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| T cells ganging up on a tumour cell |
The American
Society of Clinical Oncology’s (ASCO) annual review always makes for
interesting reading. Immunotherapy continues to feature large [ASCO 2017 Annual Report again picks immunotherapy as “Advance of the Year"] ,
with adoptive cell immunotherapy being named “Advance of the Year”.
This bespoke
treatment involves genetic manipulation of the patient’s own T-cells, in which
an engineered virus is used to insert DNA encoding a protein capable of recognising
unique molecules present on the surface of tumour cells. Transformed cells expressing
chimeric antigen receptors (CAR) are cultured in the laboratory and then
infused back into the donating patient. CAR-T cells then seek and destroy
cancer cells. Being a “living therapy”, CAR-T cells continue to multiply to
exert a persistent anti-tumour effect.
While the number
of patients who have received CAR-T therapy to date is still in only in the
hundreds and largely limited to certain haematological cancers, clinical
response results certainly justify the ASCO accolade. Kymriah® (Novartis), the first adoptive cell
immunotherapy to receive FDA approval, achieved unprecedented response rates in
children and young adults suffering from relapsed or refractory acute
lymphoblastic leukaemia (ALL). Over 80%
of Kymriah® treated patients went into remission within 3 months, with 75%
remaining still in remission after 6 months.
Impressive study
results have been reported for another hard-to-treat blood cancer, relapsed or
refractory diffuse large B-cell lymphoma (DLBCL). Response rates to available
treatments are less 10%, with survival measured in months. Complete response
rates were 40% and 30% after 1 and 6 months, respectively. Moreover, treatment
raised the probability of being relapse-free at 6 months to almost 74%. Another
FDA approved CAR-T therapy, Yescarta® (Kite Pharma, recently acquired by Gilead)
has also shown achieved complete and durable complete responses in DLBCL and
other forms of B-cell lymphoma.
The major
challenge of CAR-T treatment is management of potentially life-threatening
adverse effects, which are a direct consequence of the engineered anti-tumour
response, with the most serious being “cytokine storms” resulting from release
of potent inflammatory molecules (including IFN-γ, IL-10 and IL-6). Some degree
of neurotoxicity is common in recipients, although the long-term consequences
of this are unknown.
Other
significant challenges are logistics and cost: as personalized living
therapies, cell collection, transformation, expansion and delivery to the patient
is a complex series of steps, with consistent manufacture of a safe and
reliable product being the most demanding. While the list prices of Kymriah®
and Yescarta® are $475,000 and $373,000, respectively (Novartis offers a rebate
where patients do not respond to treatment), side effect management and other
support costs can bring the total medical bill close to $1.5 million per
patient. This, and complex reimbursement issues, are at least in part, factors
in the low uptake of CAR-T therapy. Better definition of cost-effectiveness is
needed.
Despite these
challenges, a variety of investigational adoptive cell immunotherapies is in
the works for cancers other than B-cell malignancies, with studies underway in
multiple myeloma (Bluebird Bio, Kite Pharma); ovarian cancer (Juno
Therapeutics), and glioblastoma (Mustang Bio, Aurora Biopharma). Several “next
generation” candidates incorporate drug-sensitive “safety switches” that allow
the anti-tumour response to be turned on or off.
Moving from
bespoke to “off the peg” therapy using cells collected from healthy donors (“allogeneic”
cell therapy) could substantially reduce the overall cost of cellular
immunotherapy. Early clinical studies with an allogeneic CAR-T cell product
developed by Cellectis are underway.
Cellular
immunotherapy development has proved to be a rocky road. Clinical study deaths
have resulted in the abandonment of a CAR-T candidate by Juno Therapeutics [CAR-T: A wheel falls off, but still rolling],
and clinical trial holds imposed on Cellectis (although recently lifted) and as
of this week, Bellicum Therapeutics, with three unexpected deaths occurring in
subjects under treatment for haematological cancers. Growing experience may
allow early identification of study subjects at increased risk of severe
adverse events or development of safer investigational treatment regimens.
Commercial success
could prove elusive for several developers with high product cost, small addressable
patient populations, safety issues, and competition from both cellular and
non-cellular immunotherapies, particularly in the B-cell malignancy segment,
constraining uptake. Giants such as Novartis can afford the necessary
infrastructure, flexible pricing and slow rate of uptake, but smaller players
may join Kite Pharma and Juno Therapeutics in being acquired by companies with
deep pockets.
Photo credit: NCI/NIH, Alex Ritter, Jennifer
Lippincott Schwartz, and Gillian Griffiths
I can recommend a short perspective piece on the human side of adoptive cell immunotherapy that appeared in New England Journal of Medicine last year.
Tragedy, Perseverance, and Chance — The Story of CAR-T Therapy. Lisa Rosenbaum.
N Engl J Med 2017; 377:1313-1315. Online October 5, 2017. http://tinyurl.com/y9vpgch9
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