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Cancer drug leads to ‘drastic decrease’ in HIV infection in lung cancer patient
Doctors in France have found the first evidence that a cancer drug may be able to eradicate HIV-infected cells in humans.
In a letter published in the leading cancer journal Annals of Oncology [1] today (Friday), researchers led by Professor Jean-Philippe Spano, head of the medical oncology department at Pitie-Salpetriere Hospital AP-HP in Paris, France, report that while treating an HIV-infected lung cancer patient with the cancer drug nivolumab, they observed a “drastic and persistent decrease” in the reservoirs of cells in the body where the human immunodeficiency virus (HIV) is able to hide away from attack by anti-retroviral therapy.
These reservoirs of HIV-infected cells are found in the immune system in organs such as the brain, bone marrow and genital tract. They lie dormant and cannot be eliminated by anti-retroviral therapy, nor by the weakened immune system, so that if treatment is stopped at any time, the virus starts to replicate and infect more cells again, while the immune system cannot suppress this rebound of HIV infection. If scientists could find a way of clearing away the reservoirs of HIV-infected cells, then it might enable them to eradicate the virus completely, making it possible to cure HIV patients.
HIV primarily infects CD4 T cells, which are a type of white blood cell that plays an important role in regulating the immune response. When under attack from HIV they not only become infected but also exhausted, meaning they are less able to fight the infection.
Professor Spano explained: “Dormant CD4 T cells infected with HIV are not actively producing HIV: they are latently infected. Latent HIV reservoirs are established during the earliest stage of HIV infection and throughout the course of the disease. When a latently infected cell is reactivated, the cell begins to produce HIV again. However, this re-activation is blocked in most latently-infected cells by cellular molecules called immune check-points. One of these check-points is programmed death-1 (PD-1), which also blocks the functions of CD4 T cells in fighting the virus.
“Increasingly, researchers have been looking into the use of certain drugs that appear to re-activate the latent HIV-infected cells. This could have the effect of making them visible to the immune system, which could then attack them. Drugs that inhibit immune check-points such as PD-1 are well known in the cancer field as being very efficient at restoring immune defences by removing the brake, enabling the immune cells to spring into action to reject the cancer cells. It was thought, but until now not demonstrated, that inhibitors of immune check-points could, in a similar way, wake up dormant HIV-infected cells and also the immune defences against the virus.”
Nivolumab is PD-1 inhibitor, which is used to treat several cancers in their advanced stages, including melanoma, non-small cell lung cancer and kidney cancer. The researchers used it to treat an HIV-infected patient with non-small cell lung cancer after he relapsed following surgery and chemotherapy for his tumour. So far, the 51-year-old man has received 31 injections of nivolumab every 14 days since December 2016. He was diagnosed as HIV-positive in 1995 and the cancer was diagnosed in May 2015.
When the researchers first gave nivolumab to the patient, HIV was undetectable in blood samples. It then increased progressively up to day 45 before decreasing again. At the same time T cell activity increased, with a marked increase in the activity of another T cell, CD8, from day 30 to 120. By day 120 the reservoirs of HIV-infected cells “showed a drastic and persistent decrease”, report the researchers in their letter to Annals of Oncology.
Professor Spano said: “In this patient we observed, as expected, both a re-activation of HIV and an increase in CD8 T cell responses against HIV, which resulted in the drastic decrease in the HIV reservoir, thus leading to a sustained reduction of the HIV reservoirs.
“This is the first demonstration of this mechanism working in humans. It could have implications for HIV patients, both with and without cancer, as it can work on HIV reservoirs and tumour cells independently. The absence of side effects in this patient is also good news, and suggests this could be an optimum treatment for HIV-infected patients with cancer.”
However, the researchers are also cautious about their results. Professor Spano continued: “Firstly, this is the first case of such a drastic decrease of the HIV reservoir, and we must remain careful, especially because this is only one case; we have published details of another case where there was no decrease of the HIV reservoir.
“Secondly, we have to evaluate – in clinical trials and in a group of 50 French patients we are treating currently – the potential toxicities of these drugs in HIV infected people. And finally, we have to identify markers that can predict HIV response to the anti-PD-1 therapy so that treatment can be personalised, especially as we observed one responder and one non-responder.”
Editor-in-chief of Annals of Oncology, Fabrice André, Professor in the Department of Medical Oncology, Institut Gustave Roussy, Villejuif, France, commented: “Although this is a single case study, it is an exciting result. Anti-HIV drugs usually stop virus replication but don’t cure the patients who still have reservoirs of the virus. This study generates the hypothesis that drugs that make the virus disappear could, perhaps, cure patients.”
The patient will be treated with more nivolumab later this month and his cancer will also be assessed then. “For the moment, he is doing quite well and doesn’t show any signs of disease, even though the cancer is progressing slowly, which suggests it is not optimally controlled,” said Professor Spano.
