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Chimeric Antigen Receptor enhanced T-cells (CAR T-cells)

Last update: 07/20/2017

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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.

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

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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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