Taming the Killer

As we have seen in the first and second installment of this series, the single biggest hurdle in the way of improving mini-allo transplants is the dreaded graft-versus-host disease (GVHD). It is always a good idea to understand the nature of the enemy before we explore ways to defeat it.

Below is a quick tutorial on GVHD, followed by breakthrough clinical trial (phase II) results of a cellular approach to defeat GVHD. The results are very encouraging. Since the FDA has given this technology fast-track designation as well as Enhanced Access Process (EAP), and the Phase III trial results are expected in late 2009, I thought it is time for you to hear about this very encouraging new technology.

The New Broom Has to Start Sweeping Right Away

Mini-stem cell transplants depend on the donor’s immune system to take over the job that your own immune system has flunked. As the transplant scenario unfolds, preconditioning has reduced the number of CLL cells to a minimum and made sure there are no T-cells and other killer cells left over from your own immune system to bother the graft coming in to the rescue. Here is a thumbnail sketch of what should happen immediately after you get the graft from your carefully chosen donor:

  • The donor’s stem cells gradually find their way to the recently vacated bone marrow, and once they are comfortably settled in their new home it is hoped they will begin making perfectly good platelets, red blood cells, neutrophils and other cell lines needed for your long and healthy life. This typically takes a little while, sometimes as long as a month, the engraftment period. During this time you may need transfusion support while the new stem cells gear up and get ready to work.
  • During this period, the donor’s T-cells that were infused along with stem cells have several important duties to perform. First, with your own immune system just about wiped out by the pre-transplant conditioning, you are wide open to every bug out there, an easy target with no defenses. This is where the donor T-cells do the heavy lifting. If all goes well, they will do a good job of protecting you against infections. This is called the Graft-versus-Infections effect (GVI).
  • Another vital function of the donor T-cells is to seek out and kill all the remaining CLL cells in your body. Remember, this is a mini-transplant we are talking about. Most patients have at least some traces of CLL left over after the pre-treatment process, and these malignant cells would love nothing better than a chance to grow back up to full fighting levels. Giving them a chance to do that would be the kiss of death, literally. The ability of the donor T-cells to hit the ground running is important, so that they can start hunting and killing the remaining CLL cells almost as soon as they are infused into the patient. This is the critical Graft-versus-Leukemia (GVL) effect. Patients with a strong GVL response are a lot less likely to relapse.
  • This GVL effect is what gives the hope of a full cure and sets apart allogeneic (donor derived) transplants from autologous transplants (stem cells harvested from the patient himself). Another point to remember, large, well-entrenched armies of CLL cells will have a better chance of defeating the efforts of the new immune system to get rid of them. That is why it is important to reduce the ranks of the enemy as much as possible before the transplant.
  • Would your identical twin make a perfectly matched donor for you? Not a good idea, an identical twin is a little too perfectly matched for comfort. Think of it as the consequences of nepotism and you will not be far off the mark. The new graft has to be sufficiently different from the old immune system in order to avoid making all the old mistakes. You don’t want the new immune system getting too cosy with the CLL cells, letting them thrive – the mistake made by your old immune system that allowed the CLL to take hold in the first place.

GVHD: The Pebble in Your Transplant Shoe

Basically, patients go into transplants right after pre-conditioning (usually with our ever popular fludarabine, as well as low dose radiation). Radiation and chemotherapy target rapidly dividing cells, since this is the common profile of cancer cells. However, another set of cells that divide rapidly as normal part of their functioning are skin cells and mucosal cells lining your mouth, stomach and gut and elsewhere. These cells are sloughed off daily as part of normal wear and tear, and must replenish their numbers to keep up with the losses. It is therefore no surprise that your skin and mucosal linings of the mouth, stomach, gut etc often take a beating during chemo and radiation therapy, leading to skin and gut inflammation.

Now the new graft comes in, with its bright eyed and bushy tailed new immune system cells ready and anxious to go to work. All that eager enthusiasm of the new recruits means that when they spot the inflamed areas of the skin, gut etc, they assume the worst, they assume an ongoing infection is causing the inflammation. Donor T-cells and other immune system cells from the graft flood into the area, and the mayhem that ensues can be described as a case of friendly fire gone berserk. In a nutshell, GVHD happens because the new graft cannot yet tell the difference between friend and foe and starts attacking the host – hence the name graft versus host disease. GVHD over-kill makes the initial chemo induced inflammation far worse.

Our skin and lining of the mouth and gut are important barriers that protect our vulnerable insidest from the nasty bugs and pathogens out there in the world. Inflammation often causes breakdown in this important defence barrier, and the problem is made worse by GVHD. The net result is increased risk of dangerous infections. You can see why it is important to bring this spiraling out of control inflammation under control quickly. The standard approach to controlling GVHD is to use immune suppressants (steroids like prednisone, or other immune suppressive drugs such as cyclosporine, tacrolimus etc).

