Enhanced Activity of Hu14.18-IL2 Immunocytokine against Murine NXS2 Neuroblastoma when Combined with Interleukin 2 Therapy

Neal, Zane C.; Yang, Jeannie C.; Rakhmilevich, Alexander L.; Buhtoiarov, Ilia N.; Lum, Hillary E.; Imboden, Michael; Hank, Jacquelyn A.; Lode, Holger N.; Reisfeld, Ralph A.; Gillies, Stephen D.; Sondel, Paul M.

doi:10.1158/1078-0432.ccr-03-0799

Cited by 86 publications

(77 citation statements)

References 30 publications

(40 reference statements)

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“…M21 tumors express the disialoganglioside GD2, while the hu14.18-IL18 immunocytokine consists of a GD2-specific monoclonal antibody (mAB) fused to human IL-2 able to recognize and specifically bind to GD2 C tumors. The immunocytokine has shown antitumor effects in vivo in mouse models [37][38][39][40] in a phase I/II clinical trial in pediatric patients with relapsed/refractory neuroblastoma 41,42 and in patients with metastatic melanoma. 43 Therefore, we expected that GD2…”

Section: Migration Of 19 F-labeled Nk Cells In Vivomentioning

confidence: 99%

¹⁹F-MRI for monitoring human NK cellsin vivo

et al. 2016

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The availability of clinical-grade cytokines and artificial antigen-presenting cells has accelerated interest in using natural killer (NK) cells as adoptive cellular therapy (ACT) for cancer. One of the technological shortcomings of translating therapies from animal models to clinical application is the inability to effectively and non-invasively track these cells after infusion in patients. We have optimized the nonradioactive isotope fluorine-19 ( 19

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Section: Migration Of 19 F-labeled Nk Cells In Vivomentioning

confidence: 99%

¹⁹F-MRI for monitoring human NK cellsin vivo

et al. 2016

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“…However, IV hu14.18-IL2 IC at the doses used resulted in only a transient antitumor response against well-established primary subcutaneous (s.c.) murine NXS2 NB tumors, followed by tumor recurrence [29]. In this setting, addition of s.c. continuous infusion IL2 to systemic hu14.18-IL2 IC enabled durable resolution of established NXS2 tumors [30]. Clinically, administration of higher doses of IC has been limited by the IL2-related toxicities of the IC [21,33].…”

Section: Introductionmentioning

confidence: 99%

Intratumoral immunocytokine treatment results in enhanced antitumor effects

Johnson

Lum

Rakhmilevich

et al. 2008

Cancer Immunol Immunother

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Immunocytokines (IC), consisting of tumor-specific monoclonal antibodies fused to the immunostimulatory cytokine interleukin 2 (IL2), exert significant antitumor effects in several murine tumor models. We investigated whether intratumoral (IT) administration of IC provided enhanced antitumor effects against subcutaneous tumors. Three unique ICs (huKS-IL2, hu14.18-IL2, and GcT84.66-IL2) were administered systemically or IT to evaluate their antitumor effects against tumors expressing the appropriate IC-targeted tumor antigens. The effect of IT injection of the primary tumor on a distant tumor was also evaluated. Here, we show that IT injection of IC resulted in enhanced antitumor effects against B16-KSA melanoma, NXS2 neuroblastoma, and human M21 melanoma xenografts when compared to intravenous (IV) IC injection. Resolution of both primary and distant subcutaneous tumors, and a tumor-specific memory response were demonstrated following IT treatment in immunocompetent mice bearing NXS2 tumors. The IT effect of huKS-IL2 IC was antigen-specific, enhanced compared to IL2 alone, and dose-dependent. Hu14.18-IL2 also showed greater IT effects than IL2 alone. The antitumor effect of IT IC did not always require T cells since IT IC induced antitumor effects against tumors in both SCID and nude mice. Localization studies using radiolabeled 111 In-GcT84.66-IL2 IC confirmed that IT injection resulted in a higher concentration of IC at the tumor site than IV administration. In conclusion, we suggest that IT IC is more effective than IV administration against palpable tumors. Further testing is required to determine how to potentially incorporate IT administration of IC into an antitumor regimen that optimizes local and systemic anticancer therapy.

