Multiple Myeloma: how stem cell therapies might shape future treatment
By Wideacademy - 10.01.2018
What is Multiple Myeloma?
Multiple Myeloma is a cancer of plasma cells, a type of white blood cell found in bone marrow.
Plasma cells play an important role in our immune systems. They are produced in response to infection and create antibodies which recognise and fight invading germs.
In rare cases, normal plasma cells transform into malignant myeloma cells where they produce high volumes of an abnormal antibody called M protein.
These myeloma cells grow out of control to form a tumour (isolated plasmacytoma) or several tumours, as is the case with Multiple Myeloma.
These tumours prevent your body from making enough healthy red blood cells, white blood cells and platelets — leading to anaemia, infection and bleeding.
A build up of M proteins can also cause the blood to thicken and can result in damage to the kidneys and immune system.
Symptoms of Multiple Myeloma can include:
- bone pain, notably around the ribs or hips
- bones that break easily
- frequent infection
- breathing difficulties
- bruising or bleeding
- weakness and tingling in arms and legs
- nerve damage
In some cases Multiple Myeloma has no symptoms.
Increased risk factors for multiple myeloma include:
- age – the likelihood increases as we get older
- gender – men are more likely to develop it than women
- ethnicity – it is twice as common in black populations as white or Asian populations
- weight – obesity increases the likelihood
- HIV- an already impaired immune system in HIV patients is a risk factor
How can stem cells help?
There is no known cure for Multiple Myeloma.
Doctors treat it by administering medicines that kill or inhibit myeloma cells, while also treating resulting conditions, such as anaemia or bone pain.
For old and frail patients, treatment is likely to be non-intensive. For younger people, who can withstand greater toxicity, it can be quite intensive.
Treatment is usually a combination of chemotherapy, steroids and thalidomide or bortezomib.
High-dose chemotherapy can be followed by a stem cell transplant, usually an autologous transplant, where your own stem cells are collected and stored prior to chemotherapy, before being re-transfused into the body.
Experimental stem cell therapies
T-cell immunotherapy is a promising experimental stem cell treatment designed to reprogramme the body’s immune system to fight cancer.
T-cells are a subtype of white blood cell which are known to act as tumour suppressors.
In 2013, researchers at the Memorial Sloan-Kettering Cancer Center combined the ability to reprogramme stem cells into T-cells with a way to genetically modify T-cells to seek out and destroy tumours.
Using disabled retroviruses, the scientists transferred gene information into the stem cells, specifically the gene that codes for a chimeric antigen receptor (CAR) for the antigen CD19 — a protein which can be used to identify some cancerous cells, particularly leukaemias and lymphomas.
Myeloma-related CAR T–cell research is ongoing and there are several promising areas of study that have received funding, which spells hope for new treatments of the disease.
Two companies have recently filed approval applications with the American Food and Drug Administration for CAR T-cell therapies. Both of these products target the CD19 antigen.
One of these is the Swiss pharmaceutical company Novartis, which licensed rights to CTL019, (the CAR T therapy) after promising results in a trial run by the University of Pennsylvania.
In this trial, Multiple Myeloma patients who had already undergone a stem cell transplant previously, were given an infusion of autologous T-cells, altered to target CD19.
Four out of the five patients had longer post transplant responses, when compared to their previous transplant. One patient achieved a complete absence of myeloma cells, which was still reported a year after the trial.
More recently, scientists trialled CAR T-cells engineered to target a protein on myeloma cells called B-cell maturation antigen (BCMA). CAR T- cells that target BCMA were first tested in 2014 at NCI and are being tested in several ongoing trials.
BCMA is expressed in normal and cancerous plasma cells and, significantly, is not expressed in any other cells in patients with Multiple Myeloma. This opens up the possibility of more precisely targeting malignant cells and tumours.
In a small Chinese trial, funded by Nanjing Legend Biotech, 33 out of 35 Multiple Myeloma patients went into complete remission.
Furthermore 14 out of 19 patients, who were followed for four months or more, achieved a stringent complete response, which means that there was no evidence of disease in their bone marrow, nor any other makers for the disease.
A similar trial in America is planned for early 2018.
In early December 2017, the Sarah Cannon Research Institute in Tennessee presented updated findings from their BCMA CAR T-cell trial. Of the 18 patients in the trial treated with a high dose of CAR T-cells, 94% had a tumour response and ten of those were complete responses. Nine out of those 10 had achieved stringent complete response. A phase 2 trial is planned.
Cytokine Release Syndrome can be a side effect of CAR T-cell therapy, as can neurotoxicity. Interestingly only minor side effects were reported and treated, in both the Chinese and American trials. Although other workers have reported significant CRS following CAR-T cell administration.
Cancer stem cells
Cancer stem cells are a fascinating subset of stem cell biology that holds exciting promise for highly targeted treatment of cancer in the future.
Cancer stem cells are rare, immortal cells within a tumour that self-renew. Understanding how they work and can be disabled, makes them useful subjects for cancer research. If they behave in the same way as normal stem cells, it follows that scientists can harness what they know about normal stem cells, to identify and attack cancer stem cells and the malignant cells they produce.
There are many specific types. Multiple Myeloma cancer stem cells are a rare subpopulation of multiple myeloma cells, with the capacity for self-renewal and drug resistance.
Their phenotype has not been properly defined yet, making them hard to identify. However, it is thought that they contain the antigen CD19 on their surface — which explains why CAR T-cell therapies that target this antigen are effective against multiple myeloma.
However, the CD19 protein is not found to any great extent on most myeloma cells. In fact, tests done on myeloma cells reported that 99.95% of those cells did not have any CD19.
Another theory suggests that CD19 may be involved in maintaining the myeloma cells, so that the CAR T-cell therapy works by indirectly killing off the malignant cells.
More needs to be understood about Multiple Myeloma cancer stem cells: the exact reason for their drug resistance; the signalling pathways involved in their self-renewal and differentiation; the roles of microRNAs and how they interact with the bone marrow and surrounding environment.
Global gene expression profiling is a powerful tool for identifying new targets in cancers. This, combined with research into Multiple Myeloma cancer stem cells, could shed further light on the disease and potentially make it a curable one.