Is combination immunotherapy the future? ask Edwin J Bernard and Derek Thaczuk
The search for ‘elite controllers’
Not all immune systems are created equal. Without appropriate antiretroviral treatment, most people who have been infected with HIV will progress towards more serious disease – some more slowly, others more quickly. However, about one-in-a-hundred HIV-positive people show a natural ability to at least partially control HIV infection and really slow down disease progression. These so-called ‘long-term non-progressors’ are able to maintain close-to-normal health, low viral loads, and high CD4 cell counts for up to three decades (so far), without the need for treatment. In addition, some non-progressors, so-called ‘elite controllers’, are able to maintain ‘undetectable’ viral loads (i.e. below 50 copies/ml) without the use of antiretrovirals.
Research into long-term non-progression began in the early 1990s when researchers in San Francisco realised that they had patients infected between 1978 and 1980, in the very earliest phase of the epidemic, who were still healthy, with normal immune systems and very low levels of HIV in their blood. The research,1 by Susan Buchbinder and colleagues caused excitement at the 1993 International AIDS Conference in Berlin, and led to the establishment of other studies around the world. It also led to an understanding that the phenomenon was more common than expected.
“If you talk to anyone who has a practice of 300 HIV patients, they will have [an ‘elite controller’],” noted Bruce Walker of Harvard University Medical School during the 2006 launch of the HIV Elite Controllers Consortium, an international collaboration between researchers in the United States, Canada, Europe and Australia.2
Naturally, there has been great interest in why some people are able to control their HIV for long periods of time without antiretrovirals. Part of the reason may be due to the particular strain of virus that person has been infected with. HIV has evolved into a wide variety of strains – some more potent, some less so. Infection with a ‘wimpy’ strain of virus may mean it does less damage and is more easily controlled by the immune system.
On the other hand, it may have something to do with characteristics of the infected person, rather than the virus – these are known as ‘host factors’. Professor Frances Gotch and her colleagues from Imperial College, based at London’s Chelsea & Westminster Hospital, have identified a number of long-term non-progressors and, together with several other groups of researchers worldwide, have shown that there may be a genetic component to non-progression – some people may simply be lucky enough to have inherited a protective genetic make-up from their parents.
For those lucky enough to be ‘elite controllers’, however, both factors – ‘wimpy virus’ and inherited genes – may apply.
Of course, we cannot pick and choose the virus we are infected with or the genes we are born with. But Prof. Gotch and others are investigating what we might be able to learn from the more genetically fortunate. Once we have identified the characteristics that keep non-progressors well, the next question is whether it is possible to induce these characteristics in others.
“Of most interest to us as immunologists,” Prof. Gotch tells HTU, “is the fact that many long-term nonprogressors have exceptionally good HIV-specific immune responses.” Using sophisticated technology to measure the quantity and quality of such HIV-specific cellular immune responses, Prof. Gotch and her colleagues at Imperial College have found that their group of long-term non-progressors “show particularly high levels of CD8 ‘killer cells’ as well as high levels of effective CD4 T helper cells in the blood; together these seem able to keep the levels of virus down.”
While most people with HIV are well acquainted with their CD4 cells, which communicate with other immune cells and co-ordinate the overall immune response, CD4s are actually just one of many types of immune cells that play distinct but interlocking roles in fighting infections. CD8 cells, often overlooked, are also extremely important. CD8 cells, in addition to being 'killers', are also able to act as 'suppressors' of viral replication. Killer CD8 cells destroy infected human cells, sacrificing them in a bid to keep infection from spreading further.
Immunotherapy: giving the immune system a boost
It would obviously be more desirable to be a long-term non-progressor – or even better, an ‘elite controller’ – than to be entirely reliant on anti-HIV drugs for the rest of your life. While we do not yet know whether this is realistically achievable for the majority of people with HIV, immunotherapy studies may yield ways of delaying (or possibly even avoiding) the need for HIV treatment – hopefully without introducing prohibitive costs or complications of their own.
“It seems possible that the necessary immune cells are not destroyed completely during chronic, progressive infection,” says Prof. Gotch. “They may be present, yet unable to respond properly to HIV.” Immunotherapy aims to boost the body's own immune response – especially the HIV-specific response – that may be waiting for a boost.
