Immunotherapy update

If you're like me…well, I pity you because you're living with a Myeloma diagnosis.  :)

But seriously, folks, if you're like me, you may have seen a lot of conversation about various drugs in development that end in -mab.  Thisamab and thatamab and the otherthingamab.

While I continue to hope that Total Therapy will be curative for me and I won't need to worry about a relapse, I certainly do think from time to time about how to plan for next steps in therapy should I need them.  The Arkansas protocol would be to continue the carpet bombing.  It may surprise some of you to hear that I'm not sure I'd necessarily sign up for that.

With any luck, this will be entirely an academic exercise.  But were the disease to return tomorrow, I might try to resume treatment with next-generation Velcade (Carfilzomib, or Kyprolis as it is now known) or next-generation Revlimid (Pomalidomide, or Pomalyst as it is now known).  I might try to buy some time with these drugs, because while these have been important breakthroughs, they are in existing families of drugs (Kyprolis is, like Velcade, a protease inhibitor; Pomalyst is, like Revlimid, an immunomodulatory drug).   These drugs have been demonstrated to help overcome disease that has become resistant to their older cousins, and that's an important development indeed for all Myeloma patients.

However, they aren't "game changers" the way their older cousins were.  When Velcade came out, it was the first proteasome inhibitor, and was a game changer.  It represented a new way to target and kill Myeloma.  When Thalidomide was used for Myeloma, it was the first immunomodulatory drug in the armamentarium against MM and it was also a game changer.   But subsequent drugs in these families -- while helpful and prolonging overall survival and putting patients into deeper remissions -- have been tweaks to a successful formula rather than a new way to fight.

Immunotherapy -- already used in other cancers like lymphoma -- is a potentially new way to fight MM and could be another game-changer in a few years' time.

There are two drugs in this class that I've heard a lot about: daratumimab and elotuzimab.  I had a vague idea about them but I had the opportunity to sit in yesterday on a conference call hosted by the MMRF on the topic of immunotherapy, and it was IMMENSELY valuable to an understanding of how researchers are thinking about fighting this disease with this class of drugs.   I thought I would try to synthesize the key findings and try to present them in a (relatively) easy-to-understand way.

First, we can group the types of there are two different types of immunotherapy that people are working on for Myeloma: antibody treatment, immune regulation, and vaccines.   Antibody treatment seeks to target MM cells for the immune system to kill; vaccines seek to help build an immune system capable of wiping out the MM cells.  They are similar, and yet distinct approaches.


Antibody Treatment

The idea behind antibody-based treatment is to identify MM cells and kill them.  It sounds easy when expressed that way, but the idea behind chemotherapy, for example, is that it kills everything in its path that is rapidly dividing.  The goal of antibody therapy is to do a better job of targeting the MM cells.  Once this is done, there are two different ways to kill the cell: (1) deliver a poison to the targeted cell, or (2) help the immune system kill it through its own natural means.


Identifying the Cells

Myeloma cells express proteins on the surface of the cell.  These proteins are generally identified as "clusters of differentiation" with a number associated with them, for example CD38.  Some proteins have different names, such as CS-1.   I don't know what the CS stands for and my Google-fu is inadequate to the task, even when I have found articles discussing the topic.

Proteins commonly expressed by Myeloma cells include CD38, CD138, CD45, etc.   These are the same proteins that Arkansas' highly-sensitive test for Minimal Residual Disease looks for -- they look at millions of proteins on the surfaces of cells in the bone marrow and look for CD138, CD38, CD45, CD56, CD81, CD20, CD20 and CD19.  If they can't find any, then that test is negative for MRD.


Antibody Development for Poison Delivery

Antibodies in this instance are manufactured agents that identify and attach to these specific proteins.  They are called monoclonal antibodies, because there are many of the same kind, designed to attach specifically to certain protein targets.

There are a number of them in clinical trials.  For example:

* Elotuzumab targets the CS-1 protein

* Datatumimab targets the CD38 protein

* Lucatuzumab targets the CD40 protein

* Several agents in earlier trials target the CD138 protein (these are currently called B-B4, nBT062 and DL101)

The idea in this treatment is to attach a "backpack" of poison to the antibody so that it binds to the protein on the MM cell and delivers this poison to the cell.  Since it is good at binding to those specific proteins that are generally expressed on cancer cells and not on healthy cells in the body, it's effective without causing a lot of side effects.

Sounds great, right?

Well, the problem is that MM cells are smart.   I'm not sure exactly why, but they find ways around this.  And researchers are also trying to determine how much of these drugs is enough to target the maximum number of cells -- too much of the drug in current trials reduces effectiveness, so there is an optimal dose that people are trying to triangulate.   At the same time, though, there must be other issues that have led my doctor to tell me that these therapies are not (yet, at least) ready for primetime in MM, and aren't (yet, at least) the game changers that they are in Lymphoma.


