TwinCities – February 2018: CAR-T Cell Therapy

February 10, Twin Cities Support Group: CAR-T Cell Therapy

Another cold Saturday on the Twin Cities and another well attended meeting.  After projector problems forced us to change conference rooms we finally got our meeting rolling nearly on time with a very highly anticipated presentation.  The topic was “Will there be a CAR-T Cell Breakthrough for Myeloma?” To address the question we were joined by Yi Lin, M.D., PhD, Mayo Clinic; Lead Researcher on Mayo’s Myeloma CAR-T Cell initiative.  Dr. Lin gave a very instructive presentation and answered every question we could throw at her (some from left field).
Below are some notes about the presentation.  Please read them alongside Dr. Lin’s slides.
Click HERE for the .pptx Powerpoint Version of Dr. Lin’s slide presentation.
Click HERE for the .pdf Acrobat Version of Dr. Lin’s slide presentation.

Some Highlights

CAR-T, short for “Chimeric antigen receptor T-cell therapy”, uses a patient’s own immune system to battle cancer.  Doctors remove T-cells from a patient’s body and genetically alter them to fight tumor cells. Then these reprogrammed T-cells are grown by the millions and injected back into the patient’s body to kill cancer. (for more about T-Cells see, “Beginners Guide to T-Cells“)
(Defining Chamaric:  Chimeric antibodies are hybrid substances created by combining antibodies and parts of antibodies with the potential to track down and illuminate remote and microscopic tumors.  Because they are made by combining genetic material from a nonhuman source, like a mouse, with genetic material from a human being they are less easily rejected by the body’s immune system than ordinary monoclonal antibodies. – taken; with a little re-write, from Absource)
Meeting Note Highlights:
• Currently FDA has approved CAR-T cell therapies to treat children and young adults suffering from a form of acute lymphoblastic leukemia and certain types of large B-cell lymphoma.  Both therapies target the CD19 receptor, which is not greatly expressed on Myeloma cells.  Myeloma treatments target the BCMA receptor.
• CAR-T takes your own cells, modifies them, and then returns them to you so your immune system will find and fight the cancer.
• At best, current drug therapies can maintain Myeloma as a chronic disease for an extended period of time.   CAR-T cell therapy promises to permanently control or cure Myeloma with a one or few times treatment.
• CAR-T-cell therapy modifies the immune system’s memory in a way that it reacts to types of protein rather than a specific protein.  The immune system should continue to recognize the Myeloma as it changes or mutates.
• Research on CAR-T has been ongoing since 1997 with the first true breakthrough in 2011.  Trials really have been ramping up in the last few years.
• With normal T-Cells recognition of the cancer surface protein and signalling to activate the immune system is a two-step process.  CAR-T cells merge the recognition and activation into a single process.
• China now has the most trials with the US second (Bloomberg News says US is first but it’s close,  see “China’s Great Leap Into Biotech” about how China is attempting to cut the price of CAR-T. )
• CAR-T modified cells are up to 10,000 times more sensitive to the targeted protein than are native immune system cells
• This is gene engineering and a permanent change in the body.  The FDA demands a 15 year follow-up to see if secondary cancers, other disease, physical, or mental problems develop from having had the treatment.  So far, all is good but people aren’t necessarily getting the same therapy today that people received 15 years ago.
• Lymphocites: Many cancers & treatments depress the lymphocite count.  This is usually not a problem with Myeloma patients.
• Must have active measurable disease.  CAR-T did not appear to work with leukemia patients who did not have disease which was active and measurable.
• Myeloma must not be progressing rapidly because the patient will go 2-5 weeks without any kind of treatment as the CAR-T cells are being manufactured.
• Healthy enough to handle the possible side effects.
The Process:
• Apheresis to collect white blood cells.  Many of them are in the blood so it’s quicker than the process for transplant.
• The cells are shipped to a manufacturing lab.  It takes 2-5 weeks to create enough CAR-T cells for infusion.
• The patient is treated with chemo to kill lymphocytes so when the CAR-T cells are introduced the body accepts them more easily.
• 3-days (more or less) of infusion.
• 3-month stay close to the treatment center in case of a negative reaction.
• Live and see what happens.
Possible problems
• BCMA surface markers also appear on healthy plasma cells causing the risk of “on target, off tumor” toxicity by CAR-T cells.
• Cells (cell types?) must be tested on the genetic level to define which have BCMA receptors,
• For those who can’t wait 2-5 weeks for the manufacturing process the search is on for a off-the-shelf version of CAR-T though there may be a risk of a reaction similar to GVH (Graft versus Host disease).
• It’s very early and we’re deep into the learning process for CAR-T.
The Bad News:
There have been about 10 deaths in all the combined CAR-T studies.  After 3-deaths (due to cerebral edema in patients under 25) the FDA ordered Novartis to halt Phase-2 of its JUNO trial in adult relapsed or refractory B cell acute lymphoblastic leukemia. (see story here,  FDA halts Juno CAR-T trial after three patient deaths)
The Good News:
• In those people who have been re-dosed the CAR-T cells seem to not populate ares of the body which they have previously populated. 
• CAR-T appears to be just as effective on high risk patients as those with more normal types of Myeloma.
It also appears to be equally effective with those who have over and under 50% myeloma cells by bone marrow biopsy.
The Future:
• Right now we have no real answer as to how long a response will last.
• There is not yet a comparison of price and effectiveness of autologous transplant versus CAR-T (Planned trial in the works?)
• Price: right now cost, not including clinical care is $475K.  Add clinical care and it goes to appx 750K.
Kite Pharma is floating an initial list price of $375K
Looking forward we see an increasing amount of trials by multiple manufacturers at different price points.  Each study has its pros & cons.  Only time will tell if one becomes the standard.

– Gerry Landy

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