A pilot trial of humanized anti-GD2 monoclonal antibody (hu14.18K322A) with chemotherapy and natural killer cells in children with recurrent/refractory neuroblastoma

Sara M. Federico; M. Beth McCarville; Barry L. Shulkin; Paul M. Sondel; Jacquelyn A. Hank; Paul Hutson; Michael Meagher; Aaron Shafer; Catherine Y. Ng; Wing Leung; William E. Janssen; Jianrong Wu; Shenghua Mao; Rachel C. Brennan; Victor M. Santana; Alberto S. Pappo; Wayne L. Furman

doi:10.1158/1078-0432.CCR-17-0379

A pilot trial of humanized anti-GD2 monoclonal antibody (hu14.18K322A) with chemotherapy and natural killer cells in children with recurrent/refractory neuroblastoma

Sara M. Federico, M. Beth McCarville, Barry L. Shulkin, Paul M. Sondel, Jacquelyn A. Hank, Paul Hutson, Michael Meagher, Aaron Shafer, Catherine Y. Ng, Wing Leung, William E. Janssen, Jianrong Wu, Shenghua Mao, Rachel C. Brennan, Victor M. Santana, Alberto S. Pappo, Wayne L. Furman

Internal Medicine

Research output: Contribution to journal › Article › peer-review

124 Scopus citations

Abstract

Purpose: Anti-GD2 mAbs, acting via antibody-dependent cell-mediated cytotoxicity, may enhance the effects of chemotherapy. This pilot trial investigated a fixed dose of a unique anti-GD2 mAb, hu14.18K322A, combined with chemotherapy, cytokines, and haploidentical natural killer (NK) cells. Experimental Design: Children with recurrent/refractory neuroblastoma received up to six courses of hu14.18K322A (40 mg/m²/dose, days 2–5), GM-CSF, and IL2 with chemotherapy: cyclophosphamide/topotecan (courses 1,2), irinotecan/temozolomide (courses 3,4), and ifosfamide/carboplatin/ etoposide (courses 5,6). Parentally derived NK cells were administered with courses 2, 4, and 6. Serum for pharmacokinetic studies of hu14.18K322A, soluble IL2 receptor alpha (sIL2Ra) levels, and human antihuman antibodies (HAHA) were obtained. Results: Thirteen heavily pretreated patients (9 with prior anti-GD2 therapy) completed 65 courses. One patient developed an unacceptable toxicity (grade 4 thrombocytopenia >35 days). Four patients discontinued treatment for adverse events (hu14.18K322A allergic reaction, viral infection, surgical death, second malignancy). Common toxicities included grade 3/4 myelosuppression (13/13 patients) and grade 1/2 pain (13/13 patients). Eleven patients received 29 NK-cell infusions. The response rate was 61.5% (4 complete responses, 1 very good partial response, 3 partial responses) and five had stable disease. The median time to progression was 274 days (range, 239–568 days); 10 of 13 patients (77%) survived 1 year. Hu14.18K322A pharmacokinetics was not affected by chemotherapy or HAHA. All patients had increased sIL2Ra levels, indicating immune activation. Conclusions: Chemotherapy plus hu14.18K322A, cytokines, and NK cells is feasible and resulted in clinically meaningful responses in patients with refractory/recurrent neuroblastoma. Further studies of this approach are warranted in patients with relapsed and newly diagnosed neuroblastoma.

Original language	English
Pages (from-to)	6441-6449
Number of pages	9
Journal	Clinical Cancer Research
Volume	23
Issue number	21
DOIs	https://doi.org/10.1158/1078-0432.CCR-17-0379
State	Published - Nov 1 2017

Bibliographical note

Publisher Copyright:
©2017 AACR.

Funding

Supported in part by Cancer Center GrantCA23099 and Cancer Center Support CORE GrantP30 CA 21765 from the National Cancer Institute and by the American Lebanese Syrian Associated Charities.

Funders	Funder number
National Childhood Cancer Registry – National Cancer Institute
American Lebanese Syrian Associated Charities

ASJC Scopus subject areas

General Medicine

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1158/1078-0432.CCR-17-0379

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Federico, S. M., McCarville, M. B., Shulkin, B. L., Sondel, P. M., Hank, J. A., Hutson, P., Meagher, M., Shafer, A., Ng, C. Y., Leung, W., Janssen, W. E., Wu, J., Mao, S., Brennan, R. C., Santana, V. M., Pappo, A. S., & Furman, W. L. (2017). A pilot trial of humanized anti-GD2 monoclonal antibody (hu14.18K322A) with chemotherapy and natural killer cells in children with recurrent/refractory neuroblastoma. Clinical Cancer Research, 23(21), 6441-6449. https://doi.org/10.1158/1078-0432.CCR-17-0379

