By Andrea Greif | December, 2020
More than three years after the first chimeric antigen receptor
(CAR) T-cell therapy achieved U.S. Food and Drug Administration (FDA) approval,
the revolutionary approach that has upended blood cancer treatment continues to
generate excitement.
LLS support over more than two decades helped lay the groundwork
for this approach to therapy that has been a game-changer for patients who
have relapsed multiple times and seemingly exhausted their treatment
options. The method works by infusing immune (T) cells with cancer-attacking
synthetic receptors that seek out and bind to a specific protein on the surface
of the cancer cells, causing their destruction. The CAR-T cells continue to
expand and fight the cancer cells, becoming a living drug within the patient’s
body. Pediatric acute lymphoblastic leukemia patients and adults with large
B-cell lymphomas have benefited from long-lasting remissions from the first
CAR-Ts approved. The latest CAR-T approval was in August for patients
with mantle cell lymphoma.
Consensus is building that the next CAR-Ts on the horizon will be
for multiple myeloma patients and follicular lymphoma and marginal zone
lymphoma patients who have relapsed multiple times. During this week’s virtual
62nd American Society of Hematology (ASH) annual meeting, a slew of
presentations makes clear several of these are likely to get approved in early
2021.
The myeloma CAR-Ts all target a protein called BCMA found on
cancerous plasma cells in myeloma patients. BCMA has emerged as a prime target
for myeloma treatment, and the first BCMA-targeting therapy, an antibody-drug
conjugate (an antibody bound to a cytotoxic agent), was approved by the FDA in
August – read more here.
Of the multiple companies vying in the BCMA-targeting CAR-T space,
Johnson & Johnson’s product, ciltacabtagene autoleucel (cilta-cel), appears
to be the frontrunner, with the highest response rates and longest-lasting
CAR-T cells. In a study of 97 patients, 97 percent responded to the
treatment, and 67 percent had a complete response, meaning no cancer cells were
detectable. At just over one year (the median follow-up, meaning at least 50
percent of the patients had been on the trial), 77 percent of the patients were
still alive and their cancer had not gotten worse.
Johnson & Johnson plans to submit its data to the FDA within
the next few weeks. What's more, Bristol Myers Squibb/Bluebird’s idecabtagene
vicleucel (ide-cel) – also promising while not as long-lasting in trials to
date – is already before the FDA with a decision anticipated in March. While
not involved in the study present at the ASH meeting, an LLS-funded
researcher at Emory University, Madhav Dhokapkar, MBBS, is studying this
therapy to find ways to make it more durable, safer, and more effective. Many
CAR-T products from Chinese companies were also presented at the meeting.
The length of time that BCMA-targeting CAR-T cells can last in
patients has been questionable, so the results presented at this ASH meeting
are encouraging. At the same time, the deaths of several patients on
trials have raised concerns about potential toxicities,
including dangerous neurological side effects and another extreme immune
response called cytokine release syndrome. Despite this, the FDA might
determine that the benefits for patients without other treatment options
outweigh the risks.
Patients with follicular (FL) and marginal zone lymphoma (MZL),
two slow-moving “indolent” forms of non-Hodgkin lymphoma, also have reason for
hope. Results from a clinical trial entitled ZUMA-5, testing a CAR-T developed
by Kite Pharma, a Gilead company, showed high response rates for patients with
both forms of the disease. LLS helped Kite Pharma launch their CAR-T program
through a partnership entered in 2015.
Of 104 patients evaluated, 84 with FL and 20 with MZL, 92
percent had an objective response, meaning their cancer cells were
reduced; 76 percent of patients had a complete response, meaning the
cancer became undetectable after a median follow-up of 17.5 months (the time
when 50 percent of the patients have been on trial).
Researchers across the globe – with support from LLS – continue to
work tirelessly to usher in the next generation of CAR T-cell therapies so that
they're safer and more efficacious for more patients with blood cancers.
Bispecific Antibodies – A Different Way to Harness the Boost the
Body’s Immune System
Several studies also highlighted the promise of bispecific
antibodies, which are designed to bind two proteins: one on the surface of
tumor cells (CD20) and the other on the surface of the recipient’s T cells
(CD3). The studies were in patients with lymphoma who were either too old or
sick to endure standard chemotherapy treatment, or whose previous treatments
had failed, including CAR-T in some cases. The results were impressive, with
high, durable response rates. There are advantages and disadvantages of this
treatment approach as compared to CAR-T. Manufacturing CAR-T is a long,
complicated, and costly process requiring the extraction of the patient’s own
cells. Bispecific antibodies use donor cells and can be manufactured as an
“off-the-shelf” product, so the manufacturing and wait time is far less. On the
other hand, CAR-T is a one-time infusion, while bispecific antibodies have
to be administered to the patient repeatedly for as long as the patient is
responding to the treatment. Some of the versions presented at the meeting can
be given by an injection under the skin (subcutaneous) as opposed to
intravenous infusion, requiring less time in the clinic and making the
treatment regimen somewhat less onerous for the patient. While promising, the
results for these therapies are still early so we will be keeping an eye on
these advancements.
Visit this blog again for ongoing coverage from #ASH20, and
click here to read the previous blog from ASH.
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