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The effect of anti-CTLA4 treatment on peripheral and intra-tumoral T cells in patients with hepatocellular carcinoma

  • David Agdashian
  • Mei ElGindi
  • Changqing Xie
  • Milan Sandhu
  • Drew Pratt
  • David E. Kleiner
  • William D. Figg
  • Julie A. Rytlewski
  • Catherine Sanders
  • Erik C. Yusko
  • Bradford Wood
  • David Venzon
  • Gagandeep Brar
  • Austin G. Duffy
  • Tim F. GretenEmail author
  • Firouzeh Korangy
Clinical Trial Report
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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 Biomarker 

Abbreviations

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

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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

262_2019_2299_MOESM1_ESM.pdf (996 kb)
Supplementary material 1 (PDF 995 KB)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • David Agdashian
    • 1
  • Mei ElGindi
    • 1
  • Changqing Xie
    • 1
  • Milan Sandhu
    • 1
  • Drew Pratt
    • 2
  • David E. Kleiner
    • 2
  • William D. Figg
    • 3
  • Julie A. Rytlewski
    • 4
  • Catherine Sanders
    • 4
  • Erik C. Yusko
    • 4
  • Bradford Wood
    • 5
  • David Venzon
    • 6
  • Gagandeep Brar
    • 1
  • Austin G. Duffy
    • 1
  • Tim F. Greten
    • 1
    • 7
    Email author
  • Firouzeh Korangy
    • 1
  1. 1.Gastrointestinal Malignancies Section, Thoracic and GI Oncology Branch, Center for Cancer Research, National Cancer Institute (NCI)National Institutes of Health (NIH)BethesdaUSA
  2. 2.Laboratory of Pathology, Center for Cancer Research (CCR) National Cancer InstituteNational Institutes of HealthBethesdaUSA
  3. 3.Clinical Pharmacology Program, Center for Cancer Research, National Cancer InstituteNational Institutes of HealthBethesdaUSA
  4. 4.Adaptive BiotechnologiesSeattleUSA
  5. 5.Center for Interventional Oncology, Radiology and Imaging Sciences and Center for Cancer ResearchNational Institutes of HealthBethesdaUSA
  6. 6.Biostatistics and Data Management Section, Center for Cancer Research, National Cancer InstituteNational Institutes of HealthBethesdaUSA
  7. 7.NCI CCR Liver Cancer ProgramBethesdaUSA

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