Paul Sondel, MD, PhD

Portrait of Paul Sondel, MD, PhD
Professor
Pediatrics
Address: 
4159 WIMR
1111 Highland Avenue
Madison, WI 53705-2275
Telephone: 
(608) 263-9069
Focus Groups: 
Cancer Biology
Education: 
MD, Harvard Medical School
PhD, University of Wisconsin-Madison
Research Summary: 
Cell Mediated Tumor Destruction: Efficacy and Escape
Research Detail: 

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.

Since joining the UW faculty in 1980, I have functioned as the primary research mentor for 21 graduate students and 38 post-doctoral fellows, that have all spent > 1 year full-time working within my research lab. Many of these trainees have been directly involved in the clinical studies that have been led by our lab or linked to our lab’s preclinical/translational research.

Our goal in all of this work is to: a) test novel strategies in vitro and in mice, b) clarify their cellular mechanisms in vitro, c) further develop how they may be most effective and least toxic in mice, and then d) move these concepts into clinical trials to test their safety, activity, immunologic mechanisms and ultimately their efficacy as antitumor treatments.

Selected Publications: 
Clinically Relevant Cytotoxic Immune Cell Signatures and Clonal Expansion of T Cell Receptors in High-risk MYCN-not-amplified Human Neuroblastoma.Wei JS, Kuznetsov IB, Zhang S, Song YK, Asgharzadeh S, Sindiri S, Wen X, PatidarR, Nagaraj S, Walton A, Guidry Auvil JM, Gerhard DS, Yuksel A, Catchpoole DR, Hewitt SM, Sondel PM, Seeger RC, Maris JM, Khan J.Clin Cancer Res. 2018 May 21. pii: clincanres.0599.2018. doi: 10.1158/1078-0432.CCR-18-0599. [Epub ahead of print]PMID: 29784674
Tumor-specific inhibition of in situ vaccination bydistant untreated tumor sites.Morris ZS, Guy EI, Werner LR, Carlson PM, Heinze CM, Kler JS, Busche SM, Jaquish AA, Sriramaneni RN, Carmichael L, Loibner H, Gillies SD, Korman AJ, Erbe AK, Hank JA, Rakhmilevich AL, Harari PM, Sondel PM.Cancer Immunol Res. 2018 May 10. pii: canimm.0353.2017. doi: 10.1158/2326-6066.CIR-17-0353. [Epub ahead of print]PMID: 29748391
Combining precision radiotherapy with molecular targeting and immunomodulatory agents: aguideline by the American Society for Radiation Oncology.Bristow RG, Alexander B, Baumann M, Bratman SV, Brown JM, Camphausen K, Choyke P, Citrin D, Contessa JN, Dicker A, Kirsch DG, Krause M, Le QT, Milosevic M, Morris ZS, Sarkaria JN, Sondel PM, Tran PT, Wilson GD, Willers H, Wong RKS, Harari PM.Lancet Oncol. 2018 May;19(5):e240-e251. doi: 10.1016/S1470-2045(18)30096-2. Review.PMID: 29726389
A First-in-Human Phase I Study of Subcutaneous Outpatient Recombinant Human IL15 (rhIL15) in Adults with Advanced Solid Tumors.Miller JS, Morishima C, McNeel DG, Patel MR, Kohrt HEK, Thompson JA, Sondel PM, Wakelee HA, Disis ML, Kaiser JC, Cheever MA, Streicher H, Creekmore SP, Waldmann TA, Conlon KC.Clin Cancer Res. 2018 Apr 1;24(7):1525-1535. doi: 10.1158/1078-0432.CCR-17-2451. Epub 2017 Dec 4.PMID: 29203590
Future perspectives in melanoma research "Melanoma Bridge", Napoli, November 30th-3rd December 2016.Ascierto PA, Agarwala SS, Ciliberto G, Demaria S, Dummer R, Duong CPM, Ferrone S, Formenti SC, Garbe C,Halaban R, Khleif S, Luke JJ, Mir LM, Overwijk WW, Postow M, Puzanov I, Sondel P, Taube JM, Thor Straten P, Stroncek DF, Wargo JA, Zarour H, Thurin M.J Transl Med. 2017 Nov 16;15(1):236. doi: 10.1186/s12967-017-1341-2.PMID: 29145885
The need for a network to establish and validate predictive biomarkers in cancer immunotherapy.Masucci GV, Cesano A, Eggermont A, Fox BA, Wang E, Marincola FM, Ciliberto G, Dobbin K, Puzanov I, Taube J, Wargo J, Butterfield LH, Villabona L, Thurin M, Postow MA, Sondel PM, Demaria S, Agarwala S, Ascierto PA.J Transl Med. 2017 Nov 3;15(1):223. doi: 10.1186/s12967-017-1325-2.PMID: 29100546
Neuroblastoma Patients' KIR and KIR-Ligand Genotypes Influence Clinical Outcome for Dinutuximab-based Immunotherapy: A Report fromthe Children's Oncology Group.Erbe AK, Wang W, Carmichael L, Kim K, Mendonça EA, Song Y, Hess D, Reville PK, London WB, Naranjo A, Hank JA, Diccianni MB, Reisfeld RA, Gillies SD, Matthay KK, Cohn SL, Hogarty MD, Maris JM, Park JR, Ozkaynak MF, Gilman AL, YuAL, Sondel PM.Clin Cancer Res. 2018 Jan 1;24(1):189-196. doi: 10.1158/1078-0432.CCR-17-1767. Epub 2017 Oct 2.PMID: 28972044
A Pilot Trial of Humanized Anti-GD2 Monoclonal Antibody (hu14.18K322A) with Chemotherapy and Natural Killer Cells in Children with Recurrent/Refractory Neuroblastoma.Federico SM, McCarville MB, Shulkin BL, Sondel PM, Hank JA, Hutson P, Meagher M, Shafer A, Ng CY, Leung W, Janssen WE, Wu J, Mao S, Brennan RC, Santana VM, Pappo AS, Furman WL.Clin Cancer Res. 2017 Nov 1;23(21):6441-6449. doi: 10.1158/1078-0432.CCR-17-0379. Epub 2017 Sep 22.PMID: 28939747
HLA-Bw4-I-80 Isoform Differentially Influences Clinical Outcome As Compared to HLA-Bw4-T-80 and HLA-A-Bw4 Isoforms in Rituximab or Dinutuximab-Based Cancer Immunotherapy.Erbe AK, Wang W, Reville PK, Carmichael L, Kim K, Mendonca EA, Song Y, Hank JA, London WB, Naranjo A, Hong F, Hogarty MD, Maris JM, Park JR, Ozkaynak MF, Miller JS, Gilman AL, Kahl B, Yu AL, Sondel PM.Front Immunol. 2017 Jun 12;8:675. doi: 10.3389/fimmu.2017.00675. eCollection 2017.PMID: 28659916
Irinotecan-temozolomide with temsirolimus or dinutuximab in children with refractory or relapsed neuroblastoma (COG ANBL1221): an open-label, randomised, phase 2 trial.Mody R, Naranjo A, Van Ryn C, Yu AL, London WB, Shulkin BL, Parisi MT, Servaes SE, Diccianni MB, Sondel PM, Bender JG,Maris JM, Park JR, Bagatell R.Lancet Oncol. 2017 Jul;18(7):946-957. doi: 10.1016/S1470-2045(17)30355-8. Epub 2017 May 23.PMID: 28549783