Paul Sondel

Research Description:
Our team is pursuing basic, preclinical and clinical mechanisms to induce in vivo activated innate immune effector cells to provide anti-tumor benefit.

One component of this work is focused on NK cells and uses the strategy of Antibody Dependent Cellular Cytotoxicity (ADCC), whereby tumor reactive monoclonal antibodies can home in vivo to sites of tumor, and facilitate in vivo tumor destruction by IL2 activated NK cells. In murine experimentally induced syngeneic tumor models we are evaluating the efficacy and mechanisms that enable immune interventions to induce in vivo tumor destruction. This work involves treatment with tumor reactive monoclonal antibodies and their genetically engineered derivatives. Preclinical data suggest efficacy will be best demonstrated in the setting of minimal residual disease. In a recent Children’s Oncology Group Phase III trial, we demonstrated the benefit of this approach in augmenting disease-free survival for children with high-risk neuroblastoma. We have also been investigating fusion proteins created by fusing humanized antitumor mAbs to human IL2. Our preclinical data show this approach is more potent than combinations of mAb + IL2, and demonstrate a prominent role for NK cells. We have completed single institution Phase I and II trials of the hu14.18-IL2 molecule in adults with relapsed melanoma at the University of Wisconsin Comprehensive Cancer Center (UWCCC), and Phase I and II trials in children with relapsed/refractory neuroblastoma, through the Children’s Oncology Group. The Phase II study has documented activity of this approach, particularly for children with smaller amounts of relapsed disease. Potent in vivo immunological activation has been observed, including clear demonstration that the circulating hu14.18-IL2 molecule has activated NK cells in vivo, and can enable them to mediate tumor reactive ADCC. In vitro analyses of immune activation, and analyses of genetic polymorphisms related to immune-mechanisms in these treated patients are helping to identify the in vivo pathways of anti-tumor effects. In vitro and murine model studies are being used to determine how these and related molecules might be used more effectively to provide augmented immune-mediated antitumor benefit.

A separate but related initiative is pursuing novel preclinical applications in tumor-bearing mice of 2 separate agents already in clinical trials. CD40 ligation (with agonist anti-CD40 monoclonal antibody), and Toll-like receptor-9 activation (using CpG) are being tested clinically, largely as adjuvant approaches to enhance vaccine strategies. In our preclinical studies we have shown that they are also able to activate effector macrophages to mediate in vivo antitumor responses, even in the absence of T, B or NK cells. When combined, anti-CD40 antibody and CpG are synergistic in inducing tumor growth inhibition, in a sequence dependent fashion. Preliminary data suggest that this is occurring in tumor bearing animals by converting immunosuppressive (M2) macrophages into effector (M1) macrophages. Furthermore, preliminary data are indicating that the antitumor effects of anti-CD40 + CpG can be enhanced substantially via ADCC, by co-administering a tumor reactive monoclonal antibody.

Representative Publications:
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Buhtoiarov IN, Rakhmilevich AL, Lanier LL, Ranheim EA, Sondel PM. Naïve mouse macrophages become activated following recognition of L5178Y lymphoma cells via concurrent ligation of CD40, NKG2D, and CD18 molecules. J. of Immunology.;182(4):1940-53. [PMID:19201847], 2009

Hank JA, Gan J, Ryu H, Ostendorf A, Stauder MC, Sternberg A, Albertini MR, Lo KM, Gillies SD, Eickhoff J, Sondel PM. Immunogenicity of the Hu14.18-IL2 Immunocytokine Molecule in Adults with Melanoma and Children with Neuroblastoma. Clinical Cancer Research, 15 (18): 5923-30, 2009

Johnson EE, Yamane BH, Lum HD , Buhtoiarov IN, Rakhmilevich AL, Mahvi DM, Gillies SD, Sondel PM. Radiofrequency Ablation Combined with KS-IL2 Immunocytokine (EMD 273066) Results in an Enhanced Anti-tumor Effect Against Murine Colon Adenocarcinoma. Clinical Cancer Research, 15 (15): 4875-84, 2009.

Delgado DC, Hank JA, Kolesar J, Lorentzen D, Gan J, Seo S, Kim KM, Shusterman S, Gillies SD, Reisfeld RA, Yang R, Gadbaw B, DeSantes KD, London WB, Seeger RC, Maris J, and Sondel PM. The Role for Genotypes of Killer Ig-Like Receptors (KIRs), Their Ligands, and Fcγ Receptors on Responses of Neuroblastoma Patients to Hu14.18-IL2: A Children’s Oncology Group Report. Cancer Research, 70:9554-9661, 2010 ; PMCID:PMC299644, PMID: 20935224

Shusterman S, London WB, Gillies SD, et al. Hank JA, Voss S, Seeger RC, Reynolds CP, Kimball J, Albertini MA, Wagner B, Gan J, Eickhoff J, DeSantes KD, Cohn SL, Hecht T, Gadbaw B, Reisfeld RA, Maris JM, Sondel PM. Anti-tumor activity of hu14.18-IL2 in relapsed/refractory neuroblastoma patients: a Children’s Oncology Group (COG) phase II study. J. Clin. Oncology, 28(33):4969-4975; 2010. PMID: 20921469

Buhtoiarov IN, Neal ZC, Gan J, Buhtoiarova TN, Patankar MS, Gubbels JAA, Hank JA, Yamane B, Rakhmilevich AL, Reisfeld RA, Gillies SD, Sondel PM. Differential internalization of hu14.18-IL2 immunocytokine by NK and tumor cells: impact on conjugation, cytotoxicity and targeting. Journal of Leukocyte biology, 89:625-638, 2011. PMID: 21248148

Yu AL, Gilman AL, Ozkaynak MF, London WB, Kreissman S, Chen H, Smith M, Anderson B, Villablanca J, Matthay KK, Shimada H, Grupp SA, Seeger R, Reynolds CP, Buxton A, Reisfeld RA, Gillies SD, Cohn SL, Maris JM, Sondel PM. Chimeric Anti-GD2 Antibody with GM-CSF, IL2 and 13-cis Retinoic Acid for High-risk Neuroblastoma: A Children’s Oncology Group (COG) Phase 3 Study. New England J. Med. 335:1324-1334, 2010. PMID: 20879881