Immunocytokine augments local and abscopal response and animal survival when added to radiation and CTLA-4 checkpoint inhibition in a murine melanoma model

Morris, Zachary S.; Guy, Emily I.; Francis, David M.; Gressett, Monica M.; Armstrong, Eric A.; Huang, Shyhmin; Gillies, Stephen D.; Hank, Jacquelyn A.; Rakhmilevich, Alexander L.; Harari, Paul M.; Sondel, Paul M.

doi:10.1186/2051-1426-3-s2-p308

Cited by 2 publications

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“…More recent data indicate that pretreatment with 'palliative dose' radiation therapy (12 Gy) can allow intratumoral injection of the hu14.18-IL2 to eradicate macroscopic (200 mm 3 ) GD2+ murine tumors in syngeneic mice, leaving most mice tumor free [149,150]. These tumor-free mice subsequently demonstrate a tumor specific, T-cell mediated, memory response, enabling them to reject rechallenge with GD2+ or GD2-variants of the GD2+ MEL that they initially destroyed.…”

Section: Using Anti-gd2 Mab Injected Intratumorally To Function As Anmentioning

confidence: 99%

Anti-GD2 MABS and Next-Generation mAb-Based Agents for Cancer Therapy

2016

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Tumor-specific monoclonal antibodies (mAbs) have demonstrated efficacy in the clinic, becoming an important approach for cancer immunotherapy. Due to its limited expression on normal tissue, the GD2 disialogangloside expressed on neuroblastoma cells is an excellent candidate for mAb therapy. In 2015, dinutuximab (an anti-GD2 mAb) was approved by the US FDA and is currently used in a combination immunotherapeutic regimen for the treatment of children with high-risk neuroblastoma. Here, we review the extensive preclinical and clinical development of anti-GD2 mAbs and the different mechanisms by which they mediate tumor cell killing. In addition, we discuss different mAb-based strategies that capitalize on the targeting ability of anti-GD2 mAbs to potentially deliver, as monotherapy, or in combination with other treatments, improved antitumor efficacy.

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Section: Using Anti-gd2 Mab Injected Intratumorally To Function As Anmentioning

confidence: 99%

Anti-GD2 MABS and Next-Generation mAb-Based Agents for Cancer Therapy

2016

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“…bg-IL2Rs will enhance our understanding of murine models and the mechanism of action of these molecules. As ours 54,55 and other preclinical data 56,57 are now demonstrating the potential for augmented antitumor activity by ICs when combined with other modalities, it will be important to use ICs in the clinic that simulate the IL2R biology shown to be effective in the murine models.…”

Section: Discussionmentioning

confidence: 98%

Human and murine IL2 receptors differentially respond to the human-IL2 component of immunocytokines

et al. 2018

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The humanized immunocytokine, hu14.18-IL2 (ICp), leads to the immune cell-mediated destruction of GD2-expressing tumors in mouse models, resulting in potent antitumor effects with negligible IL2-related toxicity. In contrast, when ICp is used clinically, antitumor activity is accompanied by dose-limiting IL2related toxicities. These species-specific differences in ICp toxicity may be linked to differential binding to mouse vs. human IL2 receptors (IL2Rs). We evaluated immunocytokines genetically engineered to preferentially bind either high-affinity abg-IL2Rs or intermediate-affinity bg-IL2Rs. These ICs have the IL2 fused to the C-terminus of the IgG light chains rather than the heavy chains. We found that IC35, containing intact huIL2, maintained activation of human and mouse abg-IL2Rs but exhibited a 20-fold reduction in the ability to stimulate human bg-IL2Rs, with no activation of mouse bg-IL2Rs at the concentrations tested. The reduced ability of IC35 to stimulate human bg-IL2Rs (associated with IL2toxicities) makes it a potential candidate for clinical trials where higher clinical IC doses might enable better tumor targeting and increased antitumor effects with less toxicity. Contrastingly, ICSK (IC with an IL2 mutein that has enhanced binding to the IL2R b-chain) showed increased activation over ICp on mouse bg-IL2Rs, with a dose-response curve similar to that seen with IC35 on human bg-IL2Rs. Our data suggest that ICSK might be used in mouse models to simulate the anticipated effects of IC35 in clinical testing. Understanding the differences in species-dependent IL2R activation should facilitate the design of reagents and mouse models that better simulate the potential activity of IL2-based immunotherapy in patients. Abbreviations: abg-IL2R, high affinity IL2 receptor; bg-IL2R, intermediate affinity IL2 receptor; GD2, disialoganglioside expressed on tumors of neuroectodermal origin; Hu, human; ICp, hu14.18-IL2 (humanized immunocytokine with IL2 fused to the heavy chains); IL2R, interleukin-2 receptor; IC, immunocytokine (fusion protein combining tumor reactive antibody with an immune activating cytokine); Mu, mouse; SK, superkine (mutated IL2 molecule with enhanced binding to the IL2R b-chain) KEYWORDS

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Immunocytokine augments local and abscopal response and animal survival when added to radiation and CTLA-4 checkpoint inhibition in a murine melanoma model

Cited by 2 publications

References 0 publications

Anti-GD2 MABS and Next-Generation mAb-Based Agents for Cancer Therapy

Anti-GD2 MABS and Next-Generation mAb-Based Agents for Cancer Therapy

Human and murine IL2 receptors differentially respond to the human-IL2 component of immunocytokines

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