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Cancer Immunol Immunother. 2019 Apr;68(4):599-608. doi: 10.1007/s00262-019-02299-8. Epub 2019 Jan 28.

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

Author information

1
Gastrointestinal Malignancies Section, Thoracic and GI Oncology Branch, Center for Cancer Research, National Cancer Institute (NCI), National Institutes of Health (NIH), Building 10, Room 3B43, Bethesda, MD, 20892, USA.
2
Laboratory of Pathology, Center for Cancer Research (CCR) National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
3
Clinical Pharmacology Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
4
Adaptive Biotechnologies, Seattle, WA, USA.
5
Center for Interventional Oncology, Radiology and Imaging Sciences and Center for Cancer Research, National Institutes of Health, Bethesda, MD, USA.
6
Biostatistics and Data Management Section, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
7
Gastrointestinal Malignancies Section, Thoracic and GI Oncology Branch, Center for Cancer Research, National Cancer Institute (NCI), National Institutes of Health (NIH), Building 10, Room 3B43, Bethesda, MD, 20892, USA. tim.greten@nih.gov.
8
NCI CCR Liver Cancer Program, Bethesda, MD, USA. tim.greten@nih.gov.

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:

Biomarker; Hepatocellular carcinoma; Immunotherapy; Trial

PMID:
30688989
DOI:
10.1007/s00262-019-02299-8
[Indexed for MEDLINE]

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