You will read much on this encouraging news

[Guest guest]

Snips from NEJM article with comments within.

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Chimeric ANTIGEN Receptor–Modified T Cells in Chronic Lymphoid Leukemia

L. Porter, M.D., Bruce L. Levine, Ph.D., 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 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.

⇨ 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)

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.

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.â€

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My first impression is that this result (described as CR in 2 of 3 patients, and

significant improvement in the partial responder) marks a genuine break-though

in immunotherapy.

However, we don’t know yet at what rate we will see this kind of response in

other CLL or lymphoma patients. Other questions remain, such as the consequence

of depleting all of your b-cells – perhaps indefinitely – because of the

long persistence of the activated t-cells.

... While treatment with Rituxan has a similar effect, it is generally reversible

with discontinuation of the drug.

That said, and if this kind of result is reproducible, scientists feel that they

should be able to turn off the activated t-cells with immune suppressing therapy

if needed (and other means) … so there seems to be genuine reason for

hopefulness about this new technology – even against chemo-resistant

malignant-cells, which was made possible by amazing science (each scientist

building on the insights of another) but also by patients willing to be the

first in line to receive genetically engineered t-cells into their blood.

Karl

Patients Against Lymphoma

www.Lymphomation.org

Evidence-based information on lymphoma, independent of health industry funding