Antitumor Activity of Hu14.18-IL2 in Patients With Relapsed/Refractory Neuroblastoma: A Children's Oncology Group (COG) Phase II Study

The Children's Hospital of Philadelphia, Filadelfia, Pennsylvania, United States
Journal of Clinical Oncology (Impact Factor: 18.43). 10/2010; 28(33):4969-75. DOI: 10.1200/JCO.2009.27.8861
Source: PubMed

ABSTRACT The hu14.18-IL2 fusion protein consists of interleukin-2 molecularly linked to a humanized monoclonal antibody that recognizes the GD2 disialoganglioside expressed on neuroblastoma cells. This phase II study assessed the antitumor activity of hu14.18-IL2 in two strata of patients with recurrent or refractory neuroblastoma.
Hu14.18-IL2 was given intravenously (12 mg/m(2)/daily) for 3 days every 4 weeks for patients with disease measurable by standard radiographic criteria (stratum 1) and for patients with disease evaluable only by [(123)I]metaiodobenzylguanidine (MIBG) scintigraphy and/or bone marrow (BM) histology (stratum 2). Response was established by independent radiology review as well as BM histology and immunocytology, and durability was assessed by repeat evaluation after more than 3 weeks.
Thirty-nine patients were enrolled (36 evaluable). No responses were seen in stratum 1 (n = 13). Of 23 evaluable patients in stratum 2, five patients (21.7%) responded; all had a complete response (CR) of 9, 13, 20, 30, and 35+ months duration. Grade 3 and 4 nonhematologic toxicities included capillary leak, hypoxia, pain, rash, allergic reaction, elevated transaminases, and hyperbilirubinemia. Two patients required dopamine for hypotension, and one patient required ventilatory support for hypoxia. Most toxicities were reversible within a few days of completing a treatment course and were expected based on phase I results.
Patients with disease evaluable only by MIBG and/or BM histology had a 21.7% CR rate to hu14.8-IL2, whereas patients with bulky disease did not respond. Hu14.18-IL2 warrants further testing in children with nonbulky high-risk neuroblastoma.

