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.