CAR T-Cell Therapy | FAQ with Dr. Patrick Brown

CAR T-Cell Therapy | FAQ with Dr. Patrick Brown

(ambient synthesizer music)>>I think there’s really two main reasons why there’s so much
excitement for CAR T-cells, and the first is that
for literally decades, developing immune therapy
has been considered the Holy Grail of cancer therapeutics. It’s something that I
remember being taught back in medical school had the power to really change the
landscape of cancer therapy. CAR T-cells are the culmination of that 30 years or so of research, and to see it come to fruition
and be available for patients is really a huge advance. The second reason is
because of the results, so in the diseases that
we’re using it for, and primarily in the disease that I’m most interested
in which is childhood ALL, the response rates where 90% of patients go into a deep remission and
potentially 60% of patients can be cured with this therapy, is just amazing given the
fact that those patients were simply out of standard options before this therapy came along. At this point, there’s two
main groups of patients that are candidates for CAR T-cells. One are children and young
adults with B lineage ALL, and the other are adults with an aggressive form
of B lineage lymphoma, and as it stands now patients
with both of these diseases are eligible only if they’ve
failed up-front therapy, if their disease has relapsed or it hasn’t responded
to up-front therapy. So the process starts by
identifying an appropriate patient for the therapy, and then the first step in the management of the
patient is to have them come to Johns Hopkins to
undergo what’s called apheresis, and that’s where we collect
the patient’s own T-cells. At that point, those T-cells are shipped off to the
manufacturing facility to create the CAR T-cell product. That takes anywhere from three
to four weeks on average, and during that time, we typically will have the patient
receive bridging therapy, and that’s therapy designed
to keep their leukemia or lymphoma kind of at bay if you will before their CAR T-cell product
is ready for us to infuse. We receive the product back
from the manufacturing facility, and it comes back cryopreserved or frozen, and then we bring it to the
patient’s bedside, thaw it, and infuse the product at that point. The four or five days
before we infuse the product we give the patient a little bit of conditioning chemotherapy to make the patient’s body ready to receive the T-cells if you will, and then we follow the
patient very closely for the next month which is when the first evaluation occurs. The process is very much a collaboration between the referring hospital or physician and Johns Hopkins. Really the only two parts of that process where the patient really
needs to be at Johns Hopkins or in the immediate vicinity
are the one to two days required to collect the T-cells, and then the probably four to five weeks that span the actual
infusion of the CAR T-cells. The remainder of the time
we can work with the local referring physician and hospital to provide therapy for the patient and follow up after they
receive their CAR T-cells. The two main risks of CAR T-cells are a condition called
Cytokine Release Syndrome or CRS, and neurotoxicity. The timing of these two
side effects is different. The Cytokine Release
Syndrome, the risk for that is really anytime from about one day after the CAR T-cells are
infused to about a week after, so in that first week after
receiving the therapy, and the neurotoxicity the
timing is a little bit later. It can be as long as a few
weeks after or even longer after receiving the CAR T-cells. The Cytokine Release Syndrome
is due to the activation of the patient’s T-cells after they’re given back to the patient. What happens there is the
T-cells when they get activated release chemicals called cytokines and those cytokines cause
symptoms like fever, low blood pressure, difficulty breathing, difficulty handling fluid and fluid leaking basically in the body, and that’s the Cytokine
Release Syndrome side effect. The neurotoxicity is probably also caused by the release of cytokines,
but it occurs later and it affects the function of the brain, and the two main side
effects that one can see are what we call encephalopathic symptoms and these would be things like confusion, not being able to speak properly, and then the other is seizures, so we give seizure
preventative medications. Fortunately, both
Cytokine Release Syndrome and neurotoxicity are in virtually
all cases 100% reversible and patients go back to their baseline after they’ve received that. Now this is a distinct pattern of toxicity compared to the alternative
treatments in this situation like intensive chemotherapy or transplant. So the Cytokine Release Syndrome,
neurotoxicity are unique. They occur relatively early
and they fully resolve, whereas chemotherapy and transplant can have prolonged side
effects, and so we really think there may be an advantage
to CAR T-cells in that way. And then the final thing to mention is that CAR T-cells will
eliminate normal B-cells as well as tumor B-cells, and so patients can be
left without B-cells for a long period of time. That’s called B-cell aplasia, and that can require
immunoglobulin infusions for potentially life after
patients receive this therapy. Unfortunately, no. Like most therapies or
all therapies to date, they don’t work in every patient, and there’s two main reasons why CAR T-cells currently are not working. For about 10% of patients, the T-cells simply don’t
expand and don’t engraft in the patient after they’re infused, and then in another 30% of patients, they engraft and the patient responds, but then some period of time later usually within several months, the patient’s leukemia comes back usually because it has learned and adapted and now no longer expresses the protein that the CAR T-cells are targeted against which is called CD19. That’s called CD19
escape when that happens. So there’s lots of work
going on to optimize the CAR T-cells to reduce
both of those reasons that they don’t work, to both reduce the rate of patients whose CAR T-cells don’t
engraft after they’re infused from 10% down hopefully to 0%, and also to modify the CAR T-cells so that they can target more than one protein on the leukemia to prevent that CD19
escape that’s occurring. They’re very expensive. The current price tag for
the CAR T-cell products are anywhere from 350,000 to almost $500,000 for the treatment. So far insurance companies have been reimbursing for
the cost of the CAR T-cells, and have been covering the CAR T-cell cost at least for the patients
that are being treated in accordance with the FDA indications. The companies have also set up programs to help make sure that the
treatment is affordable to as many patients as possible, so there are things like copayment, co-insurance
payments and reimbursements, there’s reimbursements
for lodging and travel associated with having to go to a different center for CAR T-cells, and there are programs where
the CAR T-cells are provided free of charge for patients
that are indigent or uninsured. Hopefully most patients can find a way to make these products
affordable over time, but it’s a concern moving
forward that with therapies this expensive that the
system will be able to sustain providing them for patients. So we are one of
approximately 40 or so centers that are able to offer this treatment to children and young adults. In our area, we’re one of the only
programs in the Mid-Atlantic. There’s, in Philadelphia is the Children’s Hospital
of Philadelphia program. There’s us and then I think the next one to the south of us is Duke, and then there’s a couple to the west out once you get to the Midwest, so we cover a pretty large
region of the United States and are taking referrals from that area. The other thing is our
children’s center I think is one of the top children’s centers for all of the different
services that it takes to make CAR T-cells a
reality, so you have to have a very high functioning
intensive care unit, cell therapy laboratory, the
ability to do pheresis on site, physicians that are used to taking care of very sick patients
with cellular therapy, and we have one of the best bone marrow transplant programs here, and we all work very closely
and coordinate very closely to make sure the patient
gets the very best care. So we’re certainly not the only center that does CAR T-cells,
but I’d like to think we’re one of the best,
and I hope that patients will feel that way when they
come here for treatment. (ambient synthesizer music) (children laughing)

3 Replies to “CAR T-Cell Therapy | FAQ with Dr. Patrick Brown”

  1. The last side effect that he mentioned is a really big deal. You are essentially left without a big and important part of your immune system. You would have to take supplements to compensate, but even that doesn't come close to what the real humoral immune system does… It's actually not that targeted of a therapy. All therapies discriminate in some way (a good thing). For example, chemotherapy helps get rid of more rapidly dividing cells (malignant cells), but affects all cells the same way. CAR T cells attack only B cells, but don't discriminate between malignant and normal ones.

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