Diffuse Large B Cell Lymphoma (knowing your ABC's and GCB's)

Growing up, I religiously read the comic strip, “The Far Side.”  In one strip I remember clearly, there was a woman reading her veterinary medicine textbook.  In chapter 9 she came to equine medicine where the remedy for just about anything that bothered a horse was exactly the same.  The captions said, “Like most students, Doreen breezed through equine medicine.”  I’ve posted a link here for a quick laugh.  Sometimes treating patients with diffuse large b cell lymphoma (DLBCL) can feel the same  - R-CHOP for all (here is a description of R-CHOP and my personal approach to DLBCL).  

If you look at the most recent update of the world health organization classification of blood cancers, they identify thirteen different types of “aggressive lymphoma.”  Most patients are familiar with the most common subtype lovingly called DLBCL-NOS (not otherwise specified).  The “plain vanilla” DLBCL proves to be far and away the most common version of the disease.

Despite being lumped together as a single entity, if you pop the hood and look deeper inside DLBCL-NOS, there is a lot of biologic heterogeneity – those differences are starting to look more and more important.  A number of years ago, one of my colleagues (who I still insist is the smartest guy I’ve ever met – Ash Alizadeh at Stanford) took advantage of a brand new technology called “Gene Expression Profiling” to look at a bunch of DLBCL samples and got his findings published in the journal Nature.  Other labs (Lou Staudt at NIH and Margaret Shipp at Dana Farber) had similar findings – it is pretty robust.  This allowed scientists to take cancer samples and test them to see which genes were turned on and turned off (a term we call “expression”) and evaluate tens of thousands of genes at a time.

What they all found was that there were two “main” subtypes of DLBCL-NOS.  Those two subtypes were the “Germinal Center DLBCL” and the “Activated B Cell DLBCL” (GCB and ABC subtypes respectively).  Purists who know the science well could fault me for not being completely precise here, but that will do for now.  When normal B cells undergo proliferation in response to discovering the “germ” they were destined for all their life, they do so in a specialized region of the lymph node called the “germinal center.”  GCB-DLBCL-NOS appears to have similar genes turned on and turned off (ie expressed) whereas ABC-DLBCL-NOS looks like a cell that has left the germinal center in an “activated” state.”

Why does this matter?  It turns out that these biologic differences have significant clinical impact.  If you segregate ABC from GCB DLBCL, the ABC do quite a bit worse than the GCB in terms of overall survival and response to R-CHOP chemotherapy. 

Since there is such a big clinical impact, you would think we would all know if our DLBCL patients were ABC or GCB subtype – but we don’t!  It turns out that gene expression profiling (GEP) is pretty expensive and it has to be done on biopsies handled a certain way that most surgeons / pathologists don’t do.  Instead of GEP testing, pathologists figured out how to make the determination of ABC vs. GCB using tests that are a lot cheaper and easier to use – called “immuno-histo-chemistry” (or IHC).  Any pathologist who looks at cancer specimens knows how to do IHC.  You essentially take a small slice of the tumor / lymph node / marrow / etc., stain it with an antibody of interest, and use a marker on the antibody to help you know if it stuck after you washed the heck out of it.  ABC has different IHC staining than GCB DLBCL when you look at markers like CD10, BCL-6, MUM-1, and so forth – so just about any lab can do this testing – but they don’t always do it!  There are two main reasons why many don’t.  First, the test isn’t nearly as reliable as GEP testing.  In fact, there are several different antibody combinations that can help make the IHC distinction, but get a bunch of pathologists together and they will only agree about 70% of the time when they do the stains themselves.  The second reason is when I come back to the far side comic strip.  At least for now, you pretty much have the same R-CHOP no matter what the test shows – but that is starting to change.

For patients interested in a purely “prognostic” test, I suggest getting this one done.  It distills all of the gene expression profiling down to two genes and can be ordered easily today.

