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Emerging Immunotherapy Options for CLL

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Published on February 26, 2016

With all the emerging immunotherapy options for CLL patients, it is difficult to know and understand what they do and how they work.  CLL experts Dr. Zeev Estrov, Dr. Michael Keating and Dr. Nicole Lamanna discuss the strategies of various checkpoint inhibitors and CAR-T cell therapies and how they work in a balancing act between both suppressing and stimulating your immune system. 

Provided by CLL Global Research Foundation, which received support from AbbVie Inc., Genentech Inc., Gilead Sciences, Janssen Pharmaceuticals, Inc., Pharmacyclics, Inc. and Teva Pharmaceuticals.



CLL Global Research Foundation

Transcript | Emerging Immunotherapy Options for CLL

Please remember the opinions expressed on Patient Power are not necessarily the views of our sponsors, contributors, partners or Patient Power. Our discussions are not a substitute for seeking medical advice or care from your own doctor. That’s how you’ll get care that’s most appropriate for you. 

Andrew Schorr:  

So in development, so Dr. Estrov, do you want to talk about any of this; what’s in development now? 

Dr. Estrov:            

Clearly the immune system can control the disease since a part of the immune system can kill CLL cells.  So how can we put the immune system to work?  One of the drugs that is out there and is not approved yet is lenalidomide (Revlimid). 

Andrew Schorr:                  

It’s used in multiple myeloma, another cancer. 

Dr. Estrov:            

Lenalidomide is a drug that’s used profoundly in multiple myeloma; almost every multiple myeloma patient receives it as part of his therapy at one point or another.  But it has activity in CLL.

And there are patients with CLL that respond to it.  Although they don’t go into remission; even when you stop the drug, still the response can last for several years.  Why?  Because it modifies the immune system, the other modifiers of the immune system, and there are two categories or classes.  One is checkpoint inhibitors.  What is a checkpoint inhibitor?

So there are immune cells that are called T lymphocytes.  A subset of T lymphocytes called CD8 cells can attack and kill CLL cells.  But they fail to do it at one point in time for two reasons.  One is that they don’t attach very well to the CLL cells.  And number two is that over time, they get overworked; they get fatigued and they express all kinds of proteins that we find in fatigued cells.  In other words, they run out of gas.  So how can we fix it?  How do neoplastic cells protect themselves from these CD8 cells?  They produce, on the surface, proteins that prevent the interaction between the T lymphocytes and the CLL cells, the cancer cells.

And when we attack these protective proteins with antibodies, suddenly the T lymphocytes can do their job.  This is called checkpoint inhibitors, and there are several of them.  They are effective in other cancers like metastatic melanoma, to which effective treatments were not available and these patients are doing now much better; at least 20 percent of them.

Andrew Schorr:                  

Lung cancer, as well.

Dr. Estrov:            

Lung cancer is one of them, and in other neoplasms we see it, as well.  We have now clinical trials in patients with CLL.  Another strategy is to generate cells in the laboratory that are called cells that have chimeric antigen receptors.

So they express in a way antibodies that can identify the CLL cells and they are inherently T lymphocytes so they can kill the CLL cells.  This strategy was discovered many years ago by a scientist in the Weizmann Institute in Israel, named Zelig Getrall.  And in recent years it started to be introduced into clinical trial and given to patients with all kinds of neoplasms, including CLL.

Andrew Schorr:                  

Let me just mention, some people saw—there was a big front page article in the New York Times a few years ago where some people were near death with CLL.  And this strategy was used to basically make a drug for them, a customized drug in the lab and then re-injected.  And they survived.  Most of them survived.  And some of them had remarkable turnaround.

Now, with these checkpoint inhibitors, I can tell you there are people that I've met who are near death in lung cancer and melanoma.  And one lady I met, incredibly now is playing golf three days a week, when she was near death.  So the question is, does this supply to a blood cancer, CLL, and the CAR-T cell area has been very expensive to produce.  How do they do it?  And then if they can figure out how to do it, in not a super customized way but a way, still, that’s right for you. Who needs it, and how do they also manage the immune system so that it doesn’t overreact?  Because you’re turning up the immune system, turning up the blast but not too much, right? 

Dr. Keating:         

The whole concept is how can you get the immune T lymphocytes to have an effective intercourse relationship with a malignant cell.  So you have to actually get it in close proximity, get the right adhesion.  The way that T cells kill of foreign cells—and their job is not just to kill off cancer cells.  But, for example, the rejection of a kidney transplant is you put in a foreign kidney, and the T cells go and they say: hey, this is not my kidney, so my job is to get rid of it.  So they stick to it, and they squirt enzymes into the kidney cell and blow it apart.

So you have to suppress that immune system for the kidney to survive.  Over years, the CLL cells are foreign, and they’ve been attacked by the T cells, as Dr. Estrov said.  A number of the malignant cells keep on getting killed.  But the survivors are playing tricks as to how to obey that mechanism.  And it’s like the T cells send out these little tentacles, and the surviving CLL cells send out neutralizing chemicals. So they get all tangled up.  So the T cell can’t move around and do its thing.  So you're in the chapel of academia at MD Anderson.

There’s a guy here, Jim Ellison, who is going to win the Nobel Prize probably in the next two years, because he developed the first checkpoint in ibida.  And this led from malignant melanoma with zero percent five-year survivors up to 20 percent.  Then you add this other one, nivolumab (Opdivo) and it gets up to about 40 percent in the lung cancer.  But we weren’t allowed to work in the leukemias, because the companies that make it didn’t have very much experience in leukemias, and they were a little bit scared it would mess up their drug development.  So he developed an antibody that would attach to these cells and open them up.

So the T cell had room to move.  And now there are a whole bunch of “me, too” type things that are looking at both sides of how you can neutralize what’s happening in the cancer cell and what’s happening in the immune cell.  And it’s a much easier thing to do than doing the CAR-T cells, because we’re using your own cells.  The drug is already there, so you don’t have to go to the lab and expand everything up, etc.  So it’s an off-the-shelf type approach that is heavily into treatment at the present time.

Dr. Lamanna:      

I just want to say one thing.  But you could see how therapies evolve.  So when folks like Dr. Keating and then us younger folks joined in, essentially we thought that just attacking the B cells was enough.  But that clearly wasn’t enough, right?  So we were harming good cells, and we were trying to kill off these malignant B cells. And you can see that there are so many other cells, as he alluded to as well; all these other immunomodulatory cells, T cells and regulatory cells; there’s so much that impacts the survival of the CLL cells.  It is not just the CLL.

And that’s why you could see these evolving trends over time of looking at different strategies to help kill obviously the cancer cells but also some of the supporting cells that may contribute to why we haven’t been successful in eradicating this fully.

And so it’s a lot more complicated but very important as we delve into new therapies.  And as they both alluded to, it’s a fine balancing act.  Because now we’re stimulating the immune system, we’re suppressing the immune system, and it may cause other complications.  And so we’re all going to have to, as we move forward in this new area, we’re going to have to balance all these things together.  Fair? 

Dr. Keating:         


Please remember the opinions expressed on Patient Power are not necessarily the views of our sponsors, contributors, partners or Patient Power. Our discussions are not a substitute for seeking medical advice or care from your own doctor. That’s how you’ll get care that’s most appropriate for you. 

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