Immune Suppression: a Double-Edged Sword

What is wrong with using massive doses of immune suppressing drugs such as steroids to control GVHD? Well, while your new immune system is taking a little steroid induced nap, thereby weaned away from doing GVHD damage and lulled into complacency by heavy doses of immune suppressive drugs, it is not doing much of anything else either. Like not keeping an eye out for legitimate infections; like not going after the remaining traces of the CLL cells still lurking around; like not doing its job in all the ways an immune system is supposed to do.

You get the picture. Put the brakes on too hard to control GVHD, you can also say bye-bye to effective GVL, as well as effective protection from infections. Patients who develop severe and acute GVHD and therefore need aggressive immune suppression for long periods of time to control it, are at increased risk of life threatening infections, as well as relapse of the CLL because the new immune system does not go out and hunt down the last of the CLL cells, before the cancer has a chance to re-establish itself. That is why transplant experts like to see a just a little bit of GVHD after transplant, because it tells them the grafted T-cells are frisky and doing their job (killing CLL cells and keeping infections under control), but not so much GVHD that it becomes a problem by itself needing lots of steroids and immune suppressive drugs.

What are mesynchymal stem cells?

I bet most of you have never heard of mesenchymal stem cells (MSC). It is important that we learn a little bit about this important variety of stem cells so that we can better evaluate this latest technology for controlling GVHD. I promise I will be brief.

Stem cells come in many flavors. Hematopoietic stem cells (HSC), for example, are the stem cells we talk about when we discuss stem cell transplants. HSC do one thing only: they create brand new copies of all the cell lines in your blood – red blood cells, platelets, T cells and B cells, neutrophils etc. That is why some researchers call these procedures HSCT rather than just SCT, “H” standing for hematopoietic.

Mesenchymal stem cells (MSC) are another variety of stem cells. Like HSC they too prefer to hang out in the bone marrow, but once in a while they take a little trip and circulate in the blood and tissue before going back home to the bone marrow. Mesenchymal stem cells are attracted to any sign of inflammation in the body and rapidly migrate to the place where inflammation is happening. Once they get there, they put out cytokines (chemical signals) that soothe the ruffled feathers of the T-cells and other killer cells firing away at random and making a bad situation worse. This is inflammation control at a cellular level, at the precise spot where the inflammation is happening.  By contrast, steroidal drugs and other immune suppressive drugs effect the whole body. Think of MSC mediated inflammation control as effective crowd control at the scene of a riot, rather than country wide clampdown that causes more problems than it solves. MSC immune suppression is more subtle and far more effective than any man made chemical immune suppressant since it has the advantage of being targeted to the spot that needs it.

In addition to tuning down the overly aggressive function of T-cells at the site of inflammation, MSC also perform another function. They put out chemical signals that encourage the local cell lining to regenerate, make new lining cells quickly in order to patch over the inflamed areas. This means the damaged areas heal more quickly and which in turn means the T-cells are no longer interested and drift away from the area. Steroids cannot accomplish this healing function.

There is one further aspect of mesenchymal stem cells that is pretty unique. Since they have to get into the thick of the melee in order to stop T-cells from making inflammation worse, they have evolved over time the ability to avoid getting attacked themselves by the T-cells. MSC do not exhibit any of the markers on their cell surfaces that attract the attention of T-cells or other killer cells. This makes MSC almost stealth cells, undetected and therefore not attacked by the immune system.

What does this mean for us? Why, it means we can use mesenchymal stem cells from donors without having to make sure they are a match for us, since they are not attacked by our T-cells! Studies have shown that these cells are universally compatible. Similar to Blood Type O which can be transfused into all patients, these MSCs may be used without tissue type matching for specific patients. How neat is that!

To date, MSCs have been tested for many different inflammatory diseases in over 1,000 patients. As best as I can tell, no major safety concerns have been observed. What happens when the inflammation is resolved and the MSC have finished their job? Animal studies have shown the MSC return to the bone marrow, and go forth again only if new tissue damage due to inflammation is detected.


Osiris Pharmaceutical has developed a mesenchymal stem cell product that they named “Prochymal”. Prochymal is adult mesenchymal stem cells harvested from the blood of normal healthy adult volunteer donors and grown into huge armies in the lab. As we discussed above, MSC do not have to be matched to the individual patient and therefore Prochymal can be used by patients across the board.

Prochymal is being evaluated in Phase III clinical trials for three indications: steroid refractory acute GVHD, newly diagnosed acute GVHD, as well as Crohn’s disease (an inflammatory autoimmune disease where the GI tract is attacked by the patient’s own immune system). It is also being developed for the repair of heart tissue following a heart attack, the protection of pancreatic islet cells in patients with type-1 diabetes, and the repair of lung tissue in patients with chronic obstructive pulmonary disease (COPD). The common theme in all these diseases is out of control inflammation.