@article{90b59bb8258c4862ba60c21f516cabfc,

title = "A pilot trial of humanized anti-GD2 monoclonal antibody (hu14.18K322A) with chemotherapy and natural killer cells in children with recurrent/refractory neuroblastoma",

abstract = "Purpose: Anti-GD2 mAbs, acting via antibody-dependent cell-mediated cytotoxicity, may enhance the effects of chemotherapy. This pilot trial investigated a fixed dose of a unique anti-GD2 mAb, hu14.18K322A, combined with chemotherapy, cytokines, and haploidentical natural killer (NK) cells. Experimental Design: Children with recurrent/refractory neuroblastoma received up to six courses of hu14.18K322A (40 mg/m2/dose, days 2–5), GM-CSF, and IL2 with chemotherapy: cyclophosphamide/topotecan (courses 1,2), irinotecan/temozolomide (courses 3,4), and ifosfamide/carboplatin/ etoposide (courses 5,6). Parentally derived NK cells were administered with courses 2, 4, and 6. Serum for pharmacokinetic studies of hu14.18K322A, soluble IL2 receptor alpha (sIL2Ra) levels, and human antihuman antibodies (HAHA) were obtained. Results: Thirteen heavily pretreated patients (9 with prior anti-GD2 therapy) completed 65 courses. One patient developed an unacceptable toxicity (grade 4 thrombocytopenia >35 days). Four patients discontinued treatment for adverse events (hu14.18K322A allergic reaction, viral infection, surgical death, second malignancy). Common toxicities included grade 3/4 myelosuppression (13/13 patients) and grade 1/2 pain (13/13 patients). Eleven patients received 29 NK-cell infusions. The response rate was 61.5% (4 complete responses, 1 very good partial response, 3 partial responses) and five had stable disease. The median time to progression was 274 days (range, 239–568 days); 10 of 13 patients (77%) survived 1 year. Hu14.18K322A pharmacokinetics was not affected by chemotherapy or HAHA. All patients had increased sIL2Ra levels, indicating immune activation. Conclusions: Chemotherapy plus hu14.18K322A, cytokines, and NK cells is feasible and resulted in clinically meaningful responses in patients with refractory/recurrent neuroblastoma. Further studies of this approach are warranted in patients with relapsed and newly diagnosed neuroblastoma.",

author = "Federico, {Sara M.} and McCarville, {M. Beth} and Shulkin, {Barry L.} and Sondel, {Paul M.} and Hank, {Jacquelyn A.} and Paul Hutson and Michael Meagher and Aaron Shafer and Ng, {Catherine Y.} and Wing Leung and Janssen, {William E.} and Jianrong Wu and Shenghua Mao and Brennan, {Rachel C.} and Santana, {Victor M.} and Pappo, {Alberto S.} and Furman, {Wayne L.}",

note = "Publisher Copyright: {\textcopyright}2017 AACR.",

year = "2017",

month = nov,

day = "1",

doi = "10.1158/1078-0432.CCR-17-0379",

language = "English",

volume = "23",

pages = "6441--6449",

number = "21",

}

Federico, SM, McCarville, MB, Shulkin, BL, Sondel, PM, Hank, JA, Hutson, P, Meagher, M, Shafer, A, Ng, CY, Leung, W, Janssen, WE, Wu, J, Mao, S, Brennan, RC, Santana, VM, Pappo, AS & Furman, WL 2017, 'A pilot trial of humanized anti-GD2 monoclonal antibody (hu14.18K322A) with chemotherapy and natural killer cells in children with recurrent/refractory neuroblastoma', Clinical Cancer Research, vol. 23, no. 21, pp. 6441-6449. https://doi.org/10.1158/1078-0432.CCR-17-0379

A pilot trial of humanized anti-GD2 monoclonal antibody (hu14.18K322A) with chemotherapy and natural killer cells in children with recurrent/refractory neuroblastoma. / Federico, Sara M.; McCarville, M. Beth; Shulkin, Barry L. et al.
In: Clinical Cancer Research, Vol. 23, No. 21, 01.11.2017, p. 6441-6449.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - A pilot trial of humanized anti-GD2 monoclonal antibody (hu14.18K322A) with chemotherapy and natural killer cells in children with recurrent/refractory neuroblastoma

AU - Federico, Sara M.

AU - McCarville, M. Beth

AU - Shulkin, Barry L.

AU - Sondel, Paul M.

AU - Hank, Jacquelyn A.

AU - Hutson, Paul

AU - Meagher, Michael

AU - Shafer, Aaron

AU - Ng, Catherine Y.

AU - Leung, Wing

AU - Janssen, William E.

