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• W4308396763 abstract "<h3>Background</h3> Neuroblastoma (NBL), a cancer derived from neural crest precursor cells, is the most common extra-cranial solid tumor in children, with a median age of diagnosis of 22 months. Patients diagnosed with NBL are segmented into prognostic categories with ~50% categorized as high-risk (HR). Of these patients, ~40% are refractory to, or relapse following, initial treatment; there are currently no effective treatment options for these patients once they have failed salvage therapy of chemotherapy combined with αGD2 therapy (dinutuximab). Our group has previously published work developing a <b>c</b>ombination <b>a</b>daptive and <b>i</b>nnate immunotherapy <b>r</b>egimen, “CAIR”, to treat a murine model of treatment-resistant, HR-NBL.^1,2 CAIR utilizes αGD2 immunocytokine (hu14.18-IL2), radiotherapy (RT), αCD40, CpG, and αCTLA4 but questions remain about the relative contribution of each component. In this study, we tested if our model of HR-NBL is resistant to salvage therapy of temozolomide and irinotecan (TEM+IRI) and αGD2-based therapy and if components of our effective CAIR therapy can be removed, in order to determine their necessity. <h3>Methods</h3> To establish 9464D-GD2 as a model for treatment-resistant, HR-NBL, tumor-bearing mice were treated with TEM+IRI and/or hu14.18-IL2. To establish the necessity of each component of CAIR, mice bearing 9464D-GD2 tumors were treated with CAIR (12Gy RT, αCD40, αCTLA4, CpG, and hu14.18-IL2) or variations of CAIR subtracting one component. <h3>Results</h3> Salvage therapy of TEM+IRI and/or hu14.18-IL2 extended the survival of mice (p<0.03) but did not result in 9464D-GD2 tumor cures. Adding RT (12Gy, SARRP) improved survival (p<0.0001), but not more than RT alone (p=0.29), and still did not cure tumors. Removing RT or hu14.18-IL2 from CAIR dramatically shortened survival (p<0.0001) and yielded few tumor cures (1/16, 0/16 versus 13/30). Conversely, removing αCD40, αCTLA4, or CpG did not alter survival (p=0.81, p=0.85, p=0.70) relative to CAIR, and resulted in similar rates of tumor cures (8/16, 9/21, 7/16 versus 13/30). Removing two of the expendable components (αCD40, αCTLA4, CpG) generally reduced efficacy, with only CAIR subtracting CpG and αCTLA4 (RT, hu14.18-IL2, and αCD40) curing a similar number of mice as CAIR (3/16 versus 13/30, survival p=0.12). <h3>Conclusions</h3> Here we demonstrate that 9464D-GD2 tumors behave similarly to human HR-NBLs that fail to be cured by salvage therapy. In contrast, these tumors can be cured by both CAIR therapy and by several versions of a reduced CAIR therapy (CAIR subtracting αCD40, αCTLA4, or CpG). We are now exploring the role of each component of CAIR in anti-tumor immune responses in this immunologically cold model. <h3>References</h3> Voeller J, Erbe A, Slowinski J, <i>et al</i>. Combined innate and adaptive immunotherapy overcomes resistance of immunologically cold syngeneic murine neuroblastoma to checkpoint inhibition. <i>J Immunother Cancer</i>. 2019;<b>7</b>:344. Aiken T, Erbe A, Zebertavage L, <i>et al</i>. Mechanism of effective combination radio-immunotherapy against 9464D-GD2, an immunologically cold murine neuroblastoma. <i>J Immunother Cancer</i>. 2022;<b>10</b>:e004834. <h3>Ethics Approval</h3> The study was approved by the University of Wisconsin9s School of Medicine and Public Health Institutional Animal Care and Use Committee (IACUC), protocol: M005984." @default.
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• W4308396763 date "2022-11-01" @default.
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• W4308396763 title "874 Optimizing a combination radio-immunotherapy regimen in a preclinical model of treatment-resistant, high-risk neuroblastoma" @default.
• W4308396763 doi "https://doi.org/10.1136/jitc-2022-sitc2022.0874" @default.
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