Since fewer than half of ABC DLBCL patients are likely to be cured with their R-CHOP chemotherapy, lots of pharmaceutical companies are interested in building a better version of R-CHOP.  Quite a few drugs have been explored in DLBCL in the last few years that seem to have preferential benefit in the ABC subtype of DLBCL.  Ibrutinib yields a 40% response rate as a single agent in relapsed ABC-DLBCL but only a 5% response rate in GCB subtype.  For Celgene’s lenalidomide, it is more like 50% versus 5%.  Millennium’s bortezomib can be added to R-CHOP and when you look at the patients with ABC vs GCB, they do almost identically suggesting that the drug overcomes the negative impact of the ABC subtype of the disease.  Indeed, adding ibrutinib to R-CHOP gives a 100% response rate in preliminary studies, and adding lenalidomide to R-CHOP makes the ABC look ever so slightly better than the GCB subtype.  Not surprisingly there is intense interest in ongoing phase III studies that restrict enrollment to patients with ABC subtype DLBCL to see if any of these three drugs can be added to standard R-CHOP.

My prediction?  I bet several of these end up crossing the finish line and getting approved by the FDA (disclaimer: I am not currently involved in ANY of these studies and have not seen any preliminary data).  So what happens if two or three such drugs actually get approved – how would a doc and patient choose which combo to take?  Now we go back deeper into the biology.

If we look at gene expression profiling or use immunohistochemistry staining to categorize DLBCL-NOS into ABC or GCB we are really only using surrogates for a more fundamental process – what mutations have occurred at the DNA level.  Several publications have recently come out where the entire genome of DLBCL has been “sequenced” and when you look at the data, you realize there are a handful of mutations that seem to recur.  Those mutations often determine which genes are expressed, and how the cell looks under the microscope when you use IHC.  In essence GEP and IHC are merely proxies for the underlying mutations.

Here is where it gets really interesting and makes a lot of sense.  The ABC subtype of DLBCL appears to have “chronic active signaling” through the B-Cell receptor (BCR).  This has some similarities to what we have seen in CLL through different mechanisms.  If you look at the BCR signaling pathway (think of an electrical circuit), you can create a “short circuit” at any number of steps along the way, yet the result seems to be a light that either won’t turn on or off appropriately.  In this case, that is a protein called NF-kB which regulates the expression of a bunch of important B cell genes.

If that short circuit is really high up in the pathway (CD79 stuck in the “on” position) or low in the pathway (CARD-11 mutation) you get the same activation of NF-kB, but turning it off at different places may make a difference.  BTK is a protein that lies just “downstream” of CD79 in the BCR signaling pathway and lies “upstream” of CARD-11.  It is also the target for ibrutinib.  You can have ABC-DLBCL where there is a mutation in EITHER CD79 or CARD11.  Interestingly, very preliminary work makes it look like ibrutinib works well when there is a CD79 mutation but it isn't clear yet how well it works when  there is a CARD-11 mutation.  This makes a lot of sense.  To get to NF-kB, BCR signaling from abnormal CD79 has to go through BTK but BCR signaling that starts from abnormal CARD-11 does not.  That would perfectly explain why ibrutinib might work in one case but not the other (if larger numbers of patients make that theory hold up).

A similar but different story may be developing for lenalidomide where either MYD88 mutations or others may explain when that drug works or doesn’t.

So my challenge to my pharma colleagues is the following: figure out which mutations confer activity for your drug (as some are trying to do right now) so that the docs know what to do once your drug is approved.  Molecular diagnostic tests are now available that enable you to test for each of these mutations all at once.  This should be in their interest anyway because the FDA loves "companion diagnostics" for selecting individuals for therapy.  I predict that in the future, DLBCL management will go like this:

Patient walks in with new diagnosis of DLBCL

Since therapy is often needed very quickly, the patient will get their first cycle of R-CHOP

While the three weeks between cycles has passes, the patient will have their cancer sent for analysis and they will find out what unique mutations they have

The patient will come back for the second dose of therapy and an appropriate targeted drug will be added based upon the mutation analysis

In some cases no “pathway specific” mutation will be found.  In these cases, there are other drugs working through the system that may be added like the antibody drug conjugates (see here and here).  Pharma companies developing such drugs would be wise to know where their drug works even if it is felt not to be mutation specific so that they can pick up the pieces for the patients who don’t get ibrutinib, lenalidomide, bortezomib or others.

