Why IMU is a multi multi bagger, page-20973

Oh, friend Wedgeman.

No problem. Can you just hold on a decade or so while I go get myself a Phd in the relevant fields? hahahahaha......

No? Oh well - here is my non-expert attempt at an answer.

Some of what you ask is easy enough - by considering the disadvantages of autologous CAR-Ts. (All current approved CAR-T's are autologous).

Autologous CAR-T's are developed by harvesting the patient's own T cells - then re-engineering them to recognise and attack a target on the cancer cells (eg CD19). The re-engineered T cells are then cloned in large quantities in the lab, and - finally, administered back to the patient as an infusion. These "Chimeric Antigen Receptor" T cells then bind to the target on the cancer cell and attack the cancer cell.

If that all works for the patient, then Yay! But there are some key problems with this approach:

• It only works if the patient has T-Cells that are healthy to be harvested and re-engineered in the lab, and still be effective/viable. However a lot of these patients are very unwell, and some patients do not have T cells that are viable for generating an effective CAR-T.
• The process also requires the services of a very specialised laboratory - and those services are not keeping up with demand. In the USA around 20% of patients are dying before they can get a "lab slot" for their CAR-T cells to be manufactured. Source: https://www.advisory.com/daily-briefing/2022/06/03/car-t-therapy
• Even if you can get a lab spot immediately, the manufacturing process takes at least 17 - 22 days. In that period, your disease may continue to get worse. Some patients just can't wait that long. Source: https://www.phgfoundation.org/briefing/car-t-cell-therapies
• The CAR-T mfg process itself is high tech, labour intensive and therefore really @$#%ing expensive!!! So that definitely limits access to treatment.
• You really do need to be close to a centre that can do all this - which also limits access

Compare this with an Allogenic CAR-T like Azer-Cel. Allogenic CAR-T's are manufacture from healthy T-Cells donated by a healthy subject. They are then "re-engineered" to eliminate graft vs host disease problems (where a patient's immune system rejects tissue generated by a different body to their own). Then the T-Cells are altered to recognise the target on the Cancer cells - eg CD19 in the case of Azer-Cel. The re-engineered cells are then mass produced and cryo-preserved (frozen) - and distributed for use.

The key to this - it's all done in advance, as a single generic product to be used for any patient who needs a CD19 CAR-T.

So there are huge advantages!:

• It does not require the patient to have healthy T cells - or to have their own T cells harvested
• There is no "waiting period" to get a laboratory spot. The CAR-T is already available "off the shelf"
• There is no waiting period for the mfg process! The mfg has already been done in bulk in advance.
• It still won't be "cheap" necessarily - but it will be a LOT cheaper than having you own T cells harvested, then specifically re-engineered and cloned in quantity just for you. This is not "bespoke" medicine. It's done in bulk as a generic product. Far cheaper.....
• Location wise - you don't need to be near a specialist lab. Within reason, the cryopreserved CAR-T can be sent to your hospital.

So those are the easy to see advantages.

Then we come down to comparing two much trickier issues: Effectiveness and Safety.

I won't deal with effectiveness here except to say that: Azer-Cel has demonstrated excellent effectiveness in patients with Diffuse Large B-Cell Lymphoma (a type of non-Hodgkins Lymphoma) who have relapsed after treatment with one of the current approved autologous CAR-T therapies. So for those patients Azer-Cell seems to be more effective than an autologous CAR-T, or it at least offers an additional effective treatment. As with any new cancer drug - you start off identifying one effective use, and hopefully get approved for that. Then - over time - the drug gets tried in other indications and - over time - you find out whether it is more effective than existing treatments for other cancer types/situations (or not). ie We don't know if Azer-Cel is generally more effective than autologous CAR-T's, but we already know that even if it shows similar levels of effectiveness, then it is far superior as a treatment overall, because of the other advantages listed above.

Now to safety - which you list as a key interest: "our Azer-cel is not showing any toxicity at this early stage. Why is that..?

