An Expert Panel Discusses Immunotherapy and CLL

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Topics include: Treatment

Immunotherapy is personalized therapy for the cancer patient.  But can immunotherapy outsmart CLL?  From one of our CLL Roundtables, Dr. John Gribben, Dr. Constantine Tam and Dr. William Wierda, along with Patient Power Founder Andrew Schorr, discuss immunotherapy advances.  Listen as Dr. Tam reports that he now tells his younger CLL patients, “We may well see the cure in your lifetime.”

Sponsored by the Patient Empowerment Network through educational grants from AbbVie and Genentech.

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Transcript

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 let’s talk about where we’re headed.  You’re gonna do different combinations, and we’ll talk about people being in trials and the benefit to that.  But when you develop cancer, your immune systems let you down.  There’s been a lot of buzz about the immuno-oncology in solid tumors, etc.  Can your immune system be helped, just like a transplant helps it, and kind of a—if you can tolerate that—with these checkpoint inhibitors that we’ve talked about in other illnesses to help fight the cancer? Bill, do you want to comment on that 

Dr. Wierda:          

Sure, and probably John is in a better position to comment on that, because he’s generated a lot of the laboratory studies that have been the basis for what we’re doing now in the clinic.  I, several years ago, was looking at one of these checkpoint inhibitors referred to as CTLA-4, and we found that there was increased levels of CTLA-4 expressed in T cells of patients with CLL.  CTLA-4 is a way that the immune system will down-modulate the activation in T cells.  And so the T cells in patients with CLL have higher levels.  And in the lab we showed that if you block CTLA-4, you could reactivate T cells against patients’ own leukemia cells.

And so for a long time, I have intended to do clinical trials in these antibodies.  The original antibody that was studied clinically was a drug that targeted CTLA-4 called ipilimumab (Yervoy).  It was very difficult for us to get access to that for patients with CLL.

Nevertheless, it went forward, and there’s clinical activity in solid tumors.  We still haven’t been able to test it in patients with CLL.  The toxicity is a little bit high.  It has a high side effect profile.  And there’s another checkpoint molecule that John can discuss I think better than I can in terms of the laboratory investigations, but it’s referred to as PD-1.  It’s over expressed—or there [are] high levels of expression of PD-1 also in T cells of patients with CLL.  And there’s an antibody that targets PD-1 that appears to be a little bit better tolerated than the CTLA-4 antibody.  So we’ve recently opened—and it’s called nivolumab (Opdivo).

And it’s a Bristol Myers Squibb drug that they’ve gained approval in solid tumors.  So we have a trial that just recently opened with nivolumab plus ibrutinib (Imbruvica) for patients with CLL.  I'm optimistic that we’ll not only see activity in terms of treating the CLL but also some evidence of immune reconstitution; fixing the defects that patients have in their immune system that predisposes them to develop infections and, perhaps, second cancers; skin cancers, etc. 

Andrew Schorr:                  

John, let me see if I understand this, and you can add your perspective.  So our immune system let us down, if you will, and we started—the CLL cells proliferated.  So this is the idea that we can help the immune system do the job that it didn’t do that time. 

Dr. Gribben:        

Sure, and it’s a little more complicated than that.  There are some cases where your immune system fails, and you develop cancer.  It looks very much in CLL as if something else happens; you develop CLL.  And CLL is very effective at switching off the immune system to be recognized.  So it’s not like some lymphomas that come from viruses in people whose immune system is suppressed.  We’ve got very clear data that it’s the CLL itself which is very immuno-suppressive. 

Andrew Schorr:                  

It’s like stealth.  It has like a shield. 

Dr. Gribben:        

Confounded by the fact that treatments that we have like fludarabine (Fludara) really, as well as killing off the CLL cell, killed off a lot of the immune system.  So we’ve spent a lot of time trying to understand what was wrong with the immune system in CLL.  We could see clearly by any measurement that you did that T cells and K cells, B cells in individuals with CLL didn’t work very well, as everyone with CLL knows in terms of the risk of increased infections.

We did a lot of work trying to understand at the molecular level why that happened and found out that one of the most important molecules that did this is the PDL-1 molecule that is the one on the CLL cell that sticks onto the PD-1 on the T cell that Bill’s got the clinical trials running on, now.  And so we had very clear evidence in CLL this was an important molecule.  Actually, long before it was being developed in the solid tumors, the issue was of course that the companies were much more interested in developing it for the bigger markets.

But I think we had very, very strong evidence to suggest that this was gonna be a really effective target here in this disease.  And, of course, another huge advantage is the toxicity profile looks pretty low.  So again, another whole arm you could add into the other types of treatments we’ve been talking about.