R-CHOP has served us well for quite a few years.  We are spoiled in NHL management that we get to cure a lot of our patients.  It is really fun as a doc to have a patient walk in doing great with their cancer a fading memory.  Unfortunately “a lot”doesn’t feel that great if you are not one of the ones who is cured.  I think we are getting really close to making some important steps forward in the management of DLBCL-NOS and it will be driven by molecular information that leads to targeted therapies that are specific to the patient.

Thanks for reading!

Jeff

Engineered T Cells

Engineered T cells are an exciting new development for patients with B cell cancers.  This will take a while to become "prime time."  Once some huge logistic details are worked out - this could potentially apply to most types of lymphoma and CLL.

The science is early but encouraging.  I've written an analysis of the technology previously (how it works / dangers / etc) but came upon this video at a Lymphoma and Leukemia Society volunteers event.

If this doesn't get you excited and bring a tear to your eye at the same time - check your pulse.    I've watched it four times and welled up with a tear every time.  It is less than four minutes - I highly encourage you to watch it!



Fire With Fire | Ross Kauffman from Focus Forward Films on Vimeo.

Cure for CLL & NHL?.... or just better control?

Newsflash: Magic Johnson has HIV!

I grew up in Southern California during the Lakers and Celtics rivalry.  At the time, Magic Johnson was a living legend.  The way he elevated the play of all his teammates was truly extraordinary.  So when he announced his diagnosis with HIV the sports world collectively gasped.  My hero had been given a death sentence that we had all seen many times before.  He was certain to die a horrible wasting death.  Purple skin lesions, muscle wasting, and infections would transform the sports legend into a pathetic state and we would see it slowly chronicled by our tabloid press.

Newsflash:  That was 22 years ago and Magic Johnson is doing great.

What changed?  Dedicated scientists learned the biology of HIV, figured out where it was most vulnerable, designed rational, smart, effective, less toxic drugs.  They figured out how to put them together into powerful combinations.  They figured out how to monitor for mutations that conferred resistance, how and when to change therapy.  They figured out how to go from 70 pills per day to two pills per day and patient compliance went up – resistance went down.  Side effects of treatment became much less.  When the global research community galvanizes against a task – huge changes are soon to follow.

The lessons from HIV serve as the foundation for where we are now in CLL and in some types of NHL.  While we may be starting to hit our stride twenty years after HIV, the pace of change has exploded so we will catch up soon – and maybe even do better?  The main question many patients rightfully ask is whether this progress will lead to prolonged disease control or actual cures.  When HIV was changed by the explosion of new drugs 20 years ago, it took a number of years to figure out how to put all the progress together to achieve the prolonged disease control we can observe today (such as Magic Johnson) but patients are still taking their medications and we do not think that a cure has been achieved.  Will the same be true in CLL/NHL? I’m not sure yet….

I had the pleasure of hearing a lecture at ASCO this weekend by Charlie Sawyers.  For individuals like myself who think in bizarre protein names, listening to someone as brilliant as Dr. Sawyers describe the multitude of discoveries his team has been a part of and to put it into one story is beyond compelling.  I need to take a detour into prostate cancer in order to talk about CLL.

After working out a lot of the science of resistance to Gleevec in CML and helping create the “second generation” of CML drugs that are incredibly effective, Dr. Sawyers decided to leave CML, move across the country,and turn his sights on prostate cancer.

Prostate cancer is almost singularly driven by testosterone.  In the past, our management of prostate cancer included removal of the testicles in an effort to deplete the body of testosterone.  That didn’t "sit well" with many men and we were all relieved when scientists figured out how to suppress testicular production of testosterone using injectable hormones to “castrate levels" (medical terminology at its finest).  Unfortunately, the body was still able to produce a trace amount of testosterone from the adrenal glands and the prostate cancer would find a way to survive by either producing its own testosterone or adapting to the very low testosterone environment.  Unfortunately, the cancer would start to grow again and we had to give chemotherapy for “testosterone independent prostate cancer.”

So we got smarter.  Prostate cancer is one of the diseases that have been revolutionized inthe past three years.  We have a ton of new rational drugs and Dr. Sawyers is taking all of us to school by figuring out how prostate cancer is adapting to the new drugs.

Several of the new drugs actually bind directly to the “testosterone receptor” and prevent its function.  These are incredibly potent and focused drugs (think extremely effective antibiotic for strep throat) that interfere with testosterone’s interaction with the prostate cancer cells.  They prolong survival in men whose prostate cancer has figured out how to survive the injectable hormone drugs that reduce the testosterone to “castrate levels.”

