A Comprehensive Safety Trial of Chimeric Antibody 14.18 With GM-CSF, IL-2, and Isotretinoin in High-Risk Neuroblastoma Patients Following Myeloablative Therapy: Children's Oncology Group Study ANBL0931

被引：71

作者：

Ozkaynak, M. Fevzi ^{[1
]}

Gilman, Andrew L. ^{[2
]}

London, Wendy B. ^{[3
,4
]}

Naranjo, Arlene ^{[5
,6
]}

Diccianni, Mitchell B. ^{[7
]}

Tenney, Sheena C. ^{[5
,6
]}

Smith, Malcolm ^{[8
]}

Messer, Karen S. ^{[7
]}

Seeger, Robert ^{[9
]}

Reynolds, C. Patrick ^{[10
]}

Smith, L. Mary ^{[11
]}

Shulkin, Barry L. ^{[12
]}

Parisi, Marguerite ^{[13
]}

Maris, John M. ^{[14
]}

Park, Julie R. ^{[13
]}

Sondel, Paul M. ^{[15
]}

Yu, Alice L. ^{[7
,16
]}

机构：

[1] New York Med Coll, Valhalla, NY 10595 USA

[2] Levine Childrens Hosp, Charlotte, NC USA

[3] Harvard Med Sch, Dana Farber Canc Inst, Boston, MA USA

[4] Harvard Med Sch, Boston Childrens Hosp, Boston, MA USA

[5] Univ Florida, Childrens Oncol Grp Stat, Gainesville, FL USA

[6] Univ Florida, Data Ctr, Gainesville, FL USA

[7] Univ Calif San Diego, Moores Canc Ctr, La Jolla, CA 92093 USA

[8] NCI, Bethesda, MD 20892 USA

[9] Univ Southern Calif, Childrens Hosp Los Angeles, Los Angeles, CA USA

[10] Texas Tech Univ, Hlth Sci Ctr, Lubbock, TX 79430 USA

[11] United Therapeut, Silver Spring, MD USA

[12] St Jude Childrens Res Hosp, Memphis, TN USA

[13] Univ Washington, Sch Med, Seattle Childrens Hosp, Seattle, WA USA

[14] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA

[15] Univ Wisconsin, Carbone Canc Ctr, Madison, WI USA

[16] Chang Gung Mem Hosp, Inst Stem Cell & Translat Canc Res, Taoyuan, Taiwan

来源：

FRONTIERS IN IMMUNOLOGY | 2018年 / 9卷

基金：

美国国家卫生研究院;

关键词：

neuroblastoma; immunotherapy; anti-GD2 chimeric antibody; cytokines; safety; cytokine biomarkers; PHASE-I TRIAL; MONOCLONAL-ANTIBODY; PHARMACOKINETICS; INTERLEUKIN-2; EXPRESSION; CYTOKINES; CH14.18; BLOOD; TOLERABILITY; PATHOGENESIS;

D O I：

10.3389/fimmu.2018.01355

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

Purpose: A phase 3 randomized study (COG ANBL0032) demonstrated significantly improved outcome by adding immunotherapy with ch14.18 antibody to isotretinoin as post-consolidation therapy for high-risk neuroblastoma (NB). This study, ANBL0931, was designed to collect FDA-required safety/toxicity data to support FDA registration of ch14.18. Experimental design: Newly diagnosed high-risk NB patients who achieved at least a partial response to induction therapy and received myeloablative consolidation with stem cell rescue were enrolled to receive six courses of isotretinoin with five concomitant cycles of ch14.18 combined with GM-CSF or IL2. Ch14.18 infusion time was 10-20 h per dose. Blood was collected for cytokine analysis and its association with toxicities and outcome. Results: Of 105 patients enrolled, five patients developed protocol-defined unacceptable toxicities. The most common grade >= 3 non-hematologic toxicities of immunotherapy for cycles 1-5, respectively, were neuropathic pain (41, 28, 22, 31, 24%), hypotension (10, 17, 4, 14, 8%), allergic reactions (ARs) (3, 10, 5, 7, 2%), capillary leak syndrome (1, 4, 0, 2, 0%), and fever (21, 59, 6, 32, 5%). The 3-year event-free survival and overall survival were 67.6 +/- 4.8% and 79.1 +/- 4.2%, respectively. AR during course 1 was associated with elevated serum levels of IL-1R alpha and IFN gamma, while severe hypotension during this course was associated with low IL5 and nitrate. Higher pretreatment CXCL9 level was associated with poorer event-free survival (EFS). Conclusion: This study has confirmed the significant, but manageable treatment-related toxicities of this immunotherapy and identified possible cytokine biomarkers associated with select toxicities and outcome. EFS and OS appear similar to that previously reported on ANBL0032.

引用

页数：14

共 27 条

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