting regimen prior to infusion of haploidentical CD3-CD56+ NK-cells, followed by m3F8. Overall and progression free survival (PFS) were assessed from the time of first NK-cell dose. Univariate Cox regression assessed relationship between dose and outcomes. Thirty-five patients received NK-cells at one of five dose levels ranging from <1×106 to 50×106 CD3-CD56+cells/kg. One patient experienced grade 3 hypertension and grade 4 pneumonitis. MTD was not reached. Ten patients (29%) had complete or partial response; 17 (47%) had no response; and eight (23%) had progressive disease. No relationship was found between response and KIR/HLA genotype or between response and FcγRIII receptor polymorphisms. Patients receiving >10×106 CD56+cells/kg had improved PFS (HR: 0.36, 95%CI: 0.15–0.87, p = 0.022). Patient NK-cells displayed high NKG2A expression, leading to inhibition by HLA-E-expressing neuroblastoma cells. Adoptive NK-cell therapy in combination with m3F8 is safe and has anti-neuroblastoma activity at higher cell doses. © 2018, © 2018 Taylor & Francis Group, LLC. |
| Keywords: | neuroblastoma; adoptive immunotherapy; nk cells; m3f8 |
| Journal Title: | OncoImmunology |
| Volume: | 7 |
| Issue: | 8 |
| ISSN: | 2162-4011 |
| Publisher: | Landes Bioscience |
| Date Published: | 2018-01-01 |
| Start Page: | e1461305 |
| Language: | English |
| DOI: | 10.1080/2162402x.2018.1461305 |
| PROVIDER: | scopus |
| PMCID: | PMC6136849 |
| PUBMED: | 30221057 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 5 October 2018 -- Source: Scopus |
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