One thing both cancer and HIV have taught us is that single drugs do not control the emergence of resistance.  Give a patient with HIV a single drug, and the disease control is fairly brief.  Give a man a single drug for prostate cancer and it too will eventually figure out a way around the drug.  In this case, the prostate cancer can either activate another receptor that acts like a surrogate for the testosterone receptor (the glucocorticoid receptor) or just get a mutation in the testosterone receptor that makes the drug useless or in some evil cases can even make the drug act like it is turning the testosterone back on.  What is cool though is that you can test for that mutation and in some cases it may suggest an alternative drug could work.

This is the same story we saw in chronic myelogenous leukemia.  The BCR-Abl protein causes CML.  Give it Gleevec and some number of cases can become resistant.  Other drugs can sometimes recapture disease control.  Sometimes “compound mutations” can render the second drug ineffective.  Sequential single agent therapy creates sequential mechanisms of resistance.

I recently wrote about ibrutinib resistance in CLL.  I went to the poster session on last Sunday where Joe Buggy presented his team’s findings (shout out to Joe for having had the ride of a lifetime sticking with ibrutinib from the very beginning - couldn't have happened to a nicer guy).  While it is only a few cases right now, there have been at least four cases where the binding site for ibrutinib on the BTK molecule gets altered and the drug stops working.  There was one other case where the mutation was in a different protein but the same chain of enzymes downstream of the B cell receptor.  This highlights a very important theme that cancer can outsmart effective drugs if given the opportunity to do so.  We just need to be smarter and take away that opportunity.

Interestingly those two different types of ibrutinib resistance would be predicted to be sensitive to idelalisib.

In HIV and even some of the lymphomas, combining drugs was key to progress.  Think R-CHOP for DLBCL or FCR in CLL.  What would happen if patients were on BOTH ibrutinib and idelalisib? (this has NEVER been studied and is not recommended outside of a clinical trial!)  Why would a patient develop a BTK mutation if it didn’t let them escape the idelalisib?  I wager that once the tidal wave of coming drugs in CLL gets approved you will see a dramatic increase in the number of studies where targeted biologic drugs are combined.  Indeed, some of those studies are taking shape now (link and link).

While patients are not particularly excited about taking a bunch of pills, I dare say that that is a problem we can only hope to have at this point.  It sure beats taking multiple different chemotherapies with all of the attendant side effects.

Another lesson of HIV was that the more disease that is present, the faster you will see resistance.  If you have a trillion little viruses all working out their mutations, one is more likely to get it right than if you only have ten thousand viruses.  We see this in CML too.  CML is “staged” differently than the normal stage I-IV.  In CML someone with very advanced disease may have what is called “accelerated phase” or even “blast crisis.”  Gleevec doesn’t really work so well there.  If you get disease control, it is often brief.  With a ton of cancer cells, they will find a way around any selective pressure.  On the other hand, if you get to a level where we cannot detect your CML, chances are you are set for life provided you stay on your drug (although trials are starting to show that SOME patients may be able to stop therapy).

I think we will see the same thing with CLL – and it makes me wonder how long it will take before we revisit the appropriate timing oftreatment in the disease.  Nobody does watch and wait in CML.  For the time being though, the reasons for starting therapy are pretty well set.  Provided those conditions are met, we would be wise to figure out combinations that get rid of as much CLL as quickly as possible. 

By now, most patients are aware that in CLL, taking ibrutinib or idelalisib causes the white blood cells to go up and then slowly drift back down.  Meanwhile the lymph nodes rapidly shrink and stay down.  This is because the cells are merely getting shuffled around from a place where they are happy (lymph nodes and bone marrow) to the blood (where they are unhappy).  Starting these drugs do not really eradicate a ton of cells right away though over time the cancer cells die off (death by neglect – a topic for another time).

We have already seen results where these drugs are combined with rituximab, ofatumumab, or several chemotherapy regimens.  I am very optimistic about what we are seeing in these studies.  I’ve had patients ask me though why we need to add the chemo on top of the non chemo drugs.  For some, it probably feels like as doctors we can’t give up a bad habit.  I might take the opposite angle and speculate that by removing a bunch of cancer cells we may allow the ibrutinib or idelalisib to be exposed to fewer CLL cells seeking to become resistant.

