We have investigated combined treatment with IL2 and tumor-reactive mAb in preclinical and clinical trials over the past decade. Our goal is to obtain anti-tumor efficacy through in vivo antibody dependent cellular cytotoxicity of tumor cells. We have focussed on the 14.18 mAb which recognizes the GD2 antigen on melanoma, neuroblastoma and certain other tumors. Anti-tumor effects have been observed, and a phase III trial is soon to be activated. In mice the anti-tumor efficacy of IL2 and 14.18 mAb treatment is profoundly enhanced when these 2 molecules are given together as a genetically engineered fusion protein. The humanized form of this fusion protein has linked an IL2 molecule to each IgG heavy chain of the humanized 14.18 mAb (and is designated hu14.18-IL2). We are now in the midst of the initial phase I clinical trial of hu14.18-IL2 for adults with GD2+ tumors. Our ongoing study is already showing that striking immune activation is seen at doses that are safe and well tolerated. We are now ready to initiate the next critical steps in the development and testing of this novel clinical approach. Our goal is to determine how to increase the clinical antitumor efficacy of hu14.18-IL2 by developing and testing treatment regimens using hu14.18-IL2 in combination with other available clinical therapies. Specifically we will: 1. Evaluate the immunological and anti-tumor effects of hu14.18-IL2 in clinical trials designed to test and enhance its efficacy. These trials will be based on past and ongoing preclinical studies (aim 3) identifying combined regimens that increase the antitumor action of hu14.18-IL2. 2. Measure the immune activation in patients receiving hu14.18-IL2. The activation of effector cells able to destroy GD2+ tumor cells will be evaluated in patients participating in hu14.18 clinical trials. 3. Determine how to combine hu14.18-IL2 with clinically available therapeutics to increase antitumor efficacy in tumor bearing mice. A syngeneic murine GD2+ tumor model will be used to test how hu14.18-IL2 can be combined with other clinical modalities (including: IL2, Anti-CD3, IFN-gamma, and IL-12) to achieve further improvements in antitumor efficacy. These results will be used to design the subsequent treatment protocols which will be tested in aim 1.
| Morris, Zachary S; Guy, Emily I; Werner, Lauryn R et al. (2018) Tumor-Specific Inhibition of In Situ Vaccination by Distant Untreated Tumor Sites. Cancer Immunol Res 6:825-834 |
| Albertini, Mark R; Yang, Richard K; Ranheim, Erik A et al. (2018) Pilot trial of the hu14.18-IL2 immunocytokine in patients with completely resectable recurrent stage III or stage IV melanoma. Cancer Immunol Immunother 67:1647-1658 |
| Rakhmilevich, Alexander L; Felder, Mildred; Lever, Lauren et al. (2017) Effective Combination of Innate and Adaptive Immunotherapeutic Approaches in a Mouse Melanoma Model. J Immunol 198:1575-1584 |
| Perez Horta, Zulmarie; Goldberg, Jacob L; Sondel, Paul M (2016) Anti-GD2 mAbs and next-generation mAb-based agents for cancer therapy. Immunotherapy 8:1097-117 |
| Morris, Zachary S; Guy, Emily I; Francis, David M et al. (2016) In Situ Tumor Vaccination by Combining Local Radiation and Tumor-Specific Antibody or Immunocytokine Treatments. Cancer Res 76:3929-41 |
| Neri, Dario; Sondel, Paul M (2016) Immunocytokines for cancer treatment: past, present and future. Curr Opin Immunol 40:96-102 |
| Erbe, Amy K; Wang, Wei; Gallenberger, Mikayla et al. (2016) Genotyping Single Nucleotide Polymorphisms and Copy Number Variability of the FCGRs Expressed on NK Cells. Methods Mol Biol 1441:43-56 |
| McDowell, Kimberly A; Hank, Jacquelyn A; DeSantes, Kenneth B et al. (2015) NK cell-based immunotherapies in Pediatric Oncology. J Pediatr Hematol Oncol 37:79-93 |
| Shi, Yongyu; Felder, Mildred A R; Sondel, Paul M et al. (2015) Synergy of anti-CD40, CpG and MPL in activation of mouse macrophages. Mol Immunol 66:208-15 |
| Goldberg, Jacob L; Sondel, Paul M (2015) Enhancing Cancer Immunotherapy Via Activation of Innate Immunity. Semin Oncol 42:562-72 |
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