2O - Activation of T cells upon treatment with bispecific antibodies correlates with the expression of co-inhibitory receptors on tumor-infiltrating lymp...

Date 21 November 2014
Event ESMO Symposium on Immuno-Oncology 2014
Session Best Abstracts Session
Topics Cancer Immunology and Immunotherapy
Lung and other Thoracic Tumours
Translational Research
Presenter Daniela Thommen
Authors D. Thommen1, J. Schreiner2, P. Herzig2, P. Mueller2, V. Karanikas3, S. Savic4, D. Lardinois5, A. Zippelius1
  • 1Medical Oncology, University Hospital Basel, 4031 - Basel/CH
  • 2Department Of Biomedicine, University Hospital Basel, 4031 - Basel/CH
  • 3Pharma Research And Early Development Oncology, Roche Glycart AG, 8952 - Schlieren/CH
  • 4Institute Of Pathology, University Hospital Basel, 4031 - Basel/CH
  • 5Department Of Surgery, University Hospital Basel, 4031 - Basel/CH



Introduction: T cell bispecific antibodies (TCB) are designed to recruit and simultaneously activate T cells against target cells such as tumor cells expressing a particular surface antigen. However, it is currently unknown how immuno-modulatory mechanisms active in the tumor microenvironment such as the expression of T cell co-inhibitory receptors may influence the therapeutic effect of TCBs.

Methods: We performed a comprehensive phenotypic analysis of tumor infiltrating immune cells from lung carcinoma digests by multicolour flow cytometry. In particular, expression of T cell co-inhibitory and -stimulatory receptors was analyzed. Tumor digests were treated with catumaxomab, a TCB directed against CD3 and EpCAM. T cell activation and effector functions were assessed upon exposure to catumaxomab.

Results: CD8+ T cells in lung carcinoma showed a broad heterogeneity in expression of the T cell co-inhibitory receptors PD-1, Tim-3, CTLA-4, Lag-3 and BTLA. Tumor stage and nodal status correlated with number and intensity of expressed receptors. Upon exposure to catumaxomab, a considerable heterogeneity in T cell activation among different tumors was observed. Of note, T cells expressing high levels and multiple co-inhibitory receptors were more impaired in their activation and effector functions after treatment with catumaxomab indicating a higher level of exhaustion. In a further analysis of CD8+ TIL subsets we found that BTLA+ T cells expressed more additional inhibitory receptors than all other subsets, namely PD-1, Tim-3, CTLA-4 and Lag-3, whereas only a small part of PD-1+ T cells expressed another receptor. Tim-3+ T cells usually co-expressed PD-1, but multiple receptors were found only on a low number of cells.

Conclusion: In summary, our data suggest that the activity of TCBs is largely affected by the expression of T cell co-inhibitory receptors on tumor-infiltrating immune cells. Furthermore, these data provide a clinical rationale for combining bispecific antibodies with compounds which antagonize T cell exhaustion.