Honestly - I think the answer is "No-one really knows." Or at least - no-one knows for sure.

I say this because - so far as I can see - no-one knows for sure why the existing CAR-T's have (for may patients) potentially serious side effects and (for some) severe neuro-toxicity which can even be fatal.

The most common side effect of CAR-T is Cytokine Release Syndrome (CRS) - essentially an inflammation caused by the immune system going into overdrive to attack. Mild CRS is not a problem - typically described as "Flu like symptoms." (Side note: That's also the description Leslie Chong has used to describe the mild side effects - so far - of Vaxinia in the MAST trial - so my assumption is that the MAST patients are also experiencing mild CRS. That makes sense - because Vaxinia is indeed an infection, and it is also alerting the immune system to attack the cancer cells. So mild CRS is to be expected - and I think welcomed as a sign that the Vaxinia is doing what it should do, and so is the immune system).

However - severe CRS is also fairly common with autologous CAR-T treatments, and severe CRS can result in extreme body temperatures, seizures, organ damage and even death. Mild CRS (Grade 1 or 2) is reported in 30% - 100% of CAR-T patients (depending on type of CAR-T and disease) but severe CRS (Grade 3 or 4) occurs in 10 - 30% of patients - and that's not good! Source: https://www.eviq.org.au/clinical-resources/oncological-emergencies/3500-cytokine-release-syndrome-associated-with-car#:~:text=Incidence%2Fprevalence&text=The%20severity%20of%20CRS%20is,CRS%20from%2010%20%2D%2030%25.

The other big potential side effect of CAR-T is "immune effector cell-associated neurotoxicity syndrome" - or "ICANS" for short. ICANS neurotoxicity is less common than CRS, but really scary. Symptoms can include word finding problems, inability to write, confusion, memory loss, speech problems, headaches... and in severe cases seizures, loss of consciousness and death. The scary part: "ICANS can progress in a few hours (18) and results in quick, fatal outcomes in a minority of patients due to fulminant cerebral edema (1–2% estimated incidence)" and "Fatal neurotoxicity has been described in pivotal studies [JCAR-015 (NCT02535364)], prompting even trial cessation, with an overall incidence of 3–9% after CD19-directed CAR T-cell infusion"
Source: Section 2.2 of https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10117964/

But why does it happen? Well - if you read section 2.3 of the same journal article (and it's less than a year old) - the authors say that "The mechanism of CAR T-cell neurotoxicity remains to be well-elucidated " - which is polite science speak for "we don't really know, dudes.' They go on to say that the "most generally accepted" explanation is that it is "driven by systemic inflammation and cytokine production." Which is - CRS!

Just why CRS causes the neurotoxicity, well.... they don't really know. You can read it yourself - but I was interested to read this part: "Several risk factors related to CAR T-cell neurotoxicity have been described, such as pre-treatment disease burden, in vivo CAR T-cell expansion, early and severe CRS, and CAR T-cell dose (3). In fact, faster CAR T-cell expansion in vivohas been related to the onset and severity of ICANS"

Really - there are saying that there is an apparent correlation between ICANS and those factors. I guess it makes sense that a severe CRS inflammation might cause brain damage - but the one that leaps out at me was the last one: "faster CAR T-cell expansion in vivohas been related to the onset and severity of ICANS." ie. The faster your new CAR-T cells multiply in your body, the more likely it is that you will get ICANS.

So why did that get my attention?

Well..... you yourself, my Wedgie mate, mention that "our Azer-cel is not showing any toxicity at this early stage" and you asked me - why?

My initial thought was FIIK, but my second thought was - well I really would like to know, and that prompted me to do some reading.

Not a lot of reading though, because I have limited time. I should add my usual disclaimer here - I'm not a scientist and this is not anything like a real literature review. Besides - Azer-Cel is a relatively new drug and the only people who really know about it are the inventors and testers - so I went reading what Precision Biosciences have said about this. I mean - it's their drug, and they did the initial clinical trials.

