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Highlights from

The European Congress of Clinical Microbiology & Infectious Diseases

29th Annual Meeting

Amsterdam 13-16 April 2019

Could immune checkpoint inhibitors be used in infectious disease?

Take-home messages
  • Immune checkpoint inhibitors have transformed the way we treat cancer in the past decade
  • These therapies aim to restore immune responses, and may therefore be efficacious in infectious disease
  • However, concomitant immunosuppressive agents used to tackle irAEs can make patients more susceptible to infection
"The rationale is very simple: if you block PD-1 on pathogen-specific T cells, you will boost your antiviral or anti-pathogen immune response, leading to better control or even a cure of the pathogen."

Olivier Lambotte, Professor of Internal Medicine, Internal Medicine and Clinical Immunology Department, Bicêtre Hospital, France

Immune checkpoint inhibitors have revolutionised the way we treat many types of cancer. Could they also play a role in infectious disease? Olivier Lambotte, Professor of Internal Medicine, Internal Medicine and Clinical Immunology Department, Bicêtre Hospital, France, explored the current evidence in a symposium at the European Congress of Clinical Microbiology and Infectious Diseases (ECCMID), 13-16 April 2019.

Immune checkpoint inhibitors in cancer

Immune checkpoints are a useful modulatory process that helps us avoid autoimmunity. T cells and pro-B cells communicate with familiar ‘friendly’ cells via the checkpoint protein PD-1, which interacts with ligands PD-L1 and PD-L2. This, in turn, inhibits T cell activation, and promotes self-tolerance.

In cancer, however, tumour cells can exploit this recognition pathway by expressing these ligands, allowing them to avoid immune recognition and destruction.

This explains why immune checkpoint inhibitors, including anti-PD-1 monoclonal antibodies (nivolumab, pembrolizumab) can restore the immune system’s ability to recognise tumour cells and mediate a cytotoxic response.

Anti-PD-1 therapies, along with anti-CTLA4 therapy (ipilimumab), have proven to be very effective in the treatment of many types of cancer. In recent years, they have initiated a paradigm shift from targeting tumour cells directly to targeting the immune cells.

This does come at a cost, however. “You remove the brake, you let your autoimmune reactive T cells and B cells go… you have a risk of seeing immune-related adverse events [irAEs],” stated Professor Lambotte, noting that the use of combination therapy only increases this risk.

In cancer and infectious disease

Initial clinical trials of checkpoint inhibitors in cancer excluded patients if they also had HBV, HCV or HIV, partly due to the risk of immune reconstitution syndrome (IRIS). This is no longer the case. “Probably the best evidence to say that is this trial,” Professor Lambotte said, pointing out a phase I/II expansion study investigating nivolumab in hepatocellular carcinoma. “The investigators enrolled patients with and without HBV and HCV infection… there was no difference in the frequency of irAEs,” he continued, “so, clearly, there is no contraindication for treating patients infected with HBV or HCV infection with immune checkpoint inhibitors.”

So, what about the risk of IRIS in HIV? “The answer is also no. There are some papers published showing the safety [of using] checkpoint inhibitors in HIV-infected patients with cancer – so it’s completely possible.” The data are still limited though, he pointed out.

In infectious disease

Taking this background information into account, Professor Lambotte moved on: “I would like to give you a kind of dream. Immune checkpoint inhibitors could be considered as new anti-infectious agents,” he said, explaining why, “The rationale is very simple: if you block PD-1 on pathogen-specific T cells, you will boost your antiviral or anti-pathogen immune response, leading to better control or even a cure of the pathogen.”

As with cancer, perhaps the treatment paradigm could shift away from targeting the infected cell and towards targeting the immune cells.

Professor Lambotte proceeded to explain that some very early-stage studies have shown evidence of anti-PD-1 efficacy in various infectious diseases, showing viral load reduction in HCV, partial recovery of B cell function in HBV, and a boost of JC virus-specific immune responses in patients with progressive multifocal leukoencephalopathy.

“[In] HIV: you have a huge bulk of papers, more than 200 publications, about the PD-1/PD-L1 axis, with the interest to block this,” he continued, “if you look at clinical trials, you have several trials of anti-PD-1 in HIV infection, four in patients who are HIV infected and have cancer… interestingly, we have three trials for patients without cancer.” There is a strong scientific rationale for PD-1 blockade in this area, he explained.

“What about sepsis? We know that the PD-1/PD-L1 pathway is involved in sepsis to limit the inflammation but could favour a secondary phase of immunodepression,” he said, highlighting that monocyte PD-L1 expression after 3-4 days of sepsis has been linked with risk of mortality. “If you block this axis, you could reduce the immunosuppression induced by the sepsis.” Nivolumab has recently completed a phase I trial in this setting.

Although this sounds encouraging, the patients’ risk of other infections could be increased due to the concomitant use of steroids and immunosuppressive drugs to control irAEs, and anti-PD-1 treatments have also been associated with tuberculosis reactivation.

Despite this, he remains optimistic. “We could say that immunomodulation could be, and I think is a new weapon in infectious disease but, today, in 2019, [we’re in the] ‘stone age’.”

The rationale certainly makes sense, and this could be an exciting development in the fight against infectious disease. However, the use of checkpoint inhibitors in this setting is certainly in its infancy and has a long way to go.

Based on Lambotte O. Immune checkpoint inhibitors and infections (symposium SY073). Presented on Sunday 14 April 2019.

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