Characterizing CD137 upregulation on NK cells in patients receiving monoclonal antibody therapy

Abstract

Background: In the era of personalized cancer medicine, identifying techniques for effectively matching patients to efficacious treatments is a critical step in the treatment process. The advent of anti-cancer immunotherapies necessitates novel approaches to biomarker identification beyond traditional genomic profiling. One promising approach is incorporation of nomograms into treatment decisions. Nomograms are prediction tools, based on statistical modeling, designed to predict treatment outcomes. As a first step toward developing a nomogram, we conducted analyses to predict CD137 expression of natural killer cells after monoclonal antibody (mAb) treatment.

Patients and methods: Patient, tumor and immune characteristics were collected from 199 patients with breast cancer (N = 62), head/neck cancers (N = 46) and non-Hodgkin's lymphoma (NHL) (N = 91), who were receiving mAb therapy as part of clinical trials. The difference in CD137 expression before and after mAb therapy was assessed by flow cytometry. To evaluate those who respond to mAb therapy via increased CD137 expression, we applied classification and regression trees (CART), multivariable lasso regression tools and Random Forest.

Results: The CD137 expression was significantly different for each cancer type [mean (SD): Breast: 6.6 (6.5); Head/Neck: 11.0 (7.0); NHL: 7.5 (7.1), P < 0.0001]. For breast cancer and NHL, FcR polymorphism and baseline CD137 expression were significant predictors of increased CD137 expression; for head/neck cancer, FcR polymorphism and age were significant predictors of increased expression.

Conclusions: Our preliminary results suggest that FcR polymorphism, pre-treatment CD137 expression and age are significant predictors of CD137 upregulation in patients. This study demonstrates that the development of a nomogram for therapy response is feasible. Further work validating our models in an independent cohort will provide the next steps in developing a nomogram that may be used to individualize this therapeutic approach for patients (NCT01114256).

Keywords: CD137; biomarker; cancer; monoclonal antibody; natural killer cells; regression tree.

© The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Figures

Figure 1.

CD137 increases on circulating NK cells in patients receiving mAb therapy. PBMCs were isolated from 199 patients with breast cancer (BC), head and neck cancer (HNC), and Non Hodgkin lymphoma (NHL). (A) Distribution of pre-mAb and post-mAb CD137 expression (% CD137+ NK cells) as a box plot for each cancer type. The left panel shows pre-mAb CD137 expression and the right panel shows post-mAb CD137 expression. The horizontal line in each box shows the median value and the diamond shows the mean value. (B) Percentage of CD137+ cells among circulating CD3–CD56+ NK cells from 199 patients prior to and following mAb therapy, stratified by tumor type (mean at each time point denoted by bar). ****P ≤ 0.0001.

Figure 2.

CART prediction results by cancer type. (A) Breast cancer. (B) Head–neck cancer. (C) Non-Hodgkins lymphoma.