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Merkel cell carcinoma and HCV infection: role of anti–PD-1 immunotherapy


Antibodies that block programmed death 1 ( PD-1 ) receptor and its ligand, PD-L1, have shown durable responses in multiple cancer types.
PD-1 has been shown to be upregulated in hepatitis C virus ( HCV ), specific CD8+ cells.
This suggests that anti–PD-1 therapy may be a therapeutic target in patients with HCV infection.
However, patients with chronic hepatitis are usually excluded from clinical trials.

Researchers have reported a case in which PD-1 antibody was administered to treat metastatic Merkel cell carcinoma ( MCC ) in a patient with untreated chronic HCV infection.
Treatment resulted in a rapid antitumor response as well as a rapid decline in HCV RNA without apparent hepatocellular injury, which suggested that not only can anti–PD-1 therapy induce antitumor immune responses, but that it may also restore antiviral T-cell function and overcome viral immune escape.

Case presentation

An 82-year-old man was diagnosed with HCV in 2008 ( HCV RNA, 5.89 log IU/mL ) for which he declined treatment.
In December 2015, he presented with stage IA primary cutaneous MCC of the right cheek, which was excised with a negative sentinel lymph node biopsy.
In April 2016, the patient developed recurrent MCC with a large metastatic subcutaneous nodule to the left shoulder.
Restaging positron emission tomography and computed tomography revealed additional metastatic disease to the left axilla and supraclavicular nodes.

Clinical course of a patient with Merkel cell carcinoma and chronic hepatitis C receiving treatment with Pembrolizumab ( Keytruda ).
(A) Clinical exams of the left shoulder subcutaneous nodule show regression of Merkel cell carcinoma after first treatment with Pembrolizumab, which was durable.
(B) Positron emission tomography and computed tomography scans show metabolic and radiologic response in the left axillary lymph node.
(C) HCV RNA and ALT ( alanine aminotransferase ) were monitored during the course of treatment.

Administration of anti–PD-1 immunotherapy was considered on the basis of phase II clinical trial data that showed a response rate of 56% in patients with advanced Merkel cell carcinoma.

After an extensive discussion about the risk of immune-related adverse effects from anti–PD-1, including hepatitis, the patient consented to anti–PD-1 therapy.
Pretreatment HCV viral load was 4.69 log IU/mL and ALT was 1.5 times the upper limit of normal.
The patient began treatment with Pembrolizumab ( anti–PD-1 ) 2 mg/kg every 3 weeks in May 2016.

Three weeks after initiation of Pembrolizumab, the metastatic subcutaneous nodule in the left shoulder had substantially regressed.
HCV viral load decreased to 3.92 log IU/mL and ALT normalized.
Positron emission tomography and computed tomography performed 3 months after initiation of Pembrolizumab showed a 50% reduction in tumor burden according to RECIST, version 1.1.
HCV viral load was nearly undetectable after two doses of Pembrolizumab with normal ALT.
The patient has not experienced immune-related adverse effects.

This case has demonstrated the role of the PD-1 pathway both in immune resistance by cancers and tolerance to chronic viral infection as well as the benefit of anti–PD-1 therapy to achieve antitumor and anti-HCV response.

A recent phase I clinical trial of a single dose of anti–PD-1 monoclonal antibody in patients with chronic HCV showed durable HCV reductions in up to 15% of patients, which was suggestive of single-agent anti–PD-1 therapy activity against HCV.

Multiple ongoing clinical trials of anti–PD-1 antibody in patients with hepatocellular carcinomas allow the enrollment of patients with untreated HCV.
The results of these trials will increase the understanding of the safety and tolerability of anti–PD-1 antibody therapy in patients with other malignancies and concurrent HCV infection.

In clinical practice, HCV infection should not be a contraindication for anti–PD-1 immunotherapy in patients with cancer who have underlying chronic HCV infection but who are otherwise appropriate for this therapy.
Close monitoring of HCV titer and liver function tests would be advised. ( Xagena )

Jang S, Venna S, Journal of Oncology Practice, 2017

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