Most patients I’ve talked to are hoping that we will be able to combine these drugs with other “targeted” agents instead of chemo.  For a variety of reasons, that is unlikely until some of the drugs get approved by the FDA – but it isn’t that far away. 

Some of the new drugs work extremely quickly.  In the long run, we will figure out how to do these combinations but we must be extremely careful.  Sometimes when you put drugs together you get unexpected side effects – we have seen that quite a few times in recent clinical trials – even with “targeted agents.” 

Another lesson from HIV is that no patient can take 70 pills per day – even when they are purposefully trying to be good patients and take all of their drugs.  Some have to be taken with food, some have to have an empty stomach.  Some make you tired, and some get you all amped up.  The problem is that treatment adherence drops the more complicated our regimens become.  When adherence drops, resistance emerges.  Patients with HIV can now take a single pill that combines several medications.  One in the morning and one at night is all some patients require (Thank Gilead for that!). 

Sometimes adherence is not about swallowing all of your pills at the right time, sometimes it is about not being able to afford the medications.  I’ve recently written on this topic and heard insightful analysis of how much the health system can afford these drugs.  It is bad enough when they are given individually but few have begun to even consider the cost of putting them all together.  If each one is 100k / year and a patient is taking two or three at a time – yikes.

In CLL there are two VITAL pathways – those are the B cell receptor pathway (with several key targets including Syk, BTK, and PI3K) and the BCL-2 cell survival protein.  I’ve written much more about the former than the later but both can now be targeted with incredibly potent research drugs.  Furthermore we have figured out how to recruit the immune system through very effective antibodies (rituximab, ofatumumab, obinituzumab) as well as several others working through the system.  There is also lenalidomide which can “re-boot” the immune system to target CLL (not approved for that purpose but being actively studied).  We have four totally different ways to hit key aspects of CLL cell survival – that can be independently targeted – without ANY chemotherapy.

Dr. Sawyers challenged the cancer research community with several lessons in his lecture 1) sequential monotherapy generates sequential mechanisms of resistance 2) combination therapies reduce risk of resistance by eliminating the total amount of disease faster so that fewer cells or viruses can experiment to find escape mechanisms AND making it harder for a single mutation to escape multiple drugs given at the same time 3) regimens do not work if the patient does not take them.

In the past, when you have been able to combine several effective treatments at the same time, that has been when you started to see cures – will we get there in CLL?  It will take a handful of years to figure out the safest, most effective way to put these together but there is more reason for optimism than ever before.

In CML a small number of highly selected patients have been able to stop their medications (under extremely controlled clinical trial conditions) and their disease has not come back after a few years of observation.  The longer they go that way, the more everyone is starting to believe they have been cured.  I believe some of our new CLL drugs are in the same league as gleevec but instead of only one target we have many (syk, btk, pi3k, CD20, CD37, BCL-2, cereblon).  So will we have a cure or prolonged control?  Let’s just say, I’m glad I know how to treat a bunch of different types of cancer…  I would hate to be out of a job.

Thanks for reading,

Jeff

Personalized Medicine - turning drug development upside down!

American Society of Clinical Oncology is meeting in Chicago this weekend.  That means that you will be hearing about a bunch of important developments in cancer medicine. 

I am very fortunate to serve as the medical director for the US Oncology Hematology Research Committee.  Leading the largest network of community practice based research sites in the world gets me access to senior leadership of many of the major pharma companies.  Spending a day with the decision makers at Novartis, Genentech, Celgene, Janssen, and Gilead makes it pretty clear what will be happening in the next several years for patients with CLL/NHL (see posts about why it takes so long and costs so much).

So what is making me so excited?  I think I can now say that drug development is getting turned upside down.  We are entering a new era where therapies are rationally designed and deployed.  This creates hope for treatments that are far more effective and far less toxic.  That "double benefit" is part of the enthusiasm behind drugs like ibrutinib, idelalisib, and the antibody drug conjugates.

