The development of immunotherapy that can cure at least a fraction of formerly deadly cancers has been the greatest medical triumph of recent years. At last week’s meeting of the International AIDS Society (IAS) in Paris, multiple presentations discussed the possibilities and practicalities of using the same approach to cure chronic viral infections.
From the beginning, cancer has had a role in the HIV story.
Public health officials first became aware of the epidemic when young men who should have had decades of good health ahead of them developed mysterious illnesses. One of those illnesses was Kaposi sarcoma (KS), a cancer that can result from infection with a strain of herpesvirus. As the immune system of HIV-infected individuals weakened, they were unable to control the chronic herpes infection.
The emergence of KS in immune-deficient individuals is one example of more general similarities between cancer and chronic viral infections.
Just as chemotherapy is initially effective in killing off tumor cells, sometimes to the point of undetectability, antiretroviral therapy (ART) quickly suppresses viral levels below the detectability limit.
But just as interrupting ART is almost always followed by rapid viral rebound, cancer remissions are frequently temporary.
At the meeting, Nicolas Chomont, assistant professor of microbiology at the University of Montreal, showed a slide illustrating striking similarities of the response to Gleevec (imatinib, Novartis AG) and antiretroviral therapies.
Chomont gave a partial overview of a pre-conference forum on “HIV Cure & Cancer” at a satellite symposium last Monday, summarizing the presentations of multiple researchers.
One of those researchers is Monsef Benkirane, whose work has shown that “HIV hides out in cells that have stem cell-like properties,” Chomont said.
Those cells, which are quiescent or slow cycling, long-lived and insensitive to ART, make up a significant fraction of the viral reservoir. Benkirane’s team has identified surface markers that can be used to identify those cells, and he and others have also shown that they express the same checkpoint blockers that are being targeted in cancer immunotherapy.
Cancer drugs for HIV
The most important of those blockers from a clinical perspective are the PD-1 blockers, a class of drugs with five approved antibodies targeting either PD-1 or its ligand, PD-L1. PD-1 signaling serves to limit immune responses by preventing T cells from becoming permanently active, but what is a useful mechanism in acute infections goes awry in cancer, where tumor cells shut down T cells before their job is done.
The IAS plenary last Wednesday featured a talk from PD-1 discoverer Tasuku Honjo, a professor at Kyoto University. Honjo gave an overview of the road from his lab’s more or less accidental discovery of PD-1 in 1992 to the current situation, where PD-1 blockers have been called “cancer’s penicillin” – an agent that, though it cannot cure everything on its own, is proof of concept that a class of often deadly diseases can turn into an easily treatable and curable one.
Honjo said that immunotherapy might also be the penicillin of chronic viral infections. “I truly believe it has advantages over chemotherapy,” he said.
At the Cancer & HIV Cure forum, Bristol-Myers Squibb Co.’s vice president of immuno-oncology discovery, Alan Korman, gave an overview of checkpoint inhibitors that are still under clinical or preclinical development. Among the checkpoint inhibitors being developed for cancer are two molecules, TIGI and Lag-3, which Benkirane’s group has found to be expressed on the stem cell-like reservoir cells that harbor latent HIV.
Another cancer drug that might be useful in treating HIV patients is recombinant interleukin-15 (IL-15), which stimulates immune cells including natural killer cells and antigen-presenting dendritic cells.
At a session on “Outsmarting the Immune System,” George Pavlakis from the National Institute of Allergy and Infectious Diseases reported that in primate studies, administering recombinant IL-15 stimulated both killer T cells and natural killer cells and affected organization of the germinal center, where antibody-producing cells mature.
In HIV trials, IL-15 decreased viral RNA and DNA in the lymph nodes of elite controllers, an indication that it may decrease reservoir size.
ALT-803 (Altor Bioscience Corp.), a mutated version of IL-15 that is several-fold more active that natural IL-15, is also in clinical trials as both a cancer and an HIV treatment.
The blind men and the elephant
One of the earliest attempts to repurpose cancer drugs for HIV was the use of epigenetic drugs. Epigenetic factors control many aspects of cell fate and activity, and so have been potential candidates both for attacking cancer stem cells and for waking up latently HIV-infected T cells
At the Cancer & HIV Cure forum, John Wherry, director of the Institute for Immunology at the University of Pennsylvania School of Medicine, gave an overview of attempts to repurpose epigenetic cancer drugs such as vorinostat, bryostatin and romidepsin for HIV treatment.
“HIV latency is regulated by epigenetic mechanisms that are also involved in the development of cancer cells,” he told the audience, though clinical trials have shown that such agents were not effective at reducing the size of the viral reservoir. Other work has shown, though, that another cancer drug was able to reactivate more latently infected cells than epigenetic drugs – namely receptor tyrosine kinase inhibitor Sutent (sunitinib, Pfizer Inc.).
Wherry gave an overview of his own laboratory’s work on T cells that become dysfunctional during chronic infections, and showed that although such cells can be reinvigorated using checkpoint blockers, their epigenetic landscape does not change when they are reactivated, which may be why checkpoint blockade, too, is still often short-lived.
More generally, he said, each of the two fields can learn from each other. The HIV field is ahead of cancer research in terms appreciation of the role of overall immune health in a therapy’s effectiveness, while the cancer field has far more therapeutic trials as well as preventive ones, and so can look at research questions in clinical cohorts.
The fields can also learn from each other’s results, he added.
“The issue is somewhat like the parable of the blind men and the elephant,” Wherry said. “It’s the same problem, it’s the same immune system, and it’s [largely] the same reaction that we’re seeing.”
Also from the International AIDS Society’s 2017 meeting, Anette Breindl reported for BioWorld on the “cautious optimism” around vaccine development in HIV science. Download her free coverage here.