Without going into too much detail, the key fact here is that yes - the latest clinical trial of Azer-Cel showed excellent safety compared to other CAR-Ts. In fact - out of 63 patients available for evaluation "No Grade 3 or greater cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), infection or graft versus host disease was observed "

Read that again - No CRS or ICANS at Grade 3 or worse. In fact no side effects of any kind beyond Grade 2.

Wow. Compare that to the figures for current autologous CAR-T quoted above. It really is a phenomenal result. And with excellent effectiveness. "Azer-Cel Achieved 83% Overall Response Rate (ORR), 61% Complete Response (CR) Rate with 55% Durable Response Greater Than or Equal to Six Months Among Evaluable CAR T Relapsed Subjects (n=18). https://investor.precisionbiosciences.com/news-releases/news-release-details/precision-biosciences-provides-update-allogeneic-car-t-0

But why? Well - apparently results in earlier trials were not as good. I haven't had time to dig up the actual data on that, but it can be inferred from their statement in their press release last year:

"Azer-Cel Safety Profile was Significantly Improved Compared to Prior Cohorts in Patients Dosed Using Optimized Product at Lower Intensity Lymphodepletion; No Grade 3 or Greater Allogeneic CAR T Related Adverse Events Were Observed. " Source: https://investor.precisionbiosciences.com/node/9926/pdf

Which still doesn't tell us exactly "why" the safety was "significantly improved." ( I would describe it as "extremely good! ") - but it does give two hints.
Hint 1: The product has been "optimised." I'm still looking - but I haven't found any more detail on that - just several references too it being "optimised." I'll keep looking. It may be code for "better gene editing" using the MaxCyte technology now in use also by Imugene. As I say - I will keep looking. Does any other reader know the answer? Please chip in if you do...

The second hint they gave is "Lower Intensity Lymphodepletion."

Say what?

OOhhh. Well - before CAR-T is administered, the first step of the treatment is to destroy your existing immune system T cells!!! They do it with Chemotherapy!!! That is the process called "Lymphodepletion." Source: https://metastatictrialtalk.org/from-the-experts/lymphodepletion/

So why do they do that? Well - the whole point of CAR-T therapy is to give you new T cells which have been engineered to attack the cancer. Destroying your "old" natural T cells has the effect of making the environment more hospitable to the new CAR-T cells. A list of advantages is shown in this website: https://multiplemyelomahub.com/medical-information/lymphodepletion-optimization-for-car-t-cell-therapy#:~:text=Lymphodepletion%20before%20CAR%20T%2Dcell,the%20efficacy%20of%20the%20procedure.

With Lymphodepletion your new CAR-T cells can expand faster, and persist longer.

I guess that's a good thing - but then I read the comment above that" faster CAR T-cell expansion in vivohas been related to the onset and severity of ICANS." ie. The faster your new CAR-T cells multiply in your body, the more likely it is that you will get ICANS.

Which jumped out at me, because Precision BioSCience is saying that their "optimised" version of Azer-Cel is administered with a "Lower Intensity" Lymphodepletion.

So presumably the "lower intensity" lymphodepletion made the environment just that bit less hospitable to the Azer-Cel CAR-Ts, causing them to expand/multiply more slowly - therefore less inflammation and less ICANS.

Note also that the lymphodepletion Chemo can itself cause neurotoxicity, so a less intensive Lymphodepletion would make that less likely to happen: "Specific toxicities associated with lymphodepletion agents: Fludarabine (Flu): fevers and neurotoxicity". Source: https://multiplemyelomahub.com/medical-information/lymphodepletion-optimization-for-car-t-cell-therapy#:~:text=Lymphodepletion%20before%20CAR%20T%2Dcell,the%20efficacy%20of%20the%20procedure.

And that's my best answer, because I'm out of time.

Hope it makes sense!

Best wishes to anyone who had the patience to read this far. Omg You are a hero...

Cheers

Dave