Friday, May 31, 2013

Live from ASCO 2013: Targeted B cell therapies

Raw review of the first session on targeted B cell therapies.

Typing fast. May have made errors but wanted to get this out

After my bad karma of a weird 35 miles and 16 minute diversion from Orange County to Ontario and then another three hour delay due to weather, I arrive in Chicago four hours late.

Today my karma was good: the hotel and shuttle were perfect. At the meeting 10 minutes early.

ABC diffuse B cell lymphoma DLBCL

NF(kappa)B signaling
Ikk(beta)kinase??

Stuck in the on position

Message from BCR- turns out that BTK is turned on upstream

Ibrutinib binds to site only found in 10 kinases covalent binds to cysteine 481, lasts all day

Inhibits BCR signaling and works other ways when BCR not turned on

Failed in primary refractory disease, worked better in relapsed/refractory

Works great in ABC type as expected Small #s

CD79B mutation 70% response rate, without still 31% response rate-
MYD88 +CD79B 4 of 5 response
MYD88 resistant Poor response??
CARD 11 downstream no response as expected

Pre-clinical trials

Ibrutinib synergizes w PI3K (inhibitor maybe alpha) mTOR, lenalidomide, steroids, chemo

IRAK4 inhibitors???- selective. Works with ibrutinib

BCR Signaling

Other Targets:


  • mTOR
  • SYK non receptor fostamanib 

BTK inhibitor (ibrutinib)

Little cumulative toxicity- marrow and elsewhere counts stay good

CLL

PFS 96%?  in RX naive (Byrd from ASH 2012) abound 60% in R/R 17 p at 2 yrs

MCL

high response rates 70%
like other biologicals improves the longer patient stays on drug

Other BTKs

CC292 (used to be AVL-292)

Didn't mention but ONO has a BTK inhibitor in early trials that  pre-clinical is strong

More Targets:

PI3K Idelalisib

CLL  significant nodal reduction including those with 17p
Also MCL and others
Little marrow toxicities, some liver enzymes up, pneumonia

Another PI3K
IPI-145 Phase 1 study  Good responses including response in Hodgkin's and T cells!

Dumping of cells from nodes and marrow into the blood (evidence from the marrow is thin- I asked)

Don't get the high WBC when mixed with chemo

EPIGENETICS (Dana Farber)

IN THE NUCLEUS that the actions happens

Sequencing cancer genomes

600,000 events altered, at least 486 important??? ( not sure of #)

Only 15 drugs that targets somatic mutation

Also progression- Need to get to master regulator in nucleus

Histone is critical

HDAC removes markers (placeholders)
Binds zinc  -removes reminder cap
Early w cardiac toxicity


Topical T cells treatment that breaks down when absorbed into blood so less toxicity

Bromodomain inhibitor JQ1

? turns off master growth MYC genes in MM

XANX  bromodomain inhibitors

Dana Farber open-source model of drug discovery.

Questions about how to control cost

That's it for now. I am sure there are mistakes in this. Please forgive. I just wanted to get this out fast in this unedited form to give you a sense of the barrage of information, but later I will of course return to my more editorial style. And videos too soon.

So much happening. So much info. This is all good.

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1 Comments:

Blogger pkenn said...

Wow! I'm glad I don't have to process all of this and then try to explain it in layman's terms! Thanks, as always for all the ways you helpmus deal with our questions and fears! Is there a file of links to your videos separate from the listing of posts? it would be nice to be able to refer people to a listing like that.

Pat

June 5, 2013 at 11:55 PM  

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