The drug targets we really need to work on are the cellular molecules that prompt the cell to stop whatever immune job it is doing and revert to its quiescent state. Both cancer cells and HIV-infected cells are particularly rich in these so-called immune checkpoint receptors. It is thought that their function is, when the body is facing a hostile environment ranging from viral proliferation to chemical attack, to sequester a proportion of the immune system away, so that not all of it is permanently damaged.
There are a number of different immune checkpoint molecules. Ones already targeted by some cancer drugs include CTL-4 (cytotoxic T-lymphocyte-associated protein 4), PD-1, where the PD stands for “Programmed Death” (one of the things PD-1 can do is make cells self-destruct), TIGIT (T-cell immunoreceptor with Ig and ITIM domains), and JAK (Janus kinase). These are all inhibitory molecules, putting cells into the reservoir state, though some like the TLR (toll-like receptor) family are excitatory, as the HDACs are, and TLR agonists (stimulators) continue to be under investigation as cell activators.
As with the HDACs, a number of CTL4, PD-1 and JAK inhibitors already exist as cancer drugs. These include the CTL-4 antagonist ipilimumab (prescribed under the brand name Yervoy for advanced melanoma), the PD-1 antagonists nivolumab (Opdivo) and pembrolizumab (Keytruda) which are used for advanced melanoma, small-cell lung cancer and kidney and bladder cancer, and the JAK inhibitors baricitinib (Olumiant) and ruxolitinib (Jakafi), which are used against a rare bone marrow cancer called myelofibrosis and also against auto-immune disorders such as rheumatoid arthritis and psoriasis. Some of these drugs have shown life-prolonging effects in cancers that used to be rapidly terminal.
The Cure and Cancer Forum heard about several experiments using these agents in cancer patients with HIV. Timothy Henrich of the University of California, San Francisco, a researcher who has previously produced spells of HIV undetectability off ART in two patients given bone marrow transplants, gave data from three patients with lung cancer and HIV who were given multiple doses of pembrolizumab.
In all three patients, measures of T-cell activation decreased and in one patient, who was on ART, the amount of intracellular DNA (a measure of how many cells in the ‘reservoir’ are infected) went down transiently. In a third patient, who was not on ART, both his general T-cell function decreased and his blood plasma viral load.
Brigitte Autran of Hôpital Pitié Salpêtrière in Paris gave data from 12 patients with non-small-cell lung cancer who had been given nivolumab. They were a diverse group. One was a cisgender and another a transgender woman, the others were gay men. They were aged between 40 and 77 and had been diagnosed between 1980 and 2005. CD4 counts ranged between 60 and 700 cells/mm3. Most had viral loads below 20 copies/ml, though in two cases they were marginally detectable, at 34 and 53 copies/ml.
In one patient, the one with the lowest CD4 count, there was a significant T-cell rise and a rise in the proportion of cells with an HIV-specific immune response. In another, a rise in the HIV-specific immune response was accompanied by a significant decrease in intracellular HIV DNA. However, he was the only one who showed indications of a shrunken HIV reservoir and other immunological effects continuing after the course of treatment. Effects in other patients were slight and transient.
Christina Gavegnano of Emory University in Atlanta, Georgia presented data from animal studies of baracitinib in recently-infected monkeys and found that, compared with treatment with lamivudine, there was a 700-fold reduction in the number of non-dividing latent CD4 T-cells established in the body. The drug could possibly be used as an addition to ART that would slowly shrink the HIV reservoir to the point where a treatment interruption could be considered. A human trial of ruxolitinib in 60 adults (A5336) is underway.
Results with PD-1 and CTL-4 antagonists, and JAK inhibitors, have not so far been impressive, with only a minority of patients demonstrating strong or durable responses, if any. Sharon Lewin of the University of Melbourne said that interpreting PD-1 blocker studies in people with cancer is already difficult because cancers are heterogeneous and people with HIV who have cancer may not be representative of other HIV-positive people.
“We need to do studies in HIV-positive patients without cancer,” she said. “And we need to study combination therapies. But combinations of immune checkpoint inhibitors, while proving to have more powerful results in some cancers, are too toxic to use with people who only have HIV.”
In some studies of patients with melanoma, as many as 50% of patients had experienced severe or life-threatening side-effects or even death from the drugs when they were used in combination.