Both of the Phase III GVHD trials completed recruitment in record quick time and no longer accepting new patients. (But read below about the “Expanded Access Program” the FDA has approved for Prochymal, to allow gravely ill patients access to this drug). Results from these late stage trials are expected later in 2009. In the meanwhile, we do have results from the earlier Phase II trials and I review them below.

Phase II Trial Overview

The results of the Phase-II trial were presented at the 2006 ASH conference.  You can also access the results at the company website.

This Phase II trial was a randomized, prospective, open label trial, conducted at 16 leading cancer centers in the US. The objective of the study was to evaluate the safety and efficacy of Prochymal at two drug dose levels (given to patients on day 1 and day 4).

Thirty one patients were enrolled in the trial, patients between the ages of 18 and 65 who had received an allo SCT transplant (mini or full blown myeloablative variety), and had been newly diagnosed with acute GVHD.  Patients were also given the usual standard of care for GVHD with steroids and second line immune suppressive drugs as needed.  (It would have been unethical to do otherwise.  Untreated acute GVHD is a sure killer).

Patients entering this disease all had acute GVHD spanning grades II – IV, high risk patients with grave prognosis.  It is important to note they had received the SCT for a variety of blood cancers including acute leukemias such as ALL, AML, multiple myeloma, aggressive lymphomas such as Hodgkin’s diesase etc.  There were only 4 CLL patients in this group. But GVHD is an equal opportunity killer and the results of this trial are relevant to us.

Response to Prochymal

The table below outlines patient response to Prochymal at the two dose levels. 

Pretty impressive results, you have to admit.  For comparison, a 2002 study evaluated 443 patients with acute GVHD at the same grades II-IV, and found that only 35% of patients had a complete response to steroids by day 28. Here is a quote from one of the participating physicians:

“In this trial, approximately twice the number of patients achieved a complete response when given PROCHYMAL as we would expect with steroids alone,” Hans Klingemann, M.D., Ph.D., Director, Bone Marrow and Hematopoietic Cell Transplant Program, Tufts New England Medical Center. “But what is most important is that this improvement in response carried over into high survival rates.”

That is a powerful recommendation, the fact that the control of acute GVHD by prochymal resulted in improvement of patient survival. Parsing the results further, here are details reported as pretty pictures on the company website.

As you would expect, patients with Grade-II acute GVHD fared better than those with the much more serious Grade-III and Grade-IV variety.

The most common sites of acute GVHD are skin and GI tract, followed by inflammation of the liver. Typically, skin based GVHD is the easiest to handle since it can be treated with topical steroid creams and such.  Liver GVHD can quickly turn lethal. Prochymal seems to have remarkable efficacy in all three sites of GVHD.

As we reported above, Prochymal was given as two infusions one each on day 1 and day 4. As you can see, the impact of Prochymal gradually increased over time, as you would expect from a cellular process.

How about safety?  Prior work in European centers with MSC has shown very little toxicity. (Please write to me if you wish to read the excellent European article as well.  This review has become long enough that I decided not to include it).  The same benign profile was reflected in earlier pediatric GVHD clinical trial conducted using Prochymal.  Here is the safety profile in the Phase-II adult acute GVHD trial we are discussing here:

Expanded Access Program for Prochymal

Originally back in May of 2008, FDA had approved expanded access to Prochymal for the treatment of pediatric GVHD patients. It was the right thing to do. Kids with steroid refractory acute GVHD are very sick patients and majority of them never make it. A clinical trial with Prochymal showed remarkable success in saving many (not all) of these kids.

Following on the heels of the Phase-II trial results reviewed above, on January 2009 the FDA broadened its expanded access program (EAP) for Prochymal. The drug is now available to adults with life-threatening GVHD.

Under the new EAP, patients anywhere from two months to 70 years of age who have been diagnosed with GVHD that is unresponsive to steroid therapy are eligible to receive Prochymal. In other words, it is possible to get access to Prochymal ahead of its final FDA approval as a commercially available drug, if you fit the criteria listed above. If you think you can benefit from it and you cannot afford to wait, best thing to do is talk to your transplant team about it. Heck, I would talk to my transplant team about Prochymal even before the transplant. In your shoes I would like to have Prochymal in my back pocket, just in case. Here is another quote from our helpful Dr. Klingemann of Tufts.

“As a transplant physician who has used Prochymal, I have seen first hand the power of this promising therapy to reverse otherwise non-responsive GvHD. This is a disease that is so devastating that survival is often measured in days. This action by FDA is significant because it now enables us to provide all of our critically ill GvHD patients with faster and more reliable access to Prochymal”

I think this quote from Dr. Klingemann says it all.  Since this post has become longer than I thought it was going to be, I will cease and desist from adding verbose editorial comments.  I think the data are impressive enough.  I look forward to your comments and a good discussion.