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Paul M. Sondel

Professor of Pediatrics, Human Oncology and Medical Genetics

Address:

K4/448 Clinical Science Center

Telephone:

263-9069

Email:

pmsondel@humonc.wisc.edu

Research Fields:

Cancer Genetics

Clinical Genetics

Human and Mammalian

Research Interests

Clinical immunotherapy of cancer and tumor immunology

Research Description

Our team is pursuing mechanisms to induce in vivo activated NK cells to provide anti-tumor benefit. This work usesthe 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. Most recently, we have been investigating fusion proteins created by fusing humanized antitumor mAbs to human IL2. We have completed a single institution Phase I trial of the hu14.18-IL2 molecule in adults with melanoma at the University of Wisconsin Comprehensive Cancer Center (UWCCC), and a Phase I trial in children with neuroblastoma, through the Children’s Oncology Group.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.Phase II successor protocols have been approved by the NCI and should be open in 2005.

We have shown that the KS-IL2 immunocytokine (IC) induces protective in vivo responses against 2 separate sub-clones of the CT-26 murine colon tumor transfected to express the human EpCAM molecule. Remarkably, the anti-tumor effect induced by KS-IL2 in BALB/C mice (syngeneic for the CT-26 tumor) is mediated by T cells against one CT-26 sub-clone, and by NK cells against the other sub-clone. These 2 tumor sub-clones appear to differ only for their level of MHC-class I expression. In a syngeneic mouse neuroblastoma model, a separate mAb-IL2 IC (hu14.18-IL2) mediates antitumor effects via NK cells. We have recently shown that syngeneic murine neuroblastomas recurring after hu14.18-IL2 treatment have dramatically up-regulated their MHC-class I antigens, to facilitate their escape from NK induced destruction. In this same model, those neuroblastomas that are resistant to T cell mediated anti-tumor effects show a down-regulation of MHC-class-I antigens, to escape T cell recognition. Thus, in both the colon carcinoma and the neuroblastoma models, the level of MHC class-I expression influences whether the IC controls tumor growth in vivo via NK cells or via T cells. Furthermore, these studies show that the preferred mechanismthese tumors use to escapefrom immunotherapy is the modulation of cell surface histocompatibility antigen (H2K and H2D) molecules, either up or down, depending upon the type of immunoselective pressure they are exposed to.

Ongoing efforts are evaluating the mechanism of tumor escape from immunotherapy in related murine systems andanalysis of the mechanisms involved in augmenting antibody dependent cellular cytotoxicity of tumor cells through co-administration of agents that act to augment macrophage (anti-CD40), T cell (Anti-CD3) or NK cell (IL2) mediated killing. IL-12.

Representative Publications

• Buhtoiarov, I.N., Lum, H.D., Berke, G., Sondel, P.M. and Rakhmilevich, A.L. 2006. Synergistic activation of macrophages via CD40 and TLR9 results in T cell independent antitumor effects. J. of Immunol. 176:309-318.
• Buhtoiarov, I.N., Lum, H., Berke, G., Paulnock, D.M., Sondel, P.M., and Rakhmilevich, A.L. 2005. CD40 ligation induces antitumor reactivity of murine macrophages via an IFN γ-dependent mechanism. J. of Immunology, 174:6013- 6022.
• Neal, Z.C., Imboden, M., Rakhmilevich, A.L., Kim, K.M., Surfus, J., Dixon, J.R., Lode, H.N., Reisfeld, R.A. and Gillies, S.D. 2004. Recurrent murine neuroblastomas increase or decrease MHC class I expression to escape NK- or T cell dependent immune destruction. Cancer Immunology and Immunotherapy, 53:41-52.
• King, D.M., Albertini, M.R., Schalch, H., Hank, J.A., Gan, J., Surfus, J., Mahvi, D., Schiller, J.H., Warner, T., Kim, K.M., Eickhoff, J., Kendra, K., Reisfeld, R., Gillies, S.D. and Sondel, P.M. 2004. A phase I clinical trial of the immunocytokine EMD 273063 (hu14.18-IL2) in patients with melanoma. J. Clinical Oncology 22:4463-4473. .
• Imboden, M., Murphy, K.R., Rakhmilevich, A.L., Neal, Z.C., Rong, X., Reisfeld, R.A., Gillies, S.D. and Sondel, P.M. 2001. Antitumor effects of targeted IL2 immunotherapy against low MHC Class I expressing HuEp-CAM transfected murine adenocarinoma. Cancer Research, 61:1500-1507.