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.

KEYWORDS:

• adoptive immunotherapy
• m3F8
• neuroblastoma
• NK Cells

Disclosure of potential conflicts of interest

The authors declare the following conflicts of interest: anti-GD2 antibodies have been licensed by Memorial Sloan Kettering Cancer Center (MSK) to Ymabs Therapeutics Inc., both MSK and NK Cheung have financial interest in this company; Shakeel Modak and Kim Kramer are consultants to Ymabs Therapeutics Inc.

Acknowledgments

We thank Alison Slocum, Chandresh Undhad, and other members of the Center for Immune Cell Therapies at MSK for their work on NK cell isolation. We thank Joe Olechnowicz for editorial assistance.

Additional information

Funding

This work was supported by the NIH National Cancer Institute (P30 CA008748), NIH R01 CA164356, FDA R01 FD-R-004128, Alex's Lemonade Stand Foundation, Society of Memorial Sloan Kettering Cancer Center, and the Cancer Center Core grant (NIH P30 CA008748, NIH O01AI069197).