In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 13_Supplement ( 2019-07-01), p. CT016-CT016
Abstract:
Interrogation of the tumor microenvironment (TME) is crucial to provide insight into biological activity, resistance mechanisms and implementation of rational combination immunotherapies. Semaphorin 4D (SEMA4D, CD100) has broad immunomodulatory effects in the TME. In preclinical models, antibody blockade of SEMA4D promoted immune infiltration and reduced function and recruitment of immunosuppressive myeloid cells within the TME. Importantly, preclinical combinations of anti-SEMA4D with immune checkpoint inhibitors (ICIs) enhanced T cell activity and tumor regression. VX15/2503 (pepinemab), an IgG4 humanized monoclonal antibody targeting SEMA4D, is currently being evaluated in window of opportunity, integrated biomarker trials to characterize immunomodulatory effects in pancreatic (PDAC), colorectal (CRC), and head and neck squamous cell (HNSCC) carcinomas, and melanoma. At present, three biomarker trials are recruiting patients with four resectable indications to investigate novel combinations of pepinemab with ICIs; 1) PDAC and CRC with resectable liver mets (NCT03373188, n=32), 2) HNSCC (NCT03690986, n=36), and 3) metastatic melanoma (NCT03769155, n=36). Prior to surgery, patients enroll in treatment cohorts including combinations of pepinemab with nivolumab and /or with ipilimumab, single agents, or no treatment. Three to seven weeks later, patients will undergo surgery and a substantial surgical section will be collected under the guidance of a pathologist for comparison across treatment groups and with a pre-dose tissue biopsy. Blood will be collected for PK, PD, and additional correlative biomarker assessments. The primary objective is to evaluate the treatment-induced effects on the immune profile in the TME and in peripheral blood. Additional objectives include, extending the previously reported safety profile of single agent pepinemab to ICI combination therapies, as well as exploring pathologic and radiographic responses in the melanoma study. Correlative multiplex flow cytometric flow panels have been established to phenotype cells in the TME and periphery. A multiplex IHC assay utilizing a sequential probe and strip procedure has also been qualified that allows co-localization, spatial orientation, and quantitation of multiple immune markers. Analysis of immune subsets include but are not limited to activated T cells, neutrophils, Treg cells, DCs, monocytes, macrophages, and importantly myeloid-derived suppressor cells (MDSCs). Target engagement and expression of SEMA4D and its cognate receptors will also be evaluated. Seven subjects have been enrolled in these studies as of 7 Jan 2019. These trials will provide the first integrated clinical assessment of anti-SEMA4D antibody activity to reprogram the TME. Citation Format: Gregory B. Lesinski, Terrence L. Fisher, Elizabeth E. Evans, John E. Leonard, Desa Rae Pastore, Crystal Mallow, Ernest Smith, Maurice Zauderer, Conor Steuer, Nabil F. Saba, Michael Lowe, Ragini R. Kudchadkar, Brian Olson, Christina Wu. Integrated biomarker trials of VX15/2503 (pepinemab) in combination with checkpoint inhibitors in window of opportunity studies in solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT016.
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2019-CT016
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2019
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2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
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