One widely investigated therapy is a cytokine (a cellular messenger chemical) called interleukin-2 (IL-2). In its natural form, as produced by immune cells, IL-2 stimulates the production and maturation of CD4 cells. Clinical trials have shown that manufactured versions of IL-2 (Proleukin) can result in very dramatic increases in CD4 cell counts. However, despite ongoing trials, there is still little evidence as to whether this translates into long-term clinical benefit. Still, a recent study3 found that short courses of IL-2 (twice-daily injections over five days, every eight weeks) may boost CD4 counts enough to delay the need for antiretroviral therapy by up to two years. Results from two trials, ESPRIT and SILCAAT, expected next year, should help us understand better the clinical benefits and risks of IL-2.
IL-2 has been around for more than a decade, but in a much more 21st century approach, several researchers are experimenting with using a person's own immune cells, modified to create a more effective response to HIV. In such ‘autologous cell’ techniques, an individual’s white blood cells are reintroduced into the body after being treated in specific ways – typically, by exposing the cells to distinctive pieces of the virus that ‘teach’ them to respond more robustly to HIV. While still highly experimental – and extremely costly – several autologous cell techniques have so far appeared safe and promising. Ultimate feasibility, effectiveness and safety of this technique remains to be seen. 4,5
Therapeutic vaccines: an alternative to lifelong treatment?
Back in May 2006 (ATU 156), when we examined the fallout from the SMART study – which found that treatment interruptions are not a safe long-term treatment strategy, due to the increased risk of serious illness and death when coming off HIV treatment compared to staying on it – we wondered whether this now means that triple drug combination HIV treatment is a lifelong prospect. When we examined whether therapeutic vaccines were a viable alternative to lifelong treatment we found short-lived early success and quite a few potential drawbacks.
In fact, when we interviewed two of the foremost HIV experts in the UK for our January/February 2007 edition (ATU 163), both were definitely unenthusiastic about the prospects of therapeutic vaccines making a difference to our treatment options. “Therapeutic vaccines won’t work,” said Dr Mike Youle, of London’s Royal Free Hospital. “At best they’re going to be mildly beneficial.” Professor Brian Gazzard, of Chelsea & Westminster Hospital agreed: “I think the chances a therapeutic vaccine will have any impact is virtually zero.”
Although there have been several promising candidates, including Remune (developed by Jonas Salk, discoverer of the polio vaccine, and no longer being studied) and DemaVir (applied to the skin, and still being studied) the best results so far have come from a team of French researchers who created a cocktail of two therapeutic vaccines – the ALVAC 1433 vaccine and HIV lipopeptide – plus IL-2. During viral-load-guided treatment interruptions (this study was done before SMART) they found that the trial participants who received the therapeutic vaccine/IL-2 combination had, on average, viral loads ten times lower, and remained off anti-HIV drugs for 40% longer, than non-vaccinated patients. 6
However, earlier this year, an international collaboration reported that a similar therapeutic vaccine – ALVAC 1542 – actually increased viral loads and reduced time off treatment - the opposite of what had been hoped.7 The investigators believe these disappointing results may be down to bad luck – they found a higher proportion of ‘natural’ non-progressors in the group that didn’t receive the vaccine than in the vaccine group. But it may also be possible that instead of stimulating anti-HIV CD8 cells, which would kill HIV-infected cells, the vaccine mainly stimulated the formation of HIV-specific CD4 cells – which might only serve as targets for more HIV replication.
Isn’t HIV treatment enough?
Currently, the most commonly used immune boosting therapy is HIV treatment itself. Most people who respond well to antiretroviral therapy have a dramatic increase in their CD4 count in the first few months of treatment, followed by a more gradual rise during subsequent months. This later phase is accompanied by improved function and restoration of a wider range of immune responses. So why do we need a therapeutic vaccine?