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“…However, three patients showed evidence of antitumor activity measured by bone marrow evaluation [95]. Treatment elicited immunologic activity, including lymphocytosis and elevated levels of soluble IL-2 receptor α [90,95]. The maximum tolerated dose was 12 mg/m 2 /dose and the mean half-life was 3.1 h. Overall, the treatment was well tolerated with pediatric patients presenting reversible toxicities such as hypotension, allergic reactions, pain, fever and hematologic toxicity.…”

Section: Antibody-(il-2) Fusion Proteinsmentioning

confidence: 97%

“…The murine monoclonal antibody 14.18 has the ability to recognize the GD2 antigen, and has been used to develop chimeric [89] and humanized antibody-cytokine fusion proteins [90]. Ch14.18-(IL-2) (Figure 2A (I)) was developed by fusing human IL-2 to the carboxy-terminus of the mouse/human chimeric antibody ch14.18.…”

Section: Antibody-(il-2) Fusion Proteinsmentioning

confidence: 99%

“…Using the model NXS2, a murine neuroblastoma cell line that expresses human GD2, ch14.18-(IL-2) was able to induce a NK-cell-mediated antitumor response that eradicates the stable bone marrow and liver metastases in a syngeneic model [94]. This antibody-(IL-2) fusion protein was humanized to generate the hu14.18-(IL-2), an IgG1 recognizing GD2 genetically fused to human IL-2 ( Figure 2A (I)) [90]. Hu14.18-(IL-2) or EMD 273063 (EMD Pharmaceuticals Inc) has been evaluated in clinical trials for its safety and antitumor activity.…”

Section: Antibody-(il-2) Fusion Proteinsmentioning

confidence: 99%

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Antibody–cytokine fusion proteins: applications in cancer therapy

Ortíz‐Sánchez

Helguera

Daniels

et al. 2008

Expert Opinion on Biological Therapy

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Background-Antibody-cytokine fusion proteins consist of cytokines fused to an antibody to improve antibody-targeted cancer immunotherapy. These molecules have the capacity to enhance the tumoricidal activity of the antibodies and/or activate a secondary antitumor immune response.Objective-To review the strategies used to develop antibody-cytokine fusion proteins and their in vitro and in vivo properties, including preclinical and clinical studies focusing on IL-2, IL-12 and GM-CSF. Methods-Articles were found by searching databases such as PubMed and Clinical Trials of the US National Institutes of Health.Results/conclusion-Multiple antibody-cytokine fusion proteins have demonstrated significant antitumor activity as direct therapeutics or as adjuvants of cancer vaccines in preclinical studies, paving the way for their clinical evaluation.

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Enhanced Activity of Hu14.18-IL2 Immunocytokine against Murine NXS2 Neuroblastoma when Combined with Interleukin 2 Therapy

Abstract: ABSTRACT

Cited by 86 publications

References 30 publications

¹⁹F-MRI for monitoring human NK cellsin vivo

¹⁹F-MRI for monitoring human NK cellsin vivo

Intratumoral immunocytokine treatment results in enhanced antitumor effects

Antibody–cytokine fusion proteins: applications in cancer therapy

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Enhanced Activity of Hu14.18-IL2 Immunocytokine against Murine NXS2 Neuroblastoma when Combined with Interleukin 2 Therapy

Abstract: ABSTRACT

Cited by 86 publications

References 30 publications

19F-MRI for monitoring human NK cellsin vivo

19F-MRI for monitoring human NK cellsin vivo

Intratumoral immunocytokine treatment results in enhanced antitumor effects

Antibody–cytokine fusion proteins: applications in cancer therapy

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¹⁹F-MRI for monitoring human NK cellsin vivo

¹⁹F-MRI for monitoring human NK cellsin vivo