Abstract
Immunostimulatory monoclonal antibodies (ISmAb) that unleash antitumor immune responses are showing efficacy in cancer clinical trials. Anti-B7-H1 (PD-L1) monoclonal antibodies (mAb) block a critical inhibitory pathway in T cells, whereas anti-CD137 and OX40 mAbs provide T-cell costimulation. A combination of these ISmAbs (anti-CD137 + anti-OX40 + anti-B7-H1) was tested using a transgenic mouse model of multifocal and rapidly progressing hepatocellular carcinoma, in which c-myc drives transformation and cytosolic ovalbumin (OVA) is expressed in tumor cells as a model antigen. Flow-cytometry and immunohistochemistry were used to quantify tumor-infiltrating lymphocytes (TIL) elicited by treatment and assess their activation status and cytolytic potential. Tolerance induction and its prevention/reversal by treatment with the combination of ISmAbs were revealed by in vivo killing assays. The triple combination of ISmAbs extended survival of mice bearing hepatocellular carcinomas in a CD8-dependent fashion and synergized with adoptive T-cell therapy using activated OVA-specific TCR-transgenic OT-1 and OT-2 lymphocytes. Mice undergoing therapy showed clear increases in tumor infiltration by activated and blastic CD8(+) and CD4(+) T lymphocytes containing perforin/granzyme B and expressing the ISmAb-targeted receptors on their surface. The triple combination of ISmAbs did not result in enhanced OVA-specific cytotoxic T lymphocyte (CTL) activity but other antigens expressed by cell lines derived from such hepatocellular carcinomas were recognized by endogenous TILs. Adoptively transferred OVA-specific OT-1 lymphocytes into tumor-bearing mice were rendered tolerant, unless given the triple mAb therapy. Extension of survival and dense T-cell infiltrates emphasize the translational potential of combinational immunotherapy strategies for hepatocellular carcinoma. Clin Cancer Res; 19(22); 6151-62. ©2013 AACR.
Highlights
Immunotherapies with cytokines, vaccines, and T-cell adoptive therapy have been tested in early clinical trialsAuthors' Affiliations: 1Centro de Investigacion Medica Aplicada (CIMA), Universidad de Navarra; 2Department of Oncology, Clinica Universidad de Navarra; 3Liver Unit, Clínica Universidad de Navarra and Centro de Investigacion Biomedica en Red de Enfermedades Hepaticas y Digestivas, Pamplona, Spain; 4Oncology Drug Discovery division, Bristol-Myers Squibb, Lawrenceville, New Jersey; and 5Department of Pathology, University of Bonn, Bonn, GermanyNote: Supplementary data for this article are available at Clinical Cancer Research Online.I
The triple combination of Immunostimulatory monoclonal antibodies (ISmAb) did not result in enhanced OVA-specific cytotoxic T lymphocyte (CTL) activity but other antigens expressed by cell lines derived from such hepatocellular carcinomas were recognized by endogenous tumorinfiltrating lymphocytes (TIL)
Extension of survival and dense T-cell infiltrates emphasize the translational potential of combinational immunotherapy strategies for hepatocellular carcinoma
Summary
Immunotherapies with cytokines, vaccines, and T-cell adoptive therapy have been tested in early clinical trials. Immunostimulatory monoclonal antibodies (ISmAb) have recently emerged as a new therapeutic tool in oncology [6, 7]. Their overall mode of action is the enhancement of the weak ongoing immune responses present in patients with cancer. Two types of ISmAbs can be categorized depending on the receptors bound on immune system cells: agonist monoclonal antibodies (mAb) for activating receptors [7] and antagonist mAbs for coinhibitory receptors [8]
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