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!