Controlling CAR-T cells
Larry H. Bernstein, MD, FCAP, Curator
LPBI
New discovery – Remote control of CAR-T cells
CAR-T cells have been emerging as an effective approach to treat cancer and autoimmune diseases. A problem with CAR-T cells is that once they are infused, they are on their own exerting autonomous activities, which can lead to severe side effects due to the extensive lysis of tumor cells. Researchers have been seeking ways to control CAR-T cells after they are infused to balance the desired therapeutic effect and the side effect. Recently, a group of researchers at UCSF found a way to control CAR-T cells after they are put into patients, through a rapamycine analogue gated chimeric receptor.
CAR-T cell system has two components: one is the recognition domain that binds to CD19 to target B cells; the other is the functional domain to activate cellular pathways to killing the targeted cells. Those two domains are typically preassembled. What this group of researchers did is to separate those two domains and make them come together only in the presence of the activating molecule, a rapamycine analogue. They showed that in the absence of the activating molecule, CAR-T cells still bound to CD19. But, they didn’t kill the targeted cells unless the activating molecule was present. In addition, by adjusting the dose of the activating molecule, the strength of CAR-T cells activities can be titrated as well.
Chia-Yung Wu, etc. (October 2015) Remote control of therapeutic T cells through a small molecule–gated chimeric receptor.Science
Remote control of therapeutic T cells through a small molecule–gated chimeric receptor
http://pharmaceuticalintelligence.com/2016/02/06/reengineering-therapeutics/
Reengineering Therapeutics
Larry H. Bernstein, MD, FCAP, Curator
LPBI
The synNotch solution: UCSF scientists engineer a next-gen T-cell immunotherapy
Sunday, January 31, 2016 | By John Carroll
CAR-T has been all the rage in cancer R&D for several years now as a slate of biotech upstarts pursue highly promising work reengineering T cells into attack weapons by adding a chimeric antigen receptor that can zero in on particular cancer cells. The approach has been highly effective in acute lymphoblastic leukemia, triggering an attack on B cells by homing in on the CD19 antigen, a breakthrough that has inspired a race to the regulatory finish line with the first CAR-Ts.
http://pharmaceuticalintelligence.com/2016/02/11/regulatory-dna-engineered/
Regulatory DNA engineered
Larry H. Bernstein, MD, FCAP, Curator
LPBI
New Type of CRISPR Screen Probes the Regulatory Genome
Aaron Krol http://www.bio-itworld.com/2016/2/8/new-type-crispr-screen-probes-regulatory-genome.html
February 8, 2016 | When a geneticist stares down the 3 billion DNA base pairs of the human genome, searching for a clue to what’s gone awry in a single patient, it helps to narrow the field. One of the most popular places to look is the exome, the tiny fraction of our DNA―less than 2%―that actually codes for proteins. For patients with rare genetic diseases, which might be fully explained by one key mutation, many studies sequence the whole exome and leave all the noncoding DNA out. Similarly, personalized cancer tests, which can help bring to light unexpected treatment options, often sequence the tumor exome, or a smaller panel of protein-coding genes.
sjwilliamspa commented on Controlling CAR-T cells
Controlling CAR-T cells Larry H. Bernstein, MD, FCAP, Curator LPBI New discovery – Remote control of CAR-T cells CAR-T …
Interesting method to use a chimeric heterodimer receptor to control CD19 activity however it would be ineresting to see if cancer replapses occur more frequently. Originally it was thought the CART would act, after initial treatment, eventually to patrol the body for any recurring tumor cells. Using rapamycin would be interesting although there had been some immunotoxic concerns with chronic use (although long term use of rapamycin and other mtor inhibitors seemed to prolong lifespan in immunodeficient animals)
Temsirolimus, an Inhibitor of Mammalian Target of Rapamycin athttp://clincancerres.aacrjournals.org/content/14/5/1286.short
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This is very insightful. There is no doubt that there is the bias you refer to. 42 years ago, when I was postdocing in biochemistry/enzymology before completing my residency in pathology, I knew that there were very influential mambers of the faculty, who also had large programs, and attracted exceptional students. My mentor, it was said (although he was a great writer), could draft a project on toilet paper and call the NIH. It can’t be true, but it was a time in our history preceding a great explosion. It is bizarre for me to read now about eNOS and iNOS, and about CaMKII-á, â, ã, ä – isoenzymes. They were overlooked during the search for the genome, so intermediary metabolism took a back seat. But the work on protein conformation, and on the mechanism of action of enzymes and ligand and coenzyme was just out there, and became more important with the research on signaling pathways. The work on the mechanism of pyridine nucleotide isoenzymes preceded the work by Burton Sobel on the MB isoenzyme in heart. The Vietnam War cut into the funding, and it has actually declined linearly since.
A few years later, I was an Associate Professor at a new Medical School and I submitted a proposal that was reviewed by the Chairman of Pharmacology, who was a former Director of NSF. He thought it was good enough. I was a pathologist and it went to a Biochemistry Review Committee. It was approved, but not funded. The verdict was that I would not be able to carry out the studies needed, and they would have approached it differently. A thousand young investigators are out there now with similar letters. I was told that the Department Chairmen have to build up their faculty. It’s harder now than then. So I filed for and received 3 patents based on my work at the suggestion of my brother-in-law. When I took it to Boehringer-Mannheim, they were actually clueless.