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Complete responses in 2 of 3 patients were
reported, and
significant improvement
in a partial responder with advanced/refractory Chronic Lymphocytic Leukemia
Is this a real breakthrough?
Yes, we feel that this report marks a genuine break-through in immunotherapy - made possible by
amazing science (each scientist building on the insights of
another) - but also by the patients willing to be the first-in-line
to receive genetically engineered t-cells into their blood
despite the risks and without prior evidence of efficacy.
Amazing science? Yes! In short, scientists
modified T-cell taken from the patient so that the cells would
kill all b-cells, malignant and normal - any cell with the
CD19 receptor.
... Further, they made changes to the cells allowing the
cells to expand and persist in the body,
leading to the reversal of chemo-resistant CLL in the first few
patients to have tried the new therapy.
How it was done is also noteworthy. The scientist "borrowed" a
technique that HIV uses to infect cells - this time for good
- in order to modify
the t-cells so that they would behave in the desired way,
but NOT to infect them with the HIV virus.
"For safety reasons lentiviral vectors never
carry the genes required for their replication.
To produce a lentivirus" ...
wikipedia.org
Are there remaining questions?
Yes, there are many remaining questions and much work to do.
First, based on clinical experiences in only 3 patients with
limited follow-up, we don’t know yet at what rate we will see
this kind of response in other CLL or lymphoma patients, noting
that it could prove effective for any b-cell lymphoma.
Second, we don't know if the complex techniques applied can
generate effectively engineered t-cells consistently (each
time in all patients) ... it
may be that they can be, but we won't know for sure until it
is verified by experience.
Further, we may yet learn that there are serious
consequences from depleting all of our b-cells (our
antibody-producing cells) – perhaps indefinitely – because of
the long persistence of the activated t-cells.
(While
treatment with Rituxan, which targets CD20 (a similar but
different antigen) has a similar effect on normal b-cells,
it is generally
reversible with discontinuation of the drug.)
Understanding the potential risks requires also an understanding of the
CD19 target:
"CD19 is expressed on
follicular dendritic cells and B cells.
Source:
miltenyibiotec pdf
There is more work to be done, and perhaps room for
improvement. For example, scientists say that they
should be able to turn off the activated t-cells with
immune suppressing therapy if needed (and other means).
Might this technology make chemotherapy obsolete?
Probably not. It should be noted that this approach
required pre-conditioning with chemotherapy to allow the
"programmed-to-kill" t-cells to be accepted by the body and
to allow them to multiply.
(The chemotherapy phase of this therapy reminds us of the "conditioning" therapy
needed prior to the so-called mini allo stem cell rescue.)
What's next to do?
In a word, plenty, starting with the need to
recruit many more patients for the studies ... to see if
the reported results can be reproduced and at what rate, and
also longer follow-up is needed to monitor
the participants for possible delayed complications.
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ClinicalTrials.gov
query for Genetically Engineered Lymphocyte therapy
http://1.usa.gov/rv1Bmn
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And here is the study
- the basis for the clinical report described within
-
which is still recruiting patients:
Protocol:
http://1.usa.gov/n03Upb |
Further, and again assuming the reported outcomes are
reproducible and long lasting, we do not know how quickly this
new technology can be scaled up in order to be delivered to the
many hundreds of thousands of patients affected by the diseases.
... This will require commercialization, licensing, and efficient
manufacturing - as with any new drug, which takes a good deal of
time - and also a profit incentive.
Access to this novel adoptive immunotherapy (even in an
Expanded Access program) would require more efficient
production methods - that the cells can be customized for
each patient in a reasonable period of time.
Is there a reason to be optimistic?
Yes, we think so, because in this case the clinical
results were dramatic in patients with very advanced
disease, and the regressions were causally linked to the
activity of the engineered t-cells by findings from samples
taken from the bone marrow.
Further, unlike chemical therapeutics, the programmed cells
have no
half-life limitation and the killing of malignant cells has very good (if not perfect)
specificity - targeting mainly mature b-cells, a type of
immune cell that one can live without (with IV
immunoglobulin support) and that could
regenerate once the programmed t-cells are disabled or
eliminated.
Finally, we can hope that resistance (to this novel,
living agent) might be futile - the cancer cells may
not be able to escape or survive them. But ...
again, we must note that there are many remaining
questions, as described above.
Karl Schwartz
Snips from a NEJM article on this subject with comments within:
Chimeric ANTIGEN Receptor–Modified T Cells
Highly Active Against Chronic Lymphoid
Leukemia
David L. Porter, M.D., Bruce L. Levine, Ph.D., Michael Kalos,
Ph.D., Adam Bagg, M.D., and Carl H. June, M.D. August 10, 2011
(10.1056/NEJMoa1103849)
“We designed a lentiviral vector expressing a chimeric antigen
receptor with specificity for the B-cell antigen CD19, coupled
with CD137 (a costimulatory receptor in T cells [4-1BB]) and
CD3-zeta (a signal-transduction component of the T-cell antigen
receptor) signaling domains.
=> A clonal population of t-cell that is modified to seek out
and destroy any cell that has the cd19 receptor – all mature
b-cells, malignant and normal.
"A low dose (approximately 1.5×105 cells per kilogram of body
weight) of autologous chimeric antigen receptor–modified T cells
reinfused into a patient with refractory chronic lymphocytic
leukemia (CLL) expanded to a level that was more than 1000 times
as high as the initial engraftment level in vivo, with delayed
development of the tumor lysis syndrome and with complete
remission. "
=> One important aspect: The cells expanded in the body by 1000 times and led to a
complete remission in patient with b-cell lymphoma/leukemia –
chronic lymphocytic leukemia (CLL). This probably could
not happen without preconditioning with chemotherapy.
"Apart from the tumor lysis syndrome, the only other grade 3/4
toxic effect related to chimeric antigen receptor T cells was
lymphopenia."
=> This could be a major side effect, however. Leading to a
deficiency in immunoglobulins and associated risk of chronic
infection.
"Engineered cells persisted at high levels for 6 months in the
blood and bone marrow and continued to express the chimeric
antigen receptor."
=> This is both good and bad – good in that it could mean
that the immune system will continue to eradicate any
lymphoma/CLL cells for a long time – we don’t know yet how long.
Bad in that the it could lead to long lasting immune deficiency.
A specific immune response was detected in the bone marrow,
accompanied by loss of normal B cells and leukemia cells that
express CD19. Remission was ongoing 10 months after treatment.
=> The immune response was confirmed by examination of bone
marrow sample – so it is very likely caused by the adoptive
t-cell treatment.
Hypogammaglobulinemia was an expected chronic toxic effect.
=> As noted above.
Link to further technical discussion in NEJM:
http://www.nejm.org/doi/full/10.1056/NEJMe1106965
copying a snip:
“The tumor lysis syndrome was diagnosed 22 days after treatment
and correlated temporally with the induction of high levels of
cytokines (interferon-γ and interleukin-6) and with an increase
in the number of circulating chimeric antigen receptor–positive
T cells to a level that was nearly 1000 times as high as the
level detected the day after infusion.
Eight months after therapy, chimeric antigen
receptor–positive T cells persisted, and the patient had no
evidence of disease on physical examination or on computed
tomographic, flow-cytometric, or cytogenetic analysis. The
expansion, persistence, and development of the memory phenotype,
not to mention antitumor effects, of these T cells were
impressive.”
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