Monoclonal antibody (mAb) therapy, including rituximab (anti-CD20), trastuzumab (anti-HER2) and cetuximab/panitumumab (anti-EGFR) has changed the natural history of patients with B cell lymphomas, breast cancer, and colorectal and head and neck cancers, respectively. Despite their promise, response rates are suboptimal at less than 25%, highlighting the need to enhance mAb activity. Natural killer (NK) cells are important effector cells mediating antibody dependent cell-mediated cytotoxicity (ADCC), a primary antitumor mechanism of action of mAbs. Combining a tumor-targeting mAb with a second antibody that activates NK cells can improve the therapeutic effects of mAbs against tumors. We have previously validated this approach using an agonistic mAb against the co-stimulatory molecule CD137 (4-1BB), a member of the tumor necrosis factor receptor superfamily that is expressed by activated T cells and NK cells. Anti-CD137 augmented ADCC in vitro and demonstrated synergistic anti-tumor activity in multiple in vivo tumor models, including lymphoma, breast, colon, and head and neck cancers each uniquely to the targeting mAb (rituximab, trastuzumab, and cetuximab).
Agonistic anti-CD137 antibodies are currently in early-phase clinical trials. In order to enhance clinical success, we sought to develop a nomogram for predicting the amplitude of CD137 upregulation following therapy with rituximab, trastuzumab, or cetuximab. This nomogram is of high importance as it has the opportunity to demonstrate the potential clinical value of anti-CD137 in combination antibody therapy by providing a biomarker of putative clinical benefit allowing selection and individualization of this therapeutic approach.
On the basis of data from ongoing clinical trials of patients with lymphoma, breast, colorectal, and head and neck cancers receiving mAb therapy, we are building a nomogram that is based on patient tumor and immune characteristics identified from peripheral blood samples collected pre-and post-mAb therapy. CD137 expression on NK cells and other immune characteristics were assessed by mass cytometry time of flight (CyTOF) analysis. The model is being subjected to bootstrap internal validation, and its predictive accuracy and discriminative ability are being measured by concordance index (C-index) and risk group stratification. Given the cost of drug development and clinical trials, the nomogram will prove highly useful for drug discovery focused on identifying synergy through CD137 immunomodulation, an innovative and paradigm changing approach to improving the survival of patients with all histologies of cancer.
Citation Format: Amani Makkouk, Cariad Chester, Serena Chang, Vandana Sundaram, Manisha Desai, Inna Sayfer, Holden T. Maecker, Holbrook E. Kohrt. A predictive nomogram to determine CD137 upregulation on NK cells in patients receiving monoclonal antibody therapy. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A042.
- ©2016 American Association for Cancer Research.