Thanks dear OvF, and good afternoon to all
Well - how about a dose of hard science to make your day? This one is definitely for the science wonks out there. Better go get a cup of coffee first.
Ready now? Okay....
Overnight, a pre-print scientific paper has appeared on the web, co-authored by the Medical University of Vienna team - the inventors of Imugene's Her-vaxx. I have copied the url at the end of this post so that you can download the paper yourself, but my advance warning is that this is
not an easy read. The paper is written by medical researchers in immunotherapy, and it is intended for other medical researchers in the same field. That does not include me - so my summary below is a simplified version aimed at other non-scientists. The paper itself is not yet peer reviewed and my summary may be based on misunderstandings - because this one is well above my pay grade. With those warnings in mind though - I hope you find my summary useful.
Here we go:
Background facts - Her-vaxx and Herceptin:Before getting to the substance of the Vienna team's paper, it is really necessary to know a few things first. Here are some key dot point factoids:
- Her-vaxx was designed to attack cancers which "over express" (have a larger than normal amount of) something called HER2. HER2 stands for "Human Epidermal Growth Factor 2" - a natural protein on the surface of the cell which has the effect of sending out signals to other cancer cells to promote rapid cell growth. ie HER2 positive (over expressing) cancers tend to grow faster and more aggressively - making them harder to control. The HER2 over expression is caused by specific genes within the cancer cells.
- The mechanism of action for Her-vaxx was designed to mimic that of an existing commercially and clinically successful drug called Herceptin (Trastuzumab) which is widely used against HER2 positive breast cancer and HER2 positive gastric cancer.
- Herceptin is a manufactured Antibody, produced in the lab in volume and then infused into patients over repeat doses. It "binds" to HER2 proteins on the surface of the cancer cell. There are two results of this: 1. It blocks the HER2 growth factor from sending signals that cause rapid cancer cell growth. 2. It identifies the cancer cell as a target for the immune system, which then attacks the cancer cells and hopefully destroys them.
- Her-vaxx does the same thing, by stimulating the immune system to produce natural B cells which produce antibodies to bind to the same HER2 proteins, with the same two effects as Herceptin. The BIG difference - because they are natural to the body - not artificially produced - the B cells and antibodies generated by Her-vaxx do not provoke any toxic side effects such as cytokine storm (inflammation) - which is a common problem with Herceptin. It also appears that the effect of Her-vaxx is permanent; once it has been "taught" how to do this by Her-vaxx, the immune system "remembers" how to produce the B cells and antibodies to bind to HER2. So if the HER2 positive cancer returns, the immune system is able to attack it. Herceptin cannot produce this kind of "immune memory."
- (The above points show why Her-vaxx could be a far better solution than Herceptin: minimal to nil toxicity; long term immune memory, a simple injection (not a major drug infusion process); much cheaper to produce and administer; far less trouble and time for the patient too.)
Limitation - some cancers are very tricky and adaptable!:Although Herceptin has been quite successful as a treatment for HER2 positive cancers, it has alway been the case that some patients who initially improve then have a relapse. Their cancer may shrink - or even apparently disappear - but then it returns and grows. This is most likely for patients who already have advanced and metastatic cancer (cancer which is spreading to other sites in the body).
About 15 years ago researchers discovered a possible cause of this relapse problem. Amazingly it seems that, for some patients, the cancer which initially started off as "HER2 positive" (expressing lots of the HER2 protein) somehow switches itself to being "HER2 negative" during the course of treatment with Herceptin. You can read more here:
https://www.breastcancer.org/research-news/20080904So at that point, of course, the Herceptin would no longer be working - because there would be no HER2 proteins to bind to, or for the immune system to then recognise and attack.
Very very tricky.
Just how/why this happens is unclear to me. I'm not sure if previously HER2 positive cells somehow switch off their HER2 gene. Alternatively - because these cancer cells are not all identical - it may be that there are some "HER2 negative" cancer cells there all along, and by killing off the HER2 positive cells the Herceptin gives them the chance to take over - a bit like evolutionary natural selection. I need to do more reading, or maybe no-one knows yet, but the outcome is what counts here - HER2 positivity can "disappear" - making the Herceptin ineffective.
The new findings by the Medical University of Vienna Team:This latest paper by the Vienna team describes their investigation of the effect of HER-vaxx, and their finding that Her-vaxx (just like Herceptin) can result (for some patients) in some cancers turning themselves from "HER2 positive" to "HER2 negative."
This should be no surprise. Although it gets there a different way, Her-vaxx is targeting the same ultimate mechanism of action as Herceptin - and it seems to work at least as well as Herceptin (and possibly better).
So yes - when the researchers looked at results in lab mice - they saw a similar problem: some of the previously HER2 positive cancers had become "HER2 negative" after treatment with HER-vaxx.
To verify this they then studied samples of a tumour from an actual
human patient in the Her-vaxx Phase 1b trial.
This patient had gastric cancer with "four target lesions (2x liver and 2x lymph) and five non-target lesions." They were given chemotherapy plus seven vaccinations of Her-vaxx. (Note - this was at the original 50μg maximum dose, but IMU is now cleared to double that dosage in the current Horizon trial).
The response was actually extremely good! "During the course of the vaccination, the patient responded to the vaccine and generated high levels of vaccine-induced antibodies against Her-2/neu... The strong antibody response in this patient, together with cellular responses ...correlated with the patient’s increase of progression-free survival and tumor reduction." (ie. the strong response of the immune system indicates that their improvement was due to the Her-vaxx, and not due to the chemo.)
