The effect of anti-CTLA4 treatment on peripheral and intra-tumoral T cells in patients with hepatocellular carcinoma
Abstract
Background
Checkpoint inhibitors have recently been approved for the treatment of patients with hepatocellular carcinoma (HCC). However, biomarkers, which will help identify patients responding to therapy, are missing. We recently tested the combination of anti-CTLA4 treatment (tremelimumab) with loco-regional therapy in patients with HCC and reported a partial response rate of 26%.
Methods
Here, we report updated survival analyses and results from our immune monitoring studies on peripheral blood mononuclear cells (PBMCs) and tumors from these patients.
Results
Tremelimumab therapy increased CD4+-HLA-DR+, CD4+PD-1+, CD8+HLA-DR+, CD8+PD-1+, CD4+ICOS+ and CD8+ICOS+ T cells in the peripheral blood of the treated patients. Patients with higher CD4+PD1+ cell frequency at baseline were more likely to respond to tremelimumab therapy. PD-1 expression was increased on alpha fetal protein (AFP) and survivin-specific CD8 T cells upon tremelimumab treatment. An increase of tumor infiltrating CD3+ T cells were also seen in these patients. Immunosequencing of longitudinal PBMC showed that one cycle of tremelimumab significantly decreased peripheral clonality, while no additional effects were seen after loco-regional therapy.
Conclusion
In summary, we observed a clear activation of T cell responses in HCC patients treated with tremelimumab and identified potential biomarkers which will help identify patients responding to immunotherapy with anti-CTLA4.
Keywords
Hepatocellular carcinoma Trial Immunotherapy BiomarkerAbbreviations
- AFP
Alpha fetal protein
- CR
Complete response
- CT
Computer tomography
- FDA
Federal Drug Administration
- HCC
Hepatocellular carcinoma
- MRI
Magnet resonance imaging
- MDSC
Myeloid-derived suppressor cell
- NCI
National Cancer Institute
- NIH
National Institutes of Health
- NR
Non-responders
- OS
Overall survival
- PR
Partial response
- PBMC
Peripheral blood mononuclear cell
- PD
Progressive disease
- RFA
Radiofrequency ablation
- R
Responders
- SD
Stable disease
- TCR
T-cell receptor
- TACE
Transarterial chemoembolization
Notes
Author contributions
DA, ME and CX planned and conducted the experiments, analyzed the data, and wrote the manuscript with support from MS, WDF and GB. DP and DEK were responsible for pathology data collection and analysis. DV conduced statistical analysis. JAR, CS and ECY performed TCR sequence analysis. BW was responsible for performing biopsies. AGD was the lead in running the clinical trial. FK and TFG designed and developed the clinical trial and also helped in writing and editing the manuscript for publication.
Funding
This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research and a Cooperative Research and Development Agreement between NCI and Astra Zeneca and NCI and Adaptive Biotechnologies. Tetramers were provided by the NIH tetramer facility. Tim F. Greten is supported by the Intramural Research Program of the NIH, NCI (ZIA BC 011343).
Compliance with ethical standards
Ethical standards
The study with the ClinicalTrials.gov identifier NCT01853618 was approved by the NCI Institutional Review Board (IRB) on 4/10/2013.
Informed consent
All patients provided written informed consent before enrollment onto the study trial to receive treatment. Patients also provided written informed consent prior to procuring biopsied tissue and blood samples to conduct research analysis understanding the deidentified data collected would be used for publication purposes.
Conflict of interest
Julie A. Rytlewski, Catherine Sanders and Erik C. Yusko all have equity and employment with Adaptive Biotechnologies. All other authors declare that they have no conflict of interest.
Supplementary material
References
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