Innovative HIV Gene Therapy Study Soon to Start Enrollment
January 17, 2013
Calimmune, a small biotechnology company, has been given the go-ahead by the U.S. Food and Drug Administration to start enrolling HIV-infected people in a first-of-its-kind gene therapy study that will modify two HIV attachment sites in CD4+ cells.
This early phase study will be looking at whether an experimental gene transfer, called LVsh5/C46 (also known as Cal-1), is safe and if it can protect the immune system from the effects of HIV without the use of antiretroviral drugs.
Cal-1 is an experimental gene transfer agent designed to inhibit HIV infection through two active parts:
- Removing a protein called CCR5 from bone marrow and white blood cells;
- Producing a protein called C46 on bone marrow and white blood cells.
CCR5 receptors, and those involved in virus-cell fusion (ruled by C46), are among the different receptors that HIV uses to infect cells. Modifying stem cells that have mutations to multiple sites has never been studied in people living with HIV. Single-receptor gene modification studies have been done recently with promising data (see "Other Players" below).
Participants in one arm of the study will only get modified stem cells, and the other two will get a single or double dose of the chemotherapy agent (busulfan) before the stem cell infusion. Cancer study data show that providing "conditioning" with a chemotherapy agent before a stem cell transplant may improve the body's "uptake" of the new cells that can then reproduce in the body.
The study is enrolling only for HIV-infected people who have an R5-tropic virus [a strain of HIV that enters and infects CD4+ cells by binding to the CCR5 receptor on the cell's membrane], as well as detectable levels of the virus, and have not taken HIV medications due to their own choice (side effects and other reasons) for at least six weeks. A CD4+ count over 500 is required. So, essentially, only "healthy" HIV-infected people are allowed.
[SIDE NOTE: In my opinion, heavily pretreated patients with multidrug resistance and non-R5-tropic virus are slowly getting left behind in HIV cure research studies like this one. Even though these patients have typically been the cornerstone of HIV drug approval and may be exposed to a better risk-to-benefit ratio, healthier patients can probably better respond to these early cure studies. Hopefully, we will see study teams in the future that will encourage advanced patient participation in future studies, although I doubt this will happen without community activism.]
Like any innovative trial, this study raised a lot of questions:
- Will this approach be safe? This study will use a lentivirus vector that has been shown to be safe in earlier studies, but data in HIV-infected patients is limited.
- Will these modified stem cells survive in the presence of HIV? It is not clear what level of engrafted genetically modified cells will be in the bone marrow without prior complete myeloablation [depletion of bone marrow prior to transplant], and what percentage of these cells in peripheral blood would be required for clinical benefit in HIV patients.
- Will the modified cells decrease HIV viral load?
- Will they populate different HIV reservoir compartments?
- Will they improve immune function and status?
- How many of these cells will be needed in the body for greatest efficacy?
- Even if these cells show some clinical benefit, will it remain so for the long term? Will they decline over time, allowing viral rebound?
We all know of Timothy Brown, the "Berlin Patient," who has been cured of HIV after high-dose conditioning and infusion of bone marrow from a donor born with double CCR5 mutations in his cells. However, it is still not clear that Timothy's apparent cure resulted solely from HIV-resistant cell transplant. His standard conditioning protocol used for his lymphoma, containing chemotherapy, immunosuppressants and other drugs could have had an additive effect, especially on HIV reservoirs, before the CCR5-mutated donor immune cells populated his body.
Luckily, some more questions will be answered when study results are made public about other patients who have been exposed to procedures similar to Timothy's. These proof-of-concept studies in patients with malignancies pave the way for other studies that use simpler and less risky approaches in HIV-infected patients who may be doing well on HIV treatment.
The answer to a more practical and potentially safer cure approach would require determining what degree of "conditioning" and modified cell uptake/persistence are required to have complete eradication or control of HIV.
As mentioned before, use of genetic engineering in the search for a cure for HIV has already had a head start. Another small biotech company, Sangamo Biosciences, has already done encouraging studies modifying CD4+ cells and infusing them in HIV-infected people. Sangamo has used zinc finger technology to modify CD4+ cells so that they contain an induced mutation of the CCR5 gene. In patients with undetectable HIV viral loads who remain on treatment, there has been a promising 7% uptake of those modified cells into the patient's immune system and gut mucosa. Some had normalization of their CD4+/CD8+ ratios, a measure of immune competence.
However, patients who stopped HIV medications in another sub-study using the same approach lost their gained modified cells with time and had viral rebound. Due to the length of the treatment interruption, we did not learn if such rebound reached a viral load set point lower than what patients had before starting HIV medications. Only one patient's immune system seemed to later control HIV. That patient was found to have been born with one mutation in his CCR5 receptor. Sangamo is now doing a study looking at this minority of people.