And the initial results were excellent: "After 182 days of treatment, the patient had a partial response (PR) for target lesions with a 71% reduction in the sum of diameters (SOD) from 177 mm to 52 mm, and a complete response (CR) for four of five non-target lesions. By day 266, the target lesion SOD (nadir) was reduced by 79% (from 177 to 37 mm). "
That is a great result - a 71% reduction in the target tumours and 4 of the 5 non target tumours were eliminated (complete response).
However, "350 days after treatment, the patient showed disease progression, and the primary tumor size increased by 16% to 43 mm, according to RECIST 1.1. The patient also developed a newly identified metastatic lesion in the stomach,
which was Her-2/neu negative [10], suggesting immune evasion of the metastatic tumor during Her-2/neu therapy."
So in other words, this was just like the result seen in some Herceptin patients - the surviving cancers somehow switched from being HER2 positive to being HER2 negative. The cancer was "evading" the treatment!
But there was more: As well as becoming HER2 negative (no over expression of the HER2 growth factor)
the cancer had also become positive for the PD-L1 protein! Before treatment, the patient's cancer had been
negative for the PD-L1 protein!
Oooh.... So why is that important? Well - here is a really good simple explanation of what PD-L1 is, and what it does:
"
Normally, PD-L1 is found on certain healthy cells. It acts as a kind of "brake" to stop cells in your immune system, called T cells, from attacking healthy cells in your body. If cancer cells have high amounts of PD-L1, they can turn your T cells off so they can't attack the cancer cells." Source: https://medlineplus.gov/lab-tests/pdl1-immunotherapy-tests/For a more detailed explanation:
https://jhoonline.biomedcentral.com/articles/10.1186/s13045-020-01027-5Basically - the PD-L1 protein on the cancer cell binds to and blocks a receptor on the immune cell called PD1, and that blocking action stops it from attacking the cancer cell.
So - instead of using HER2 to stimulate rapid cancer cell growth, the cancer was now using the PD-L1 protein to tell the immune system "don't attack me!"
This is not all bad news:
The researchers point out that the same effect of "switching on" PD-L1 has been reported with Herceptin, when used (as in the Her-vaxx trial) against gastric cancer. Again - no surprise. (In fact it's an indication of just how well Her-vaxx mimics the effect of Herceptin).
And the bad news (your cancer is now PD-L1 positive, and blocking the immune system) can also be seen as good news - because cancers which are PD-L1 positive are vulnerable to another kind of immunotherapy - a "checkpoint inhibitor" which can "block" the PD-L1 protein and stop it from turning off the immune system.
The researchers conclude that this indicates the need for combination therapy - using Her-vaxx plus a PD-L1 checkpoint inhibitor, in combination. They note that Imugene is planning two combo trial of Her-vaxx: one with Avelumab (Bavencio) - which is a PD-L1 blocker. The other trial is with Pembrolizumab (Keytruda) which is a blocker for the PD1 protein (another kind of checkpoint inhibitor). (See action 5 - Conclusions - of the Vienna team's paper. url is at the end of this post).
I believe the "NeoHERIZON" trial with Avelumab/Bavcencio - the anti PD-L1 - has been put on hold, whereas the NexHERIZON trial - Her-vaxx plus Pembrolizumab (Keytruda) - has been prioritised.
However, Keytruda is extensively prescribed as a drug for use against PD-L1 positive cancers. See this url for details:
https://www.keytrudahcp.com/biomarker-testing/pd-l1/#:~:text=Advanced%20Cervical%20Cancer-,KEYTRUDA%2C%20as%20a%20single%20agent%2C%20is%20indicated%20for%20the%20treatment,by%20an%20FDA%2Dapproved%20test.
One other interesting piece of news:
In the paper, the Vienna team disclose that they have also developed a variant of Her-vaxx - a new and improved version - which combines the original HER2 targets (which mimic the effect of Herceptin) with additional HER2 targets which mimic the effect of another drug - Perjeta (Pertuzumab). Perjeta is commonly used in combination with Herceptin to attack HER2 positive breast cancer. The two drugs hit
different HER2 proteins on the cancer cell - and they seem to have a stronger effect when used together.
So now there is a version of HER-vaxx which achieves the same combination. This would imply an intention to start a trial in HER2 breast cancer at some point. Those with a very long memory may recall that the very first trial of HER-vaxx, conducted by the Vienna team themselves, before the involvement with Imugene, was a limited Phase 1 trial in HER2 positive breast cancer. That was a very early formulation of Her-vaxx, far less powerful than the current version, but it produced good evidence of immune system stimulation and was their initial "proof of concept" for the B cell immunotherapy approach.
Read it for yourself:Here is the url to download the Vienna team's latest paper. Better get another coffee first. Better make it a strong one:
https://www.google.com/url?sa=t&rct=j&q=&esrc=s&source=web&cd=&ved=2ahUKEwi0gMmNwdiCAxUXavUHHUxgC7wQFnoECAkQAQ&url=https%3A%2F%2Fwww.preprints.org%2Fmanuscript%2F202311.1400%2Fv1%2Fdownload&usg=AOvVaw3hrC8ALqwit8UErW_jkbuh&opi=89978449Cheers
Mmmmm - yummy science!!! Enjoy!!!!
Cheers
Dave
PS This is a complex one. All corrections welcome!!!!
(20min delay)