The ch14.18 mAb recognizes GD2 on human melanomas (MEL) and neuroblastomas (NBL), and has recently been proven to prevent recurrences of high risk NBL when combined with GM-CSF and IL2. The hu14.18-IL2 immunocytokine (IC) links IL2 to the hu14.18 anti-GD2 mAb. This IC mediates much more potent antitumor activity in mice than the combination of Ab and IL2, particularly in the setting of "non-bulky" disease. Our phase I and II trials, in patients (pts) with MEL and NBL, show that hu14.18-IL2 is safe and induces immunologic activation. Complete tumor responses were observed, particularly in NBL pts with nonbulky disease. The goal of this project is to further evaluate and enhance the antitumor efficacy of hu14.18-IL2, through the following specific aims: 1. Evaluate the antitumor effects of hu14.18-IL2 in 3 clinical trials: i) A Phase II trial in children with NBL [through the Children's Oncology Group (COG)] to confirm the antitumor activity seen in NBL pts with nonbulky disease, and to pilot-test a combined regimen that the COG is committed to include in a separate upcoming Phase III trial. ii) A pilot study in stage 3 and 4 MEL pts who achieve no evidence of disease (NED) status with surgery, to test whether the activity achieved in NBL pts will be seen in MEL pts with high probability of relapse. This study will also evaluate, via immunohistochemistry, the in vivo response of the tumor to intravenous (IV) hu14.18-IL2 in pts with resectable metastatic MEL. Pilot data on the time to recurrence for pts achieving NED status with surgery and subsequent treatment with IC will also be collected. iii) A phase I/II clinical trial of hu14.18-IL2 injected directly into MEL lesions. This intratumoral (IT-IC) trial will evaluate toxicity and antitumor effects clinically and histologically. 2. Measure the in vivo effects of hu14.18-IL2: Blood and tumor specimens from treated pts will be tested for biologic and immunologic factors to help clarify the mechanisms of antitumor effects and of toxicity. 3. Increase antitumor efficacy of hu14.18-IL2 preclinically in tumor-bearing mice: We will test our hypothesis that enhanced antitumor efficacy will result from augmenting the level and longevity of IC binding to tumor cells and from combining hu14.18-IL2 with clinically applicable agents in order to simultaneously induce distinct mechanisms of tumor recognition and destruction.
Despite progress in cancer treatment and research, the majority of adults with metastatic melanoma and children with metastatic neuroblastoma die from the continued growth and spread of their malignant diseases. The hu14.18-IL2 immunocytokine (IC) molecule has been designed to direct the immune system to recognize and destroy melanoma and neuroblastoma. This project will continue these laboratory and clinical studies in order to further determine how to best use hu14.18-IL2. First, we will perform clinical trials in children and adults with neuroblastoma or melanoma to evaluate and expand the clinical information already obtained. Secondly, we will obtain blood and tumor specimens from treated patients in order to measure the effects of hu14.18-IL2 on the cancers and on the immune systems of treated patients. Third, we will continue experiments in mice with neuroblastoma or melanoma in order to see which additional treatments might best be combined with hu14.18-IL2 in order to further maximize anti-tumor efficacy.
|Navid, Fariba; Sondel, Paul M; Barfield, Raymond et al. (2014) Phase I trial of a novel anti-GD2 monoclonal antibody, Hu14.18K322A, designed to decrease toxicity in children with refractory or recurrent neuroblastoma. J Clin Oncol 32:1445-52|
|Alderson, Kory L; Luangrath, Mitchell; Elsenheimer, Megan M et al. (2013) Enhancement of the anti-melanoma response of Hu14.18K322A by ?CD40 + CpG. Cancer Immunol Immunother 62:665-75|
|Van De Voort, Tyler J; Felder, Mildred A R; Yang, Richard K et al. (2013) Intratumoral delivery of low doses of anti-CD40 mAb combined with monophosphoryl lipid a induces local and systemic antitumor effects in immunocompetent and T cell-deficient mice. J Immunother 36:29-40|
|Yang, Richard K; Kalogriopoulos, Nicholas A; Rakhmilevich, Alexander L et al. (2013) Intratumoral treatment of smaller mouse neuroblastoma tumors with a recombinant protein consisting of IL-2 linked to the hu14.18 antibody increases intratumoral CD8+ T and NK cells and improves survival. Cancer Immunol Immunother 62:1303-13|
|Qu, Xiaoyi; Felder, Mildred A R; Perez Horta, Zulmarie et al. (2013) Antitumor effects of anti-CD40/CpG immunotherapy combined with gemcitabine or 5-fluorouracil chemotherapy in the B16 melanoma model. Int Immunopharmacol 17:1141-7|
|Gubbels, Jennifer A A; Gadbaw, Brian; Buhtoiarov, Ilia N et al. (2011) Ab-IL2 fusion proteins mediate NK cell immune synapse formation by polarizing CD25 to the target cell-effector cell interface. Cancer Immunol Immunother 60:1789-800|
|Soto, Brenda L; Hank, Jacquelyn A; Van De Voort, Tyler J et al. (2011) The anti-tumor effect of resveratrol alone or in combination with immunotherapy in a neuroblastoma model. Cancer Immunol Immunother 60:731-8|
|Buhtoiarov, Ilia N; Sondel, Paul M; Wigginton, Jon M et al. (2011) Anti-tumour synergy of cytotoxic chemotherapy and anti-CD40 plus CpG-ODN immunotherapy through repolarization of tumour-associated macrophages. Immunology 132:226-39|
|Alderson, Kory L; Sondel, Paul M (2011) Clinical cancer therapy by NK cells via antibody-dependent cell-mediated cytotoxicity. J Biomed Biotechnol 2011:379123|
|Lange, Beverly J; Yang, Richard K; Gan, Jacek et al. (2011) Soluble interleukin-2 receptor * activation in a Children's Oncology Group randomized trial of interleukin-2 therapy for pediatric acute myeloid leukemia. Pediatr Blood Cancer 57:398-405|
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