Dr. Wierda:          

Just to add to what John’s saying, he mentioned PDL-1.  We also have a clinical trial with another monoclonal antibody that’s directed against PDL-1, which is again the molecule…

Andrew Schorr:                  

So PD-1, PDL-1…

Dr. Wierda:          

Right. 

Andrew Schorr:                  

Okay. 

Dr. Wierda:          

But the PDL-1 is on the CLL cells, and that’s how they suppress the T cells.

Andrew Schorr:                  

But all the ideas to help the immune system do its job and help the CLL cell be recognized. 

Dr. Gribben:        

What you’d really hope is that, as Con was mentioning earlier, if you’ve got a cell that’s in there becoming resistant to BTK inhibition, what you're really hoping at the same time is we can use someone's own immune system as it recovers to go in and attack those cells.  So you’re looking to attack those cells from every direction.

And really what we want to get to—don’t get me wrong; it’s a great advance.  We’ve got agents like ibrutinib and ABT-199 that you could go onto and take for the rest of your life.  But I think what all of us are looking for is you get rid of the last cell, and you stop the last treatment, and you’re off it, and we’ve really cured the disease.  And at the speed with which things have been changing in this disease, I'm really optimistic that we will get there.

Andrew Schorr:                  

Really?  So the C word could be cure? 

Dr. Wierda:          

Soon. 

Dr. Gribben:        

Soon, yeah.

Andrew Schorr:                  

Really? 

Dr. Tam:                 

Yes, absolutely.

Andrew Schorr:                  

So you hear that, folks?  We’re talking about cure with this different science coming together with more power; power to outsmart the CLL cell, which has been…

Dr. Gribben:        

Pretty smart.

Andrew Schorr:                  

...pretty smart.  Widely.  Okay.  So that means, then, can we hope that even if we’re taking powerful medicines now, and they’re working pretty well. They’re not without side effects. There’s no free lunch with powerful medicines.  But many people do pretty well, or there’s another medicine they can switch to, now, that may not have the same side effect profile.  But we all hope we can be without medicine and go on with our life.

So are you saying—when you see patients, can you say I'm working in the lab, and I'm also seeing patients, I can see that day coming?  You can? 

Dr. Tam:                 

Yes, I do.  I think from our younger patients, what I tell them is you have a disease that we conventionally think it’s incurable.  We’ve got very good treatment for it, but we conventionally think it’s incurable.  But the rate at which things are moving, we may well be seeing the cure in your lifetime. 

Andrew Schorr:                  

Yeah, you’d be out of business, Con.  You’re going to have to go and do something else.

Dr. Tam:                 

I can always sell gelatti or something else. 

Andrew Schorr:                  

Okay.  So let’s talk about one other area that there’s been buzz about.  And that is these CAR T cells, okay?  Let me ask you first, Bill.  So the idea was could you make a medicine that, again, working on the immune system, had been expensive to make?  There’s been some talk could there be sort of an off-the-shelf approach where you add something from the patient, but you have kind of a foundation, and it’s cheaper.

Where are we with that?  Is that still out there 

Dr. Wierda:          

It’s still out there for a couple of reasons.  So for sure there’s activity in using the CAR T cells directed against CD-19 to treat patients with CLL.  There [have] been reports.  The U-Penn group has reported excellent outcomes and long-term remissions for patients who’ve received the—patients with CLL who have received CAR T.  There’s toxicity associated with it, and it’s not insignificant toxicity.  So nearly a quarter of the patients end up needing intensive care unit level care during their initial portion of treatment.

For patients who are on ibrutinib or have all these oral options, and they’re working and doing relatively well, that’s a hard pill to swallow.  So it’s gonna be initially a treatment that we talk about with patients with very high-risk disease that we’re very worried about or who may be failing and becoming resistant to these newer, more effective agents.

There’s been a lot of resources that have been directed at developing the CAR Ts.  There are pharmaceutical companies that are involved now.  It’s very expensive.  It’s a whole new treatment.  There isn’t really anything that’s like it other than transplant.  And so it requires a lot of reagents that are new and different.  It’s a personalized therapy.  There are production facilities that they’ve had to develop just to do the clinical trials.

And so that’s been a slow process, because it’s completely new. It’s a completely new strategy.  And a lot of the infrastructure that’s been built has been built just to initiate the clinical trials.  And the initial clinical trials have been written to treat ALL, which is a very aggressive type of leukemia.  ALL and diffuse large B cell lymphoma.  So these trials are now opening.

We’ll be treating those patients with CAR Ts initially with DLBCL or ALL.  I think we’ll learn a lot during that experience.  It’ll become safer; we’ll know how to better do it.  And then the time will come for CLL, and we’ll have that.  It’s gonna be a year or two off, I think, before there’s a significant number of trials that open for patients.

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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Page last updated on March 22, 2016