Expert Reaction
These comments have been collated by the Science Media Centre to provide a variety of expert perspectives on this issue. Feel free to use these quotes in your stories. Views expressed are the personal opinions of the experts named. They do not represent the views of the SMC or any other organisation unless specifically stated.
Dr Clovis Palmer is a Assistant Professor in the Department of Microbiology and Immunology at Tulane University in Louisiana USA
This new data revive hopes that it is possible to reprogram immune cells in HIV-positive persons to fight the infection.
Immune cells in these persons are what we call 'exhausted' - they are incapable of fighting HIV by themselves. This work demonstrates that immune cell exhaustion can be reversed.
However, previous studies employing this drug (nivolumab) in HIV-positive showed less impressive results or no effects at all. Therefore, at best, this type of treatment will have to be personalised, and in the context of HIV cure that means many, often poor and vulnerable communities will be left out of any benefits.
The team examined the HIV reservoir in immune cells from the blood. The major challenge toward an HIV cure is to eradicate the reservoir from sanctuary organs like the gut and brain where most of the hidden HIV resides. There is no evidence that this drug decreases the reservoir in these tissues.
Further, it is unknown whether first line cancer therapy given to this patient before nivolumab impacted the outcome of the reservoir size, and the clinical benefits since the patient did not interrupt their antiretroviral medication.
Notwithstanding, the results confirmed that it is possible to re-energise the immune system in HIV-positive persons.
But there are many challenging questions ahead: Can the energised immune cells seek out and kill reservoir cells in sanctuary organs? And what about viral rebound is HIV treatment is interrupted?
Dr Mark Polizzotto is head of the Therapeutics and Vaccine Research Program at The Kirby Institute for Infection and Immunity in Society
There is widespread interest in the possibility that cancer drugs acting on the immune system could also help eradicate HIV infection from the body.
Several studies, including two here in Australia, are evaluating this hypothesis in people with HIV and cancer who require these drugs for their cancer treatment.
This report of a single person with HIV and cancer offers encouragement that this approach has potential. However, as a single case it requires confirmation in larger studies.
It is also important to note that these cancer drugs have significant side-effects that make them less suitable for healthy people with HIV who do not require cancer treatment. The pathway to HIV eradication will require significant advances in our scientific understanding, and the development of safer drugs.
People living with HIV in Australia can be encouraged by the long term scientific interest in Australia and internationally in eradicating HIV. These results are encouraging but preliminary, and ongoing studies in people with HIV and cancer, including one being conducted at the Kirby Institute, will be crucial.
Associate Professor Sanjaya Senanayake is a specialist in Infectious Diseases and Associate Professor of Medicine at The Australian National University
Treating HIV infection has never been easier than it is today due to the variety of antiviral medications available; however, HIV still cannot be cured. Even people with no detectable HIV in the blood are still infected. This is because the virus hides in cells in places such as the brain, digestive system and blood system.
This reservoir of HIV-infected cells is called latent (or dormant) because the cells are not actively producing HIV. This lack of activity means that the immune system can't find and destroy them. Therefore, being able to find and destroy this group of dormant infected cells could potentially lead to a cure of HIV.
In this paper, a drug used to treat cancer in a HIV-positive man appeared to "wake up" the sleeping or latent HIV-infected cells, allowing the immune system to identify and eliminate them.
While this is very exciting, the obvious limitation is that this is from a single case report, which means that it's unclear if this result would be reproducible if given to other people with HIV. In other words,well-designed clinical trials would have to be carried out with large numbers of HIV patients to see if this drug is effective and doesn't cause untoward side effects in HIV-positive people.
The other feature of this case worth highlighting is that a cancer drug appears to have an effect on an infection.
It is not uncommon for new medications, designed for one purpose (e.g. depression) to end up being used for another (e.g. as an antibiotic).
Prof Martyn French is an Emeritus Professor in the Faculty of Health and Medical Sciences at the University of Western Australia
This publication describes the effects of nivolumab therapy on HIV infection in a single patient with cancer who also had treated HIV infection. Nivolumab consists of synthetic antibodies that specifically block a protein (Programmed Cell Death Molecule-1 [PD-1]) that under normal circumstances is expressed by immune cells to regulate immune responses and prevent excessive inflammation.
Some types of cancer activate PD-1 inappropriately and suppress killer immune cells trying to kill the cancer cells. In addition, HIV infection increases PD-1 on killer T cells so that they become ‘exhausted’ and less effective at clearing the reservoirs of HIV-infected cells that persist in patients treated with antiretroviral therapy.
The patient in this report received nivolumab to treat aggressive lung cancer, but the investigators also showed that blocking the activity of the PD-1 protein also released HIV from reservoirs of persistent infection and enhanced the activity of killer T cells to decrease the number of HIV-infected cells.
The data presented are impressive and highly relevant to research on HIV cure strategies. However, the effects of this therapy were demonstrated in only one patient and the results of clinical trials on large groups of patients are needed before conclusions about the role of this type of therapy in curing HIV infection can be made.