“Taking antiretroviral therapy does not normally rejuvenate the HIV-specific immune responses needed to keep the virus under control [if you ever stop treatment],” argues Professor Gotch. “Consequently, if the drugs are stopped or fail in some way, the levels of virus will rebound and CD4 cell counts will plummet.” She also argues that antiretroviral therapy is not available to at least 70% of HIV-positive people in the developing world who require it, although some experts wonder whether potentially expensive and complex combination immunotherapy could be a realistic alternative for resource-limited settings.
A new study in combination immunotherapy
With these things in mind, and with lessons learned from past immunotherapy and therapeutic vaccine studies, Prof. Gotch and her colleagues at the St Stephen’s AIDS Trust, Chelsea & Westminster Hospital, and Imperial College, are about to start a Medical Research Council-funded study (called IMIRC1003) in HIV-positive people who are on successful HIV treatment (defined as viral loads below 50 copies/ml and CD4 T-cell counts over 400 cells/mm3) which will combine several new immunotherapeutic approaches.
They will use a new kind of DNA vaccine boosted with several different cytokines and hormones (see below) in a strategic attempt to regenerate missing HIV-specific cellular immune responses. “Our goal,” says Prof. Gotch, “is to make chronically infected people act more like ‘elite controllers’. Our hope is that, in the future, we may be able to take people off antiretroviral therapy.” She adds that the study has been reviewed and approved by GTAC8 (the Gene Therapy Advisory Committee – the ethical review panel for all research involving gene therapies in the UK).
What is different about this study, compared to those in the past, is that this one combines several different immune modulating cytokines and hormones with a therapeutic vaccine, notes Dr Nesrina Imami, a colleague of Prof. Gotch who is working on the study. They have also thought long and hard about the timing and dosage of each of the individual components. “No consensus has yet emerged concerning the optimal timing and dosing regimens of vaccines and cytokines,” Dr Imami tells HTU, “but recent studies from ourselves and others have suggested that sustained responses may be induced by:
Treating patients with antiretrovirals before CD4 T-cell counts fall below 200 cells/mm3.
Allowing reconstitution of CD4 T cells to a level equal or above 400 cells/mm3.
Inducing or reintroducing specific cellular and humoral (antibody) responses by priming with vaccines representing a broad spectrum of antigens with novel adjuvants.
Increasing survival of vaccine responses through the administration of cytokines/hormones.
Boosting memory responses with further immunisation.”
What’s in the vaccine?
GTU [Gene Transport Unit]–Multi-HIV B clade vaccine is produced by a small Finnish biotech company, called FITBiotech. It is a DNA vaccine containing parts of HIV’s genetic material (for the geeks amongst you, these are: complete sequences of Rev, Nef, Tat, p17/p24 proteins, and an epitope stretch of previously identified T cell epitopes in pol and env) and is designed to stimulate cellular immune responses to HIV.
The vaccine has been evaluated in phase I/II clinical trials in Finland, both in healthy volunteers and in anti-HIV-treated individuals, all of whom were infected with subtype B. In these studies the vaccine was found to be safe.
Initial results from a phase II study9 of 60 treatment-naïve individuals in South Africa (all of whom were infected with subtype C) were presented last month at the AIDS Vaccine 2008 meeting in Cape Town. The participants had an average CD4 count of 560 cells/mm3 and an average viral load of 41,000 copies/ml. A total of 20 participants received 0.5mg of the vaccine injected under the skin, 20 received 1mg injected into the muscle, and 20 received a placebo (a fake vaccine) at the start of the study, and one and three months later. These were then boosted after 19 and 20 months with two more injections at double the initial doses. None took HIV treatment during the study.
The investigators found that there were no vaccine-related serious adverse events although there were some mild to moderate side-effects including bruising, itching and swelling at the injection site. Interestingly, although the intramuscular injection resulted in stable CD4 counts (whereas those on the placebo fell) and a small but significant (0.5 log) decrease in viral load compared to those on placebo, increases in immune function were only observed in those receiving the under-the-skin vaccination (which is how the Chelsea & Westminster study will deliver the vaccine).
What is being used along with the vaccine, and why?
Along with the GTU vaccine, the study will be using the followingcytokinesandhormones (chemicals which serve as ‘triggers’ to immune functions):
Recombinant human granulocyte macrophage colony-stimulating factor (rhGM-CSF). This is a naturally occurring protein. When produced as a medicine by Novartis it is known as sargramostim (brand name, Leukine), and is used to stimulate the production of white blood cells.
