ASH 2014

Engineering stem cell resistance to HIV for two-pronged approach to HIV-associated lymphoma

Prof Amrita Krishnan - City of Hope National Medical Center, Los Angeles, USA

We know that viruses cause cancer in part by this concept of chronic antigen stimulation on the immune system. We also know that now we can control HIV but we can’t cure HIV with the medicines that we have. We can treat lymphoma in the HIV setting very effectively with autologous transplant but ultimately if you really want to win the game you need to cure the HIV and cure the lymphoma. That’s why we’re using this approach of gene therapy modifying haematopoietic progenitor cells to make them resistant to HIV.

Now we’ve been hearing quite a lot about engineering cells and putting them back into patients to achieve things here at the American Society of Haematology meeting. You’ve been engineering stem cells, what did you do? In what situation, first of all, was this? What clinical situation?

The first situation we did it in was patients who needed a transplant for their HIV lymphoma. We gave them a standard “garden variety autologous transplant regimen” and gave them back regular garden variety stem cells. But in conjunction with that we also gave them back these engineered stem cells that were resistant to the HIV virus and we showed that those stem cells could engraft and that those stem cells could last. We saw those stem cells up to three years after the transplant.

And this is because you can knock out the receptor that deals with HIV?

Those stem cells were engineered, exactly, to be resistant the HIV virus by knocking out CCR5, the receptor for HIV entry into cells as well as targeting two other sites of HIV replication in the cell.

Now, you’ve done this with patients, what did you do?

Exactly that. We gave them high dose chemotherapy, first of all we collected the stem cells and then in the lab we engineered them with a vector to make those cells resistant to the virus. We then gave them high dose chemotherapy, knocked out their bone marrow, re-infused those stem cells after the high dose chemotherapy and then monitored the patients as we do any transplant patient.

This achieved what clinically?

That was called a proof of concept principle, that we could get engineered stem cells to engraft in these patients; we could see those stem cells lasting up to three years later, so durability of these engineered stem cells was also important. But now we’re really ready to move to the next phase.

To begin with, then, you’ve been looking at patients who had lymphoma and also had HIV but now you’ve got something else, what is it?

Exactly. This is what we’re incredibly excited about is ultimately our goal is curing HIV, obviously a big goal. So we wanted to go to target that population of patients who have HIV who are not responding well to anti-retroviral therapy. So they have low CD4 counts, the so-called immune non-responders. We are going to collect their stem cells, engineer them with a targeted way of knocking out CCR5 and then re-infuse those stem cells into patients after chemotherapy.

And how does this fit in with the so-called Berlin case where someone was apparently cured of their HIV?

It really came upon the idea from the Berlin case where that patient received stem cells from a donor who had a genetic mutation that made him CCR5 negative. That mutation is rare, it’s in 1% of Caucasians so the chance of finding that in the general population obviously is rare and that kind of transplant, an allogeneic transplant, is certainly much higher risk than using your own cells. So, again, it was the proof of principle that the Berlin case showed us and now we can move on to try and do that for a wider population and hopefully in a safer manner too.

So in theory you can engineer the cells, get them back in to do exactly as well as the Berlin case?

As well, hopefully even better actually.

So could you pull this together and tell me where are you at this moment and I want to ask, of course, what doctors should read into this?

We have several trials that are on-going right now using different vectors doing this and the trial for just patients with HIV, no lymphoma, is going to open next year. So I would definitely encourage physicians to look for that trial on clinicaltrials.gov and we’re happy to see patients. So we’re looking for basically patients who have HIV infection not responding to the anti-retroviral therapy.

What do you think this means practically both for HIV and for lymphoma therapy, especially in the context of HIV?

If this is something that obviously works and works well, that we’re able to stop anti-retroviral therapy in patients and control HIV long term it’s a tremendous advance. Ultimately lymphoma in the HIV setting is again driven by the virus so if you can cure the virus or treat the virus you’re also going to see a dramatic further improvement in the incidence of patients developing lymphoma.

So the bottom line message for doctors?

That stay tuned, stem cell engineering for HIV has come and hopefully is going to become something widespread use.

And for HIV it means that you will impact the incidence of lymphoma?

Yes, if we can ultimately cure HIV, absolutely.