1 Follower
  • Source
    • "Recently, immunotherapy was found to increase overall survival when combined with maintenance therapy (Yu et al, 2010) and has now become part of the standard of care, despite proving ineffective in patients with recurrent or refractory bulky disease (Shusterman et al, 2010). Moreover, these therapeutic options are all extremely aggressive and toxic (Ishola and Chung, 2007; Shusterman et al, 2010; Yu et al, 2010), suggesting that the limit of therapy intensification may have been reached. Safer and more efficacious therapeutic options are urgently needed, thus warranting the evaluation of innovative therapeutic strategies in clinically relevant models of high-risk neuroblastoma. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Background: The use of β-blockers for the management of hypertension has been recently associated with significant clinical benefits in cancer patients. Herein, we investigated whether β-blockers could be used in combination with chemotherapy for the treatment of neuroblastoma. Methods: Seven β-blockers were tested for their antiproliferative and anti-angiogenic properties alone, and in combination with chemotherapy in vitro; the most potent drug combinations were evaluated in vivo in the TH-MYCN mouse model of neuroblastoma. Results: Three β-blockers (i.e., carvedilol, nebivolol and propranolol) exhibited potent anticancer properties in vitro and interacted synergistically with vincristine, independently of P-glycoprotein expression. β-blockers potentiated the anti-angiogenic, antimitochondrial, antimitotic and ultimately pro-apoptotic effects of vincristine. In vivo, β-blockers alone transiently slowed tumour growth as compared with vehicle only (P<0.01). More importantly, when used in combination, β-blockers significantly increased the tumour regression induced by vincristine (P<0.05). This effect was associated with an increase in tumour angiogenesis inhibition (P<0.001) and ultimately resulted in a four-fold increase in median survival, as compared with vincristine alone (P<0.01). Conclusion: β-blockers can increase treatment efficacy against neuroblastoma, and their combination with chemotherapy may prove beneficial for the treatment of this disease and other drug-refractory cancers.
    British Journal of Cancer 05/2013; 108(12). DOI:10.1038/bjc.2013.205 · 4.82 Impact Factor
  • Source
    • "In Ewing sarcoma, this can be achieved by applying T-cell therapy in the context of lymphopenia after high-dose chemotherapy with autologous stem cell rescue. Theoretically, off-target effects with G D2 -positive normal bone marrow MSCs may interfere with haematopoietic stem cell engraftment in this context; however, no haematological toxicity was observed in any clinical trial in patients receiving G D2 mAbs or conjugates (Shusterman et al, 2010; Yu et al, 2010) or G D2 -reengineered T cells (Pule et al, 2008). Increasing knowledge regarding local and systemic mechanisms of immune escape (Berghuis et al, 2011; Holmes et al, 2011) will further help to optimise integration of immunotherapies into the treatment of Ewing sarcoma. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Novel treatment strategies are needed to cure disseminated Ewing sarcoma. Primitive neuroectodermal features and a mesenchymal stem cell origin are both compatible with aberrant expression of the ganglioside antigen G(D2) and led us to explore G(D2) immune targeting in this cancer. We investigated G(D2) expression in Ewing sarcoma by immunofluorescence staining. We then assessed the antitumour activity of T cells expressing a chimeric antigen receptor specific for G(D2) against Ewing sarcoma in vitro and in vivo. Surface G(D2) was detected in 10 out of 10 Ewing sarcoma cell lines and 3 out of 3 primary cell cultures. Moreover, diagnostic biopsies from 12 of 14 patients had uniform G(D2) expression. T cells specifically modified to express the G(D2)-specific chimeric receptor 14. G2a-28ζ efficiently interacted with Ewing sarcoma cells, resulting in antigen-specific secretion of cytokines. Moreover, chimeric receptor gene-modified T cells from healthy donors and from a patient exerted potent, G(D2)-specific cytolytic responses to allogeneic and autologous Ewing sarcoma, including tumour cells grown as multicellular, anchorage-independent spheres. G(D2)-specific T cells further had activity against Ewing sarcoma xenografts. G(D2) surface expression is a characteristic of Ewing sarcomas and provides a suitable target antigen for immunotherapeutic strategies to eradicate micrometastatic cells and prevent relapse in high-risk disease.
    British Journal of Cancer 02/2012; 106(6):1123-33. DOI:10.1038/bjc.2012.57 · 4.82 Impact Factor
  • Source
    • "In the second stratum, there were 5/24 (21.7%) CRs as defined by metaiodobenzylguanidine (MIBG) scintigraphy or bone marrow biopsy [25]. Most of the IC stays on the surface of the tumor, and NK cells endocytose the moAb. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The Second International Conference on Immunotherapy in Pediatric Oncology was held in Houston, Texas, USA, October 11-12, 2010, to discuss the progress and challenges that have occurred in cutting edge immunotherapeutic strategies currently being developed for pediatric oncology. Major topics included immune targeting of acute lymphoblastic leukemia and pediatric solid tumors, chimeric antigen receptors (CARs) for hematologic malignancies and solid tumors, enhancing graft-versus-leukemia for pediatric cancers, overcoming hurdles of immunotherapy, strategies to active the innate immune system, and moving immunotherapy beyond phase I studies. Significant progress has been made in the last 2 years both in the development of novel immunobiologics such as CARs, and in establishing survival benefits of an anti-GD2 monoclonal antibody in randomized studies. Although there is much excitement going forward, a great deal of laboratory and regulatory challenges lie ahead in improving the efficacy of each of these modalities as well as getting them to patients in a timely and cost-effective fashion. The resulting discussions will hopefully lead to new collaborations and insight for further translational and clinical studies.
    Pediatric Hematology and Oncology 09/2011; 28(6):459-60. DOI:10.3109/08880018.2011.596615 · 0.96 Impact Factor
Show more


Available from