Recombinant human IL-2, which is manufactured by Novartis under the brand name Proleukin. IL-2 is normally produced in the body during an immune response and will be used in this trial to boost the immune response to the vaccine.
Recombinant human growth hormone (rhGH) has mainly been used in studies to treat the central weight gain that might accompany lipodystrophy, although recent studies10 suggest it may also have a beneficial effect on the immune system. The therapeutic form of rhGH is produced by Serono International with the brand name Saizen.
The theory is that the vaccine will induce useful cellular immune responses able to recognise HIV, and that such immune responses will be maximally enhanced by the use of this combination of cytokines and hormones. Eventually, following a booster vaccination, this should result in a long-lived pool of mature memory cells which mimic those seen in long-term non-progressors and ‘elite controllers’ and may be able to control HIV without the need for antiretroviral therapy (although a treatment interruption to try to show this will not be part of this study).
If you are considering taking part in this study, you should be aware that there may well be drawbacks as well as potential benefits. As with most trials, some side-effects can be anticipated. In particular, flu-like symptoms (such as fever, muscle aches and tiredness) may accompany injections of IL-2 and GM-CSF, although the investigators will be using low doses of these substances, which should help to minimise these symptoms (and which can be controlled by taking ibuprofen or paracetamol). IL-2 may also sometimes cause mood changes, including irritability, insomnia, confusion, or depression, and which can continue for several days after they are stopped. Side-effects of rhGH can include headache, muscle pain, joint pain, salt and water retention and rare instances of carpal tunnel syndrome (pain or tingling in the first three or four fingers of the hand).
“We cannot, of course, promise that the study will directly help the participants,” says Prof. Gotch, “but we sincerely hope that the information we get from the trial may help improve treatment for others with HIV in the future. In the absence of an effective preventative vaccine, thousands of people are still becoming infected with HIV every day. It is essential to design novel therapies to enable people living with HIV/AIDS to lead long and productive lives.”
The authors would like to thank Professor Frances Gotch, Dr Nesrina Imami, and Dr Mark Nelson of Chelsea & Westminster Hospital, London, for their contributions to this article.
1. Buchbinder S et al. Healthy long-term positives (HLPs): genetic cofactors for delayed HIV disease progression. Ninth International AIDS Conference, Berlin, abstract WS-BO3-2, 1993.
2. See: www.massgeneral.org/aids/hiv_elite_controllers.asp
3. Molina et al. Interleukin-2 (IL-2) therapy to prevent CD4 T-cell loss and defer HAART in antiretroviral naïve HIV-1 infected patients – Interstart ANRS 119 trial. 17th International AIDS Conference, Mexico City, abstract TUPDA105, 2008.
4. Routy et al. Autologous dendritic cells immunotherapeutic (Arcelis): tolerability and immunogenicity in HIV-1-infected subjects treated with ART. 17th International AIDS Conference, Mexico City, abstract TUPDA101, 2008.
5. Aronson et al. A clinical trial of CD4 zeta gene-modified T cell infusion with and without IL-2 in HIV infected participants. 17th International AIDS Conference, Mexico City, abstract TUPDA104, 2008.
6. Lévy Y et al. Sustained control of viremia following therapeutic immunization in chronically HIV-1-infected individuals. AIDS 20(3), 405-413, 2006.
7. Autran B et al. Greater viral rebound and reduced time to resume antiretroviral therapy after therapeutic vaccination with ALVAC-HIV vaccine (vCP1452). AIDS 22(11):1313-1322. 2008.
8. See: www.advisorybodies.doh.gov.uk/genetics/gtac/
9. Vardas E et al. Safety, immunogenicity and clinical profile evaluation of a GTU -MultiHIV B Clade DNA therapeutic vaccine in treatment-naıve subtype C HIV-1 infected. AIDS Vaccine 2008, Cape Town, abstract P17-03, 2008.
10. Napolitano LA. Growth hormone enhances thymic function in HIV-1–infected adults. J Clin Invest 118(3), March 2008.