Immune Regulation

Another way that immunotherapy can be used to fight MM is by strengthening the immune system's response.

The human immune system is extremely complex.  One key part of it as T-cells (a type of lymphocyte, which is itself a type of white blood cell).  T-cells are called T cells because they express something called a "T cell receptor" on their surface, and this is responsible for recognizing certain antigens, or hostile cells in the body.   T cells float through the body and "interrogate" the cells they find.  When they find something that expresses the particular protein that they are looking for, they bind to that cell and look for a secondary signal.   This is basically a "failsafe" mechanism so T cells don't kill cells that they aren't supposed to kill.   They notice something wrong, and zoom in for closer inspection, essentially.  This is called a "checkpoint."

Now, Myeloma cells are smart.  Normally, when a cell is abnormal (like a Myelomic cell would be) and the T cell locks on to it, the conversation goes like this:

T Cell:  Hello.  We've had reports of disturbances in the neighborhood.  Is everything okay?

Abnormal cell:  Hey, uh, no.  There's three burglars in here.  Blow up the house.

T Cell:  Okay.  I will blow up the house.

Instead, the smart Myeloma cell conversation is like this:

T Cell:  Hello.  We've had reports of disturbances in the neighborhood.  Is everything okay?

Abnormal cell:  Oh sure, officer, everything's fine.  I heard shots down the street, you should check that out instead.  I so appreciate you coming by, though. 

T Cell:  Okay.  Sorry for the inconvenience.

There are two ways to prevent this from happening.   The first is preventing the occupant of the house from answering the officer's question, which causes the officer to blow up the house.  The second would be preventing the officer from understanding the abnormal cell's response, which again would cause the officer to blow up the house.

In both these cases, the "checkpoint" process is being disrupted.  Hence, this class of drugs is called a "checkpoint inhibitor."

The answer from the Myelomic cell (the "nothing to see here, officer" response above) is a protein on the Myelomic cell called PD-L1.  There is a trial now of a checkpoint inhibitor called BMS-936559 (really rolls off the tongue, eh?) that blocks expression of this protein.

The ability to HEAR the answer from the tumor relates to a protein on the T cell called PD-1.  There are two drugs being developed that target this -- nivolumab and lambrolizumab.



Vaccine Development

Vaccines for Myeloma would notionally work the same way that other vaccines work -- these vaccines essentially train T cells in our bodies to recognize and kill tumor cells, in the same way that they are trained to recognize and kill measles.

While there are several different sub-approaches within this category, the basic idea is that T cells are infused with the "memory" to identify and kill Myeloma.  Generally, these cells are removed from the body, sent to school to learn to identify and kill Myeloma, grown so that there are a lot of educated T cells, and put back in the body.   There is some interesting work being done in this area in Chronic Lymphoid Leukemia and it looks to be quit promising.

We aren't there yet in Myeloma, but people are working on it.  It again relates to finding the best targets that can be used to help teach the T cells what to kill.



Where this goes from here?

In the future, the hope is that immunotherapy will yield a number of targeted treatment options that will induce remission, and that a combination of vaccines, engineered T cells and immune checkpoint inhibitors can stimulate strong and durable anti-myeloma immunity to eliminate any minimal residual disease.  

This might be introduced in a post- transplant setting where there is very little disease left, and we could then see if the immunotherapy was enough to kill the small amount remaining.   With more sensitive testing for minimal residual disease, we could then track the effectiveness of these immunotherapies.

The doctors on the presentation both thought it would be 5-10 years before we saw the full import of this research, and both were resistant to admit that the treatment could be curative.  But they both expressed some qualified hope that they might be in some cases, and they both were very optimistic that immunotherapy could represent an important new arrow in the quiver of Myeloma treatment.

I'm off to a small event that I'm co-hosting with the MMRF this evening, and look forward to reporting back on anything interesting that I hear.   Have a good weekend, friends!

So what exactly is an Autologous Stem Cell Transplant?

I have been counseling a number of folks lately -- seemingly an increasing amount -- about their treatment options in this disease.  And in the case of newly diagnosed patients with standard risk characteristics who are young enough to benefit from being cured versus not being cured, I urge them to consider transplants in general, and tandem transplants in particular as part of a Total Therapy regimen.

In the midst of this, my good and extremely learned friend SR was kind enough to educate me a bit on the specific way that certain types of chemotherapy work (alkalyting agents, such as those used in stem cell transplants).   So I thought it might be useful for me to explain a bit about what an autologous stem cell transplant procedure really is (hint: it's not a transplant) and why it is effective in many cases of standard risk myeloma.

So with your permission, a quick chemistry lesson as pertains transplants.

A true transplant -- such as an allogeneic transplant where the patient receives the immune system of a donor -- is just that: a transplantation of the donor's immune system into the patient's immune system.  You're taking something from somebody else and installing it.  Like a heart and lung transplant, or a liver transplant, or a kidney transplant.

