It is simple- even for B cell lymphoma Expression of HYAL2 mRNA, hyaluronan and hyaluronidase in B-cell non-Hodgkin lymphoma: Relationship with tumor aggressiveness- MORE HA in DLBCL- worse CAR-T response there too than olther lymphomas.
Article first published online: 25 AUG 2004
Hyaluronidases and their substrate, hyaluronan (HA), were mainly explored in solid tumors but rarely in hematologic malignancies. While HA involvement was demonstrated in invasion and metastasis in most cases of solid tumors, the role of hyaluronidases in cancer progression remains controversial. One of the hyaluronidases, HYAL2, is suspected to be involved in the first step of HA degradation. In this work, HYAL2 mRNA, HA and total hyaluronidases expression were examined in lymphoma tissue extracts and correlated to the lymphoma subtype. Real-time RT-PCR was performed to evaluate HYAL2 mRNA. HA and hyaluronidase were assayed by enzyme-linked sorbent assay. Our results showed that HYAL2 mRNA expression was correlated to lymphoma diagnosis (p = 6 × 10−3) and was significantly lower in high-grade lymphoma, i.e., diffuse large B-cell diffuse lymphomas (DLBCLs). Several forms of hyaluronidase were detected by zymography and total hyaluronidase activity detected in tissue extracts was not significantly different according to tumor grade. HA levels also correlated to lymphoma subtype (p = 1 × 10−5) and were higher in DLBCLs. Moreover, HYAL2 mRNA and HA expressions were inversely correlated (p = 0.035). HYAL2 gene is localized on chromosome 3p21, which contains candidates tumor suppressor genes. Our results suggest that HYAL2 may have a prognostic significance in lymphomas and an antioncogenic activity. Conversely, HA overexpression in high-grade lymphomas is in favor of its involvement in tumor development and could provide a useful target for lymphoma therapy using HA-binding peptides.
CAR-T cells goes where their target is- So, if that target is sitting behind Hyaluronan, man activated CAR-T cells are bound via CD44 & killed- Not so w Blood Cancer targets-No Hyaluronan pericellular cuff- So to keep Blood and Solid CAR-T levels equal- imn effect to keep efficacy equal- one needs to Remove Hyaluronan from solid tumor cells or just just use CAR-T to treat Blood Cancer.
They have not announced plans on BTD application. They already HAD End-of-Phase 2 mtg- the March meeting- so they can start Phase 3 before ending phase 2- which will last as long as there are survivors.
Why just 7.5 mos as of March 2nd? Becuse the OS is being calculated in post halt patients- all of whom have had Heparin- which we know has a beneficial effect in PDA- see MNTA.
Good summary- 2 things I can offer- 1. the FDA awarded PFS as a surrogate endpoint in Metastatic Panc Ca for the 1st time to HALO -per Citibank analyst. OS is traditionally the Primary endpoint. 2, Celgene has been rejected by NICE on Abraxane and was rejected again- on cost/effect ratio- PegpH20 changes that in Celgene's favor.
The News At ASCO Will not be good for HALO shorts.
And Still counting- 11.1 is Best on Record- Folfirinox- Will pass it before July.
Please compare that to the response in Phase 1 ALL with CAR-T= Complete Remissions- 2/6 "stable disease for 4mo" 1 reduction of signal by a liver met - could be chance- no p value. No I'll sticjk w "fail" in comparison to previous CAR-T responses- What's the difference? Access.
Here's Dr June on AL P1:
"CRI: The results from your phase I study that were published last year were impressive and got a lot of media attention. Were you expecting those results, or were your surprised?
Dr. June: We were astonished. It worked better in humans than it did in our preclinical studies where we made CAR T cells in mice with leukemia. This was a major exception. So in the mice we found that each of the CAR T cells killed about 40 tumor cells, and as I said in humans they killed more than 1,000 tumor cells. For some reason it works better in humans than it does in mice. It’s usually the other way around. So it was a pleasant surprise. Our first patients that we reported are just now past their two-year anniversary and they remain leukemia-free, so it remains very promising."
I always say, you shouldn't treat Blood Cancer by placing your CAR-T infusion in the middle of a Pancreatic tumor- and Vice Versa.
This was the only analyst that put AACR data to work with regard to HALO.
Melanoma is not a high Hyaluronan tumor- so with all due respect, you are answering a question I didn't ask. Halozyme preclinical work on activated T cells as well as the work of others-
Eur J Immunol. 2011 Apr;41(4):1108-19. doi: 10.1002/eji.201040870. Epub 2011 Mar 1.
Hyaluronan binding identifies the most proliferative activated and memory T cells.
Maeshima N1, Poon GF, Dosanjh M, Felberg J, Lee SS, Cross JL, Birkenhead D, Johnson P.
J Immunol. 2008 Nov 15;181(10):7044-54.
Hyaluronan induces cell death in activated T cells through CD44.
Ruffell B1, Johnson P.
Demonstrates that treating Pancreatic cancer through a blood delivered Rx lacking hyaluronidase is as futile as trating ALL with an intrapancreatic Ca injection. Hyaluronan Binds and is Toxic to Activated T cells. CAR-T therapy is just that.
HALO CEO Intrigued by AACR data- said in Response to Question on CAR-T + PegpH20 by CITI @ Q1 15 Earnings mtg.
Kennen Mackay - Citigroup Global Markets Inc
Hi thanks for taking my question, I have a question on the – study that came out this quarter there is lot of evidence suggesting PEGPH20 really reinstall contributes to access to solid tumor given the (CAR-T) therapies have had some issues with solid tumor access have you been in discussion with [indiscernible] companies who have the potential to combine with PEGPH to increase the selling and this is something that you are capable considering?
Helen Torley - President, Chief Executive Officer and member of the Board of Directors
Kennen thanks for that question, we are certainly are excited by the data that was presented at AACR and the potential to be able to we combined also with CAR-T as you know they are quite early in their development in terms of solid tumors but based on the mechanisms we understand to-date we certainly see that as potential and something that we are going to be continuing to follow upon and potentially exploring the future.
3. CEO says she's in late stages of talks to partner with an experienced Diagnostic Co.- Could be Roche Diagnostic or Illumina.
Keytruda is leading Optivo in Melanoma but trailing in NSCLC- so it's a grear opportunity for PegpH20 to increase the target patient population to include those under 59% PD-1 positive. I expect increased PFS and similar (v high) ORR data at ASCO but MOS is still counting in my opinion- will be about 10.5 mos in end of May- will pass Folfirinox in June and continue- there's approx a 1.4 ratio of PFS to OS, so I think there's a while to go.
Small mind shows itself again- I mean at this point with the last 5 analyst Price Target upgrades, the 9.2 mo interim PFS/71% RR, and the positive FDA B meeting, you'd have to be an imbecile to short this stock- the short interest has fallen by 25% in the past 4 months-per NASDAQ- only the dumbest of the dumb are hanging on like a pit bull - and LIKE a pit bull- that includes a brain 3 sizes too small for human discourse. Hey Fido- all 3 of my UPCOMING (of that long Catalist) HALO catalysts DO involve PegpH20.