If you are not aware of the book, The Emperor of All Maladies I highly recommend you purchase a copy of it and read it cover to cover.  It was written by one of my classmates from residency and was awarded the Pulitzer Prize.  The book details the history of cancer medicine in a way that keeps you awake and burning through the pages.  I gave a 4 part you tube lecture series that is a broad overview of the book that doesn't do justice to Sid's book, but can hit the highlights pretty quickly.  Furthermore, my version is probably a good antidote to the insomnia you are suffering currently that has you reading my blog in the first place.

One theme that comes out clearly through the book and is forcefully validated in all of my pharma meetings is that the old way of developing drugs is running out of steam and a new era is starting to take shape.

So what is the old way?

In the old way, you might take a "compound library" which was merely an inventory of random chemicals.  Sometimes these came from sources like the pacific yew tree or the indian sea hare (not kidding).  You then grew some cancer cells in a laboratory dish and looked to see if you would wipe them out with your chemical of interest.  If that worked, you gave it to mice.  If the mice died from cancer - you abandoned the effort.  If they died from the horrible toxic brew that you just gave them, that was a bad sign too.  If the mice somehow survived the treatment and you saw ANY improvement in the mouse's survival - you took it to a phase I clinical trial.  In the old model, the likelihood of deriving clinical benefit in a phase I trial was less than 5% and many ethicists debated if such trials were fair to the patient.

Provided you could demonstrate that you could get the drug into patients, you then tested it on just about every type of cancer there was.  If you got lucky, most patients survived the treatment and you saw a few cancers shrink.  If that was "successful," you then did a randomized phase three study in a population of patients with a specific type of disease (perhaps you had seen patients with breast cancer respond in earlier studies).  You crossed your finger that the patients treated with drug x did a little better than patients with drug y.  If that difference was big enough, or you proved it in a large enough sample of patients.... you had a drug.

I am sure I have just thoroughly offended a bunch of medicinal chemists and drug developers with my grossly oversimplified version of the story - but that was the general theme.  There is a reason why people dread cancer so much.  For years, we made a bunch of drugs toxic enough to wipe out the cancer cells but often wiped out the patient in the process.  Provided the patient was able to get through the process, they might have been marginally better off for going through it.... feeling miserable the whole time.

The whole process was very empiric.  It wasn't based so much on good science as much as it was the remarkable strength of so many patients who wanted to live a day longer no matter what the cost.  I call it a "drug led process" meaning we had drugs - we didn't necessarily know why they should work, or who they should work in - but give it to enough people and you could often figure it out.

What is the new model?  I think we are entering a "diagnostic led" era.  Some have called this "precision oncology" others have called it personalized medicine.  What it means is that we are leaving the "drug led" process into a "diagnostic led" period.  We are several years into a remarkable transformation in cancer medicine that is only picking up speed.  We are matching drugs the appropriate mutations and doing a vastly better job helping patients live longer - WHILE FEELING BETTER!

The human genome project has unleashed an unbelievable set of discovery tools in cancer medicine.  This gave way to the cancer genome atlas which has systematically categorized the fundamental causes of a bunch of different cancers.  Now you can go to a single webpage like COSMIC (which stands for catalog of somatic mutations in cancer) and look up a single type of cancer and figure out what the important mutated genes are.

What you find is that there are really only a small handful of really bad mutations that cause a bunch of different types of cancer and the same mutations crop up in a bunch of different diseases.  Mutations in RAS, B-RAF, P53, Notch and others keep popping up just about everywhere you look.  In total there are about 100-150 really important targets (out of a genome of 4 billion base pairs).

If you take a disease like lung cancer - just a few years ago we looked into a microscope and said it was either small cell lung cancer or non-small cell lung cancer.  By the time I was in medical school, it was helpful to figure out if the non-small cell lung cancer was adenocarcinoma (gland like) or squamous cell (like the skin).  By todays standards that would be grossly insufficient in many cases.

Today you have to know their RAS mutation status.  If that is negative, you might like to know if their EGFR is normal or not, their ALK translocation status, and maybe even their ROS status.  If they are EGFR mutated, you need to know where the mutation is because exon 19 mutations might be predict sensitivity to erlotinib but T790M mutation mean erlotinib won't work yet afatinib will. 