In contrast, an autologous stem cell transplant takes one's own cells.  There is no transplantation.  An autologous stem cell transplant is simply administration of a type of chemotherapy in high-dose to kill myeloma cells, followed by a "rescue procedure" that involves putting one's own cell back into one's body in order to rebuild blood and…uh…not die, essentially.

Generally speaking, the chemotherapy administered with an auto transplant is called an alkalyting agent.  The most common one is called Melphalan, and the second most common one is called Bendamustine.  Cyclophosphomide, which is the C of VDT-PACE that is used for induction in Total Therapy, is another alkalytor.

Alkalytors work like this:

* An alkyl is a portion of a molecule.  There are many different kinds of alkyls.

* An alkalyting agent like the above-mentioned chemotherapies (which all derive from mustard gas, by the way…fun stuff) transmits a synthetic alkyl into the DNA of a cell.  It joins with the DNA in the cell, and since the alkyl the agent transmits is inherently unstable, this screws up (highly medical term there) the DNA of the cell.

* Once the DNA of a cell gets screwed up, the cell takes inventory of itself, dutifully raises its hand and says "umm, I'm screwed up, time for me to cash in the chips here, guys."  In more technical terms, the cell is activated for programmed (i.e. intentional) death.   This is the normal response for a cell with damaged DNA to be removed from the body, and this process is called apoptosis.

* For a reason I do not know at this time at the biochemical level, this occurs with fast-dividing cells.  Cancer, hair, and digestive tract (hence hair loss and GI issues from transplant meds).  The DNA that gets mangled is concentrated in your cancer cells, but it's there in plenty of normal cells, too.

So what, exactly, is an auto-transplant and what does it have to do with this?

An auto-transplant is the administration of a high-dose of an alkalyting agent, followed by steps to help the patient recover from the damage the medicine does.  Simple as that.

The medicine is administrated in a "mega-dose" (100X a "normal dose" of these agents) and it murders the hell out of Myeloma, while also causing a lot of collateral damage.  It does such an effective job of killing that it temporarily destroys the body's ability to make blood -- no more red blood cells, no more white blood cells, no more platelets.  Hopefully no more (or very little, to be more accurate) myeloma, either.

If no steps were taken to help the patient, the patient would die in a matter of days.  After all, you need red blood cells to live, white blood cells to keep an infection from killing you, platelets to keep from bleeding out from a cut (or suffering internal bleeding that kills you).   Turns out all those blood cells are important!   So in an auto transplant, after chemo is given, the patient is given their own immature blood cells that restore the patient's marrow and help to manufacture new blood.  This is not a transplant of another's immune system -- it is a rescue procedure.  Not too different from giving somebody low in potassium some potassium, or giving somebody low in red blood a unit or two of blood.  Just a bit higher stakes, is all.

So when people (doctors or laymen) say they believe in a transplant -- whether a single transplant to deepen remission, or tandem transplants to hopefully cure the disease -- all they are really saying is that they believe that in most cases, melphalan kills myeloma cells.  A lot of them.  Maybe almost all of them, even.

In Total Therapy, or a tandem transplant setting, all that is happening is the patient is getting twice as much Melphalan.  There's no magic to it beyond that -- you're simply giving the patient more of a medicine that is believed to be effective against standard risk disease.

In summary auto transplants are just that: a type of medicine, highly effective in most cases, from which help is required to recover.

Interestingly, SR went on to explain one particular type of disease biology that is not as responsive to current transplant protocols.   Some of you may have come across the concept of "deletion 17p" as a means of defining disease biology.   There is a genetic component of DNA called TP53 (for tumor protein 53) and it is part of the long arm of chromosome 17 (17p).   TP53 is the part of the DNA that says "okay, the cell raised its hand and is ready to bow out gracefully" (more accurately: TP53 allows the body to assess DNA damage to a cell and either repair it or target it for apoptosis -- programmed cell death).    If a patient does not have this genetic characteristic, the alkalyting agents do their part by screwing up the DNA, but the body does not recognize that for what it is, and fail to kill the cell.  Consequently, patients who have del17p don't respond as well to transplants as those who don't have that particular genetic abnormality.

One last note: Revlimid has been associated with the risk of secondary cancers -- I had a squamous cell carcinoma in my finger that was likely related to ongoing Revlimid use.  But Revlimid is only associated with increased risk of secondary cancers if the patient has received alkalyting chemotherapy. Something to keep in mind.   If you do a transplant followed by Revlimid maintenance, make sure you understand the reason behind it (i.e., is the doctor pursuing cure) and you are informed about the trade-offs.  In my own case, the risk of getting a secondary cancer that might kill me was lower than dying from the Myeloma -- that was the calculation I made and I'm happy with it, even in hindsight.

Okay, that's enough for today.  :)    But hopefully, this entry can be useful to those who are considering a transplant and want to understand a bit more about what it is, and why it works.