Antibodies In Preclinical Models Research Articles

Randomized multicenter double-blind phase II trial: The immunological adjuvant OPT-821 with or without a trivalent ganglioside vaccine in metastatic sarcoma patients following metastasectomy.

TPS10103 Background: The gangliosides GM2, GD2, and GD3 are strongly expressed in sarcoma and represent novel antitumor targets. We have demonstrated the safety and immunogenicity of individual monovalent ganglioside conjugate vaccines when administered with OPT821, a synthetic saponin adjuvant that augments the T-cell response. Antitumor effects are observed with anti-ganglioside antibodies in preclinical models, with greatest benefit seen in the micrometastatic setting. Patients (pts) with metastatic sarcoma rendered disease-free by surgery are at high risk for disease recurrence, with no therapy demonstrated to improve outcomes. Therefore, this population is ideally suited to test the efficacy of vaccine induced anti-ganglioside antibodies. We thus initiated this randomized double-blind phase II study of OPT821 with or without a trivalent ganglioside vaccine composed of GM2, GD2 lactone and GD3 lactone conjugated to KLH, an immunogenic carrier protein. Methods: A total of 134 pts will be randomized on a 1:1 basis stratified by disease state (relapsed disease vs metastasis at time of diagnosis), disease-free interval and number of relapses. Key inclusion criteria include stage IV sarcoma (locoregional recurrence is not sufficient) rendered disease-free following surgery or multi-modality therapy, no more than 8 weeks since surgery, and no continuous use of anti-inflammatory medications. Pts with Ewings sarcoma, GIST and rhabdomyosarcoma (except pleomorphic/anaplastic) are ineligible. Eligible pts will receive 10 subcutaneous injections in the outpatient setting over 84 weeks. The primary endpoint is progression-free survival (PFS). Secondary objectives include overall survival (OS) and 1- and 3-year PFS rate. Exploratory objectives include correlation of serologic response to outcome, comparison of tumor ganglioside expression at baseline and at recurrence, and analysis of circulating tumor cells. Enrollment began in July 2010. As of January 1, 2012, 83 patients had been recruited from 12 participating sites. Clinicaltrials.gov#: NCT01141491. Funded by Mabvax Therapeutics and NIH (R21CA13386).

Evaluation of combination treatment with a BRAF inhibitor (BMS-908662) and CTLA-4 monoclonal antibody in preclinical models.

e13055 Background: The antitumor activity and immunomodulatory effect of an ipilimumab homolog antibody in combination with BMS-908662, a selective RAF inhibitor, were assessed in preclinical model...

Molecular predictors of response to a humanized anti–insulin-like growth factor-I receptor monoclonal antibody in breast and colorectal cancer

The insulin-like growth factor-I receptor (IGF-IR) pathway is required for the maintenance of the transformed phenotype in neoplastic cells and hence has been the subject of intensive drug discovery efforts. A key aspect of successful clinical development of targeted therapies directed against IGF-IR will be identification of responsive patient populations. Toward that end, we have endeavored to identify predictive biomarkers of response to an anti-IGF-IR-targeting monoclonal antibody in preclinical models of breast and colorectal cancer. We find that levels of the IGF-IR itself may have predictive value in these tumor types and identify other gene expression predictors of in vitro response. Studies in breast cancer models suggest that IGF-IR expression is both correlated and functionally linked with estrogen receptor signaling and provide a basis for both patient stratification and rational combination therapy with antiestrogen-targeting agents. In addition, we find that levels of other components of the signaling pathway such as the adaptor proteins IRS1 and IRS2, as well as the ligand IGF-II, have predictive value and report on the development of a pathway-focused panel of diagnostic biomarkers that could be used to test these hypotheses during clinical development of IGF-IR-targeting therapies.