This story is evolving right in front of our CLL focused eyes with a new understanding of ibrutinib resistance and a bunch of other unique prognostic markers / mutations.

At the same time a bunch of the new drugs may inhibit several of these important enzymes with a single drug.  Take a drug like gleevec (imatinib).  This drug inhibits the key protein in chronic myelogenous leukemia, but it also inhibits different enzymes that drive the growth of some intestinal cancers, skin cancers, and even rare melanomas.  In fact, the drug is approved in 10 different cancer settings where it is truly revolutionary in most of them.   

So we have two parallel developments going on at the same time.  We can find out what makes a patients cancer actually tick and in many cases we can give a drug unique for their profile.  That is personalized medicine and it is happening now.  Today my organization announced a joint effort with a company called Foundation Medicine to do tumor profiling on thousands of patients in order to get them into appropriate clinical trials.

So why is drug development "upside down?"

The traditional model to get a drug approved was to test it in a bunch of patients with a single disease and hope it worked.  Now we can find patients with specific mutations (regardless of what sort of cancer they actually have), give them specific drugs and the results can be dynamite.... but there is a problem.... a bunch of these mutations are uncommon in a single disease (2-10% of cases) which makes it REALLY HARD to do the sort of clinical trials to prove a point.

Let me give an example.

I was taking care of a patient with multiple myeloma.  He had some of the truly most awful myeloma I've ever seen.  His disease was way off the charts in terms of severity.  He didn't respond to two different types of powerful treatment.  Finally a super potent regimen got him into remission.  He got a stem cell transplant and within two months his disease was exploding once again.  In the process, he fractured several bones, became virtually bedbound and slept 16-18 hours per day. 

I was able to get him tested with one of these fancy diagnostic tests and found he had a specific mutation that is only seen in 2% of all myeloma cases (not going to say which one because the next part of the story gets a little more adventurous than I would typically recommend).  Amazingly there is a drug approved by the FDA for a totally different cancer that targeted his particular mutation.  Even more amazingly, I was able to get his insurance to cover the drug. 

His response was unbelievable.  His blood markers rapidly improved, his transfusion dependence ended, he felt better, he was able to get back to doing home repairs, etc. He survived several extra months, feeling MUCH BETTER (until the cancer came back in his brain where the drug couldn't get to).

So here is the challenge.  An individual patients cancer may have a small and unique number of critical mutations that make the disease grow.  Another patient with the exact same type of disease has a different set of mutations.  Take 100 patients with the same disease and you begin to see patterns to suggest that there may only be 10-20 important mutated genes for a single type of cancer  and 2-4 important ones for a single patient.

The challenge is that they can be in various combinations for different patients - but fortunately a drug from an unrelated type of cancer might work provided the right mutation is there.  Instead of studying a single disease to get a drug approved - we need to study a single mutation in a bunch of different types of cancer.  For a bunch of reasons that is really hard to do but companies like Novartis, Seattle Genetics, and Genentech are starting to figure it out and that makes me really excited.

Now we have tests that can tell us what an individuals profile is and in many cases we have research drugs that might work in their unique profile.  We are no longer in a "drug led" era but we are in a "diagnostics led" era.  We can make a pretty informed decision about what sort of therapy might work in a particular patient - even if we have to borrow a drug from melanoma or kidney cancer to treat a patient with leukemia.

I hope I've made this complicated subject actually make sense.  If I've failed, I encourage you to pick up a copy of "The Emperor of All Maladies" - Sid is far more clear about the subject than I am.

Thanks for reading.
Jeff

Genetically Modified T-Cells for CLL (and evetually NHL)

(Sept update of prior post after I heard Carl June present at German CLL conference last weekend)

Last summer there was quite a splash when researchers at University of Pennsylvania used genetically manipulated T-Cells to fight off CLL.  The studies were simultaneously published here in New England Journal of Medicine and here in Science.  This past weekend, I had the opportunity to hear Carl June update us on the progress of this technology so I wanted to update this post in light of what I learned.

Looks like Novartis is going to purchase the technology and in my mind that is the best possible outcome for making this move more quickly.  While I love the science done in academic settings - those settings are not designed to bring these breakthroughs to patients on a broad scale.  I know many of the folks at Novartis and they are very good at advancing technology quickly.