These are exciting times that present a lot of hope; but we should also be careful about false hope that may induce some people to join these studies that may offer more risks than benefits. I advise all potential participants to be informed and make educated decisions before enrolling in any clinical study. I am involved in a group of activists whose goal is to inform the community about studies so that they can make educated decisions about enrollment.
I am excited to see so many meetings where people are sharing ideas and data to work on the cure together!
The cure for HIV depends on patient altruism, community advocacy involvement, sufficient funding, and collaboration among groups racing toward being the first to get to the cure.
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Comment by: tg green
Sat., Feb. 16, 2013 at 6:21 pm EST
why not just make these stories private since it seems most therapies are held for people that are friends with someone on the study maybe they have favoritism in who is chosen for these studies it seems?
Comment by: paps
Thu., Feb. 7, 2013 at 2:29 pm EST
this is great news to me. how can we in zambia join the eperimental group?
Comment by: Charles
Fri., Feb. 1, 2013 at 6:57 am EST
More great news from the scientists. Thank you, Nelson. I hope the scientists pursue these trials with haste, and care. People like me are suffering seriously from the side-effects of certain ARVs.
Comment by: Mico
Thu., Jan. 31, 2013 at 5:40 pm EST
Sadly, if one is co-infected, as I am, with HepB, all under control, along with hiv, I am disqualified from the study.
Comment by: ron reddy
(Wailuku, Hi. 96793)
Mon., Jan. 28, 2013 at 2:46 pm EST
Is there a local place to get this work?
Comment by: BRIAN P.
Fri., Jan. 25, 2013 at 3:29 pm EST
HOW DO I SIGN UP TO PARTICIPATE IN THIS STUDY?
Comment by: Zac Morris
Fri., Jan. 18, 2013 at 4:59 pm EST
Very pleased to see many of the "details" that I feel are left out of the "Study Record Detail" (because they are assumed?).
One thing that I would bring a bit more attention to, so that readers fully understand, is that your usage of "conditioning" is a bit euphemistic in that the function of the "chemotherapy agent" [Busulfan, in two arms of this study] is to intentionally kill healthy bone marrow cells.
So correct me if I'm wrong but the process looks something like this:
Participants will first be connected to a machine for approximately two hours wherein their blood (through two separate IV sites) will go through a process of Apheresis to separate out a large enough sample of white blood cells (returning the rest of the cells to the body). Those white blood cells will then undergo in virtro introduction of a carrier lentivirus [which "base" virus being used is not mentioned] that has been genetically modified itself to integrate its RNA2DNA into the infected CD4 cell's DNA.
Two arms of the study will then receive different strengths of Busulfan that will cause apoptosis (cell death) of their healthy bone marrow [estimated kill rate not mentioned in the study notes].
Then the sample of white blood cells that were taken earlier, that have undergone genome modification, will then be reintroduced to the person they were taken from (thus minimizing any chance of rejection).
In those people that were given Busulfan, the hope is that through natural processes the body will trigger [re]integration of those blood cells back into stem cells, that thus contain the mutation that will be passed into subsequent differentiated progeny cells?
I specifically ask about the lentivirus being used because I'm curious if Integrase inhibitors might have any impact on the effectiveness of introducing the desired genome change, and thus on the "strength" of thefinal product, or is the - not taking meds six weeks prior starting the study - supposed to negate that?
Comment by: Rob P
Thu., Jan. 17, 2013 at 5:07 pm EST
Thankyou. This is the best article written on the state of play for an HIV cure using gene therapy I've seen. Finally someone's captured and compared the Sangamo Zinc Finger trial and the lentivirus delivered RNAi approach being used by Calimmune.
Encouragingly Calimmune's study is already 'next generation' in this viral delivered RNAi approach.
City of Hope has completed a pilot safety study, and have just finished enrollment as of December for a pilot safety and efficacy study using much higher modified cell transfection.
For the initial safety study, one patients engraftment lasted out over 3 years and last advice was this patient had 6x the number of modified immune cells that were initially transfected.
The lead investigator for the City of Hope work, John Rossi, is also on the scientific advisory board for Calimmune. So Calimmune's efforts won't be starting from scratch.
One of the CoH investigators said it was their goal to be able to one day use a partial bone marrow ablation (conditioning) in a day procedure. That's obviously a long way down the road and will depend greatly, as you point out, on how many cells get uptaken.
Here's a link to the City of Hope pr on the initial safety trial.
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