AU - Wu, Jianrong

AU - Mao, Shenghua

AU - Brennan, Rachel C.

AU - Santana, Victor M.

AU - Pappo, Alberto S.

AU - Furman, Wayne L.

PY - 2017/11/1

Y1 - 2017/11/1

N2 - Purpose: Anti-GD2 mAbs, acting via antibody-dependent cell-mediated cytotoxicity, may enhance the effects of chemotherapy. This pilot trial investigated a fixed dose of a unique anti-GD2 mAb, hu14.18K322A, combined with chemotherapy, cytokines, and haploidentical natural killer (NK) cells. Experimental Design: Children with recurrent/refractory neuroblastoma received up to six courses of hu14.18K322A (40 mg/m2/dose, days 2–5), GM-CSF, and IL2 with chemotherapy: cyclophosphamide/topotecan (courses 1,2), irinotecan/temozolomide (courses 3,4), and ifosfamide/carboplatin/ etoposide (courses 5,6). Parentally derived NK cells were administered with courses 2, 4, and 6. Serum for pharmacokinetic studies of hu14.18K322A, soluble IL2 receptor alpha (sIL2Ra) levels, and human antihuman antibodies (HAHA) were obtained. Results: Thirteen heavily pretreated patients (9 with prior anti-GD2 therapy) completed 65 courses. One patient developed an unacceptable toxicity (grade 4 thrombocytopenia >35 days). Four patients discontinued treatment for adverse events (hu14.18K322A allergic reaction, viral infection, surgical death, second malignancy). Common toxicities included grade 3/4 myelosuppression (13/13 patients) and grade 1/2 pain (13/13 patients). Eleven patients received 29 NK-cell infusions. The response rate was 61.5% (4 complete responses, 1 very good partial response, 3 partial responses) and five had stable disease. The median time to progression was 274 days (range, 239–568 days); 10 of 13 patients (77%) survived 1 year. Hu14.18K322A pharmacokinetics was not affected by chemotherapy or HAHA. All patients had increased sIL2Ra levels, indicating immune activation. Conclusions: Chemotherapy plus hu14.18K322A, cytokines, and NK cells is feasible and resulted in clinically meaningful responses in patients with refractory/recurrent neuroblastoma. Further studies of this approach are warranted in patients with relapsed and newly diagnosed neuroblastoma.

AB - Purpose: Anti-GD2 mAbs, acting via antibody-dependent cell-mediated cytotoxicity, may enhance the effects of chemotherapy. This pilot trial investigated a fixed dose of a unique anti-GD2 mAb, hu14.18K322A, combined with chemotherapy, cytokines, and haploidentical natural killer (NK) cells. Experimental Design: Children with recurrent/refractory neuroblastoma received up to six courses of hu14.18K322A (40 mg/m2/dose, days 2–5), GM-CSF, and IL2 with chemotherapy: cyclophosphamide/topotecan (courses 1,2), irinotecan/temozolomide (courses 3,4), and ifosfamide/carboplatin/ etoposide (courses 5,6). Parentally derived NK cells were administered with courses 2, 4, and 6. Serum for pharmacokinetic studies of hu14.18K322A, soluble IL2 receptor alpha (sIL2Ra) levels, and human antihuman antibodies (HAHA) were obtained. Results: Thirteen heavily pretreated patients (9 with prior anti-GD2 therapy) completed 65 courses. One patient developed an unacceptable toxicity (grade 4 thrombocytopenia >35 days). Four patients discontinued treatment for adverse events (hu14.18K322A allergic reaction, viral infection, surgical death, second malignancy). Common toxicities included grade 3/4 myelosuppression (13/13 patients) and grade 1/2 pain (13/13 patients). Eleven patients received 29 NK-cell infusions. The response rate was 61.5% (4 complete responses, 1 very good partial response, 3 partial responses) and five had stable disease. The median time to progression was 274 days (range, 239–568 days); 10 of 13 patients (77%) survived 1 year. Hu14.18K322A pharmacokinetics was not affected by chemotherapy or HAHA. All patients had increased sIL2Ra levels, indicating immune activation. Conclusions: Chemotherapy plus hu14.18K322A, cytokines, and NK cells is feasible and resulted in clinically meaningful responses in patients with refractory/recurrent neuroblastoma. Further studies of this approach are warranted in patients with relapsed and newly diagnosed neuroblastoma.

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AN - SCOPUS:85033593800

SN - 1078-0432

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JF - Clinical Cancer Research

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A pilot trial of humanized anti-GD2 monoclonal antibody (hu14.18K322A) with chemotherapy and natural killer cells in children with recurrent/refractory neuroblastoma

Abstract

Bibliographical note

Funding

ASJC Scopus subject areas

UN SDGs

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