Genetically Modified T-Cells for CLL - Novartis Acquisition

I've had a lot of patients ask me about these studies so I thought it might be interesting to describe the technology at play.

The "brains" of the immune system is probably the T-Cells with the B-Cells being second in command.  T-Cells help coordinate many aspects of immunity and heavily rely upon their "T-Cell Receptor" (TCR) which is unique to each individual T-Cell to figure out when to engage a target or not.  B-Cells also have a "B-Cell Receptor" aka. antibody / (BCR).

We've gotten pretty good making artificial antibodies and they are a good therapy (rituxan, GA-101, herceptin, ofatumumab, etc).  So far we have no idea how to make a good T-Cell Receptor.  Much to my surprise though, you can take the part of the BCR that hangs out outside of a cell and the part of the TCR - stick them together as a "fusion gene,"  and the thing works as a "chimeric receptor" (I forget the greek story of the half lion, half human - called a chimera - I may also have my story completely wrong but the idea is the same).

Now you can make your artificial B cell receptor - plug it onto a T-Cell receptor and make T-Cells do things you want them to do - like get rid of cancerous B cells (aka CLL/NHL).  There were a number of other key features (costimulatory molecules, lymphoid depletion, etc) but for now it is reasonable to focus on the main technology.

Viola - it works!  The have now treated about 11 patients at Penn.  Most were CLL but a few were Acute Leukemia.  If it works in ALL, that is very interesting.  That disease is extremely aggressive and new therapies are needed there even more than CLL.

But there are potentially problems.
1)  To get this new T-Cell chimeric receptor into the T-Cell, you need to infect the cell with a virus that has some resemblance to HIV.  It is heavily modified, but you can get the picture, there is need for caution.

2) So far, many of the patients who respond favorably to the therapy undergo a very medically frightening reaction when the T cells attack the B cells.  In some cases it has been life threatening and required ICU level support.  As if that is not bad enough, you cannot predict when this will happen.  In some patients it happens a few days later, in others, it may be 3-4 weeks later.

3)  The manufacturing of the genetic modified T cells may be finicky and it is possibly the reason this does not work in all patients - when they try to achieve scale to make this work for lots of patients, this may be a big problem.

4)  If this works, it permanently depletes all health and cancerous B cells.  So much for B cell immunity.  Furthermore, it looks like plasma cells (the professional antibody producing cells) also slowly disappear.  Therefore you may need monthly IVIG shots for the rest of your life.

5)  What happens if the T-Cells and B-Cells fight to a draw?  Do the T-Cells keep proliferating?  What happens then?  Right now there is no "off switch."  You might be able to program in a "suicide gene" but that was not a part of this treatment.  Talking with some folks at the conference, it sounds like that may be a future consideration with these treatments.

6)  Gene therapy periodically causes a whole different kind of cancer - a really nasty one.  Hard to exchange a slow disease for a chance of a  fast one unless that slow one has ran out of other good options.  They are using a "lentivirus" platform instead of a "retrovirus" platform.  They feel this minimizes this problem but I'm not convinced.  Either way, the FDA requires that patients get observed for 15 years since that is the standard for "gene therapy" studies.

7)  Timing - this is not likely to be available for another 5-10 years at best.  In the meantime, new CLL drugs like ABT-199, ibrutinib, CAL-101, GA-101 and so forth are making CLL such a different disease that it may render this approach less interesting.  It could still be extremely valuable in NHL where we need more breakthroughs.

So who will this be appropriate for?

In CLL, I would send someone for this if they required a stem cell transplant.  This may be quite a bit better than getting someone else immune system as it will get rid of the graft vs host disease.  This may be great therapy for the patient with NHL - particularly DLBCL that has relapsed.  Furthermore, it may make some older patients eligible for immune intervention who may otherwise be ineligible for a transplant.  I would NOT think this is a good front line therapy for anyone - not any time soon at least.

Many of these limitations may have answers and I am excited that a company is willing to invest in the idea - it often moves ideas a lot faster than the grant cycles of the universities.  Hopefully this goes someplace exciting but for now it is still a ways off for mainstream CLL treatment.  Huge gratitude to the brave patients who are the first ones on this experimental therapy - they may be paving the way for many others.  Will keep you posted as I hear more....