Who Responds Best to the Multiple Myeloma BCMA Bispecific Antibodies?
Posted: Jul 21, 2022
Who Responds Best to the Multiple Myeloma BCMA Bispecific Antibodies? image

Most of us are familiar with the quandary of good or not-so-good outcomes of myeloma treatment(s), either through first-hand or from fellow patient experience. We are also familiar with the lines, “Myeloma is a heterogeneous disease” and “one size does not fit all.”

Those lines are small comfort for patients that are at the short end of the “not-so-good” experience(s). In addition, as time is going by we now have increased options to help us along at time of relapse with every new drug/treatment program that has entered clinical practice.

One such class of treatments are the bispecific antibodies (BsAbs) that target BCMA on our myeloma cells and one of the proteins (e.g., CD3) on our T-cells. Health Tree for Multiple Myeloma has provided plenty of information already regarding the bispecific antibodies and there is no need to review all of it here.

At times, however, the outcome(s) of this recent/novel contribution to myeloma treatment falls short of expectations and then the question asked is “Why?” We we have read things such as “tired T-cells” and/or “inadequate BCMA proliferation.”

A group of researchers from the Berghofer Medical Research Institute (Queensland, Australia) and the Peter MacCallum Cancer Centre (Melbourne, Victoria, Australia) has dug deeper into the why some patients do well with bispecific antibodies and others do not.

The results of a pre-clinical (non-human study)  have been published in the most recent issue of the journal Blood Advances. The first conclusion reached is: 

“Notably, the BsAb-mediated immunostimulatory and anti-tumor effects were abrogated in mice lacking invariant NKT (iNKT) cells. Myeloma progression was associated with reduced numbers of BM iNKT cells.

In other words, the patient has to have an adequate store of iNKT cells in peripheral blood in order for the bispecific antibodies to be successful.

What are these invariant NKT cells? I will help myself to an understandable definition published by the British Society for Immunology,  

“Invariant natural killer T (iNKT) cells, also known as type I or classical NKT cells, are a distinct population of T cells that express an invariant aβ T-cell receptor (TCR) and a number of cell surface molecules in common with natural killer (NK) cells. Although iNKT cells are rare in the human blood pool, comprising just 0.01-1% of peripheral blood mononuclear cells (PBMCs), they are important immunoregulatory cells rapidly producing copious amounts of cytokines that can influence other immune cells.”

The link given above provides some added, understandable, reading material and a nice graphic showing the links between iNKT-cells and T-cells/NK-cells.

You can ask the question now whether it is possible to increase the number of iNKT-cells in a patient? The answer is a possible/most likely yes, by loading a patient’s dendritic cells with alpha-Galactosylceramide.

Let’s answer a couple of questions you will have.

“Dendritic cells are bone marrow (BM)-derived leukocytes and are the most potent type of antigen-presenting cells. They can also be propagated in vitro from bone marrow and blood using various combinations of growth factors, such as granulocyte macrophage-colony stimulating factor (GM-CSF).”

(Many of us are familiar with this GM-CSF as this is the Neupogen/filgrastim that was injected as part of the conditioning protocol we went through prior to stem cell transplant.)

The Australian team, though, mentioned alpha-Galactosylceramide to boost the propagation of dendritic cells (and then later on the propagation of the needed iNKT cells). This is a synthetic compound that is isolated from the marine sponge Agelas mauritianus.

The research team concluded: 

“Importantly, the therapeutic efficacy of a single dose of the CD3/BCMA BsAb was remarkably augmented by restoring iNKT cell activity using adoptive transfer of α-galactosylceramide-loaded dendritic cells. Together, these results reveal iNKT cells as a critical player for the anti-tumor activity of CD3-engaging BsAb’s, providing important translational implications.”

And there you have it. Health Tree for Multiple Myeoma has previously explained the importance of bispecific antibodies to give us hope at time of relapse and the Australian research team has now added insights that will make these antibodies (or at least the CD3xBCMA bi-specifics) more beneficial to more of us.

Allow me to make a final comment. These days we are overloaded with mention and information about a variety of cells and very few of us have been exposed to what these cells are and what their function is during our prior education. The British Society for Immunology (mentioned earlier) has a nice website that explains this cell business in language we can all understand.

Click on the link just mentioned and you will find the example for dendritic cells and on the right-hand side of the webpage you will find a nice list of different cell types you can explore yourself. It is highly recommended. An educated patient is a patient who can advocate better for themselves.

 

The author Paul Kleutghen

about the author
Paul Kleutghen

I am a patient diagnosed in 2014 with primary plasma cell leukemia (pPCL), a rare and aggressive variant of multiple myeloma and have been very fortunate to find successful treatment at the division of Cellular Therapy at the Duke University Cancer Institute. My wife, Vicki, and I have two adult children and two grandsons who are the ‘lights of our lives’. Successful treatment has allowed Vicki and I to do what we love best : traveling the world, albeit it with some extra precautions to keep infections away. My career in the pharmaceutical industry has given me insights that I am currently putting to use as an advocate to lower drug pricing, especially prices for anti-cancer drugs. I am a firm believer that staying mentally active, physically fit, compliant to our treatment regimen and taking an active interest in our disease are keys to successful treatment outcomes.

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