Activation of tumor destructive effector cells can be accomplished by in vivo administration of cytokines such as IL-2. Enhancement of tumor selective reactivity by these cytokine-activated-effectors can be accomplished using monoclonal antibodies (mAb), that are selectively able to recognize human tumors, provided they can facilitate antibody dependent cellular cytotoxicity (ADCC). Clinical trials are now underway testing co-administration of effector-activating cytokines and tumor reactive mouse or chimeric antibodies. The applicant's team is testing the combined effects of IL-2 with the chimeric anti-GD2 antibody ch14.18 in patients with melanoma and other GD2+ tumors. However, the use of systemic IL-2 does not localize the effector cell activation process to the cellular micro-environment where tumor cells are located. In order to better localize effector cell activation to sites of tumor growth, the fusion protein (FP) ch14.18-IL-2 was created, which linked the human IL-2 molecule to the Fc end of each heavy chain of the ch14.18 mAb. This ch14.18-IL-2 FP can mediate potent ADCC with in vitro activated IL-2 responsive effectors, and mediate protective anti-tumor reactivity in SCID mice bearing micrometastases of a GD2+ human tumor. They have been testing this reagent with human cells in vitro and in vivo for murine toxicity/pharmacology studies. In this application, they plan to further clarify the immune pathways utilized by this FP to activate anti-tumor reactivity, finalize needed preclinical data required to initiate clinical testing in a Phase I trial, and evaluate the in vivo physiologic and immunologic effects of this FP in treated patients. To accomplish this they propose to: (1) measure the activity and efficacy of clinical grade FP in vitro and determine the pathways of target cell lysis, and effector cell activation utilized by this molecule. (2) Complete in vivo murine testing required to finalize IND application and initiate human trials. In vivo preclinical testing will be performed using similar regimens anticipated for use in the clinical testing, in order to model the specific variables to be studied subsequently in GD2+ tumor bearing patients. (3) Initiate and complete a four-part Phase I/IB trial of ch14.18-IL-2 in patients with GD2+ tumors. (4) Perform detailed laboratory analyses on tumor biopsies, serum, and peripheral blood leukocytes from patients participating in these clinical trials. The goal of these in vitro, preclinical and clinical studies is to determine: (a) how best to utilize mAb-cytokine FPs as a means to initiate effector cell activation at micrometastatic sites, and (b) identify a dose and regimen for subsequent Phase II testing of the ch14.18-IL-2 FP in patients with GD2+ tumors.
| 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 |
| Jensen, Jeffrey Lee; Rakhmilevich, Alexander; Heninger, Erika et al. (2015) Tumoricidal Effects of Macrophage-Activating Immunotherapy in a Murine Model of Relapsed/Refractory Multiple Myeloma. Cancer Immunol Res 3:881-90 |
| 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 |
Showing the most recent 10 out of 165 publications
