Our team is pursuing basic, preclinical and clinical mechanisms to induce in vivo activated innate immune effector cells to provide anti-tumor benefit. See a history of our work in 45 Years of Cancer Immunotherapy Research: A Journey of Persistence, Luck, Mentors, Colleagues and Students.
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.
Additional Research Activities
The St. Baldrick’s Foundation-Stand Up 2 Cancer Pediatric Cancer Dream Team, which includes pediatric faculty members Christian Capitini, MD, associate professor, Ken DeSantes, MD, professor, Mario Otto, MD, PhD, associate professor, and Paul Sondel, MD, PhD, professor, was selected for the American Association …April 24, 2021
Four University of Wisconsin School of Medicine and Public Health researchers have been honored with prestigious awards from the Association for Clinical and Translational Science (ACTS), in recognition of their excellence and outstanding performance in …April 21, 2021
Paul Sondel, MD, PhD, professor, Hematology, Oncology & Bone Marrow Transplant, has been named the 2021 Edward H. Ahrens Junior Distinguished Investigator Award for Patient-Oriented Research by the Association for Clinical and Translational Science (ACTS). ACTS, a …April 7, 2021
Congratulations to Peter Carlson, PhD, graduate research assistant, along with mentor Paul Sondel, MD, PhD, professor, Hematology, Oncology and Bone Marrow Transplant, on the funding of their project, “Systemic pharmacokinetics of intratumorally injected hu14.18-IL2.” This one-year MSTP …February 24, 2021
Congratulations to Paul Sondel, MD, PhD (Professor, Division of Hematology, Oncology & Bone Marrow Transplant), on being selected as UW-Madison’s nominee for the Association of Clinical and Translational Science (ACTS) 2021 Distinguished Investigator Award. Sondel was …January 11, 2021
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