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Good points. From here the SP will be driven by data and any deals that can be struck, however a clear statement from the company regarding how they plan to proceed with solid tumors would be welcomed by the market, IMO. More antigens? Higher dosing? Earlier dosing? Longer dosing? Combinations with checkpoint inhibitors?
For any patient that is progressing on or off chemo in TACTOPS, they could P1 or compassionate use new antigens in pep mixes. These unfortunate patients have essentially received a death sentence so it is either hospice or a supercharged pep mix, perhaps with follow on checkpoint antibodies.
I'd like to see an aggressive, pro-patient plan outlined, that pulls out all stops for pancreatic cancer.
All that is needed is another CR in TACTOPS and it would be quite clear that Multi-TAA is active in PC, as CRs are so rare with chemo alone. The first one could have been chance, but not a second one IMO (at least the probability of 2 is remote in such a small trial).
Sure. If they have a patient showing progressive decrease in size of tumor on serial CT scans, he/she may be headed for a CR. Problem is they may stop dosing cells before they get there (max 6 doses).
I think if they get another CR in Arm A in the remaining patients, it would confirm activity of the combo in PC and they would PR it. I think if presented in the context of all the data including immune responses, the market would clearly understand the CR was not chance because they are so rare with chemo alone. IMO the next CR will most likely be seen with Folfirinox, as was the first. Oxalloplatin may be a key ingredient as it produces immunogenic cell death.
Makes perfect sense to partner for PC. This will be a significant commitment, as there is a lot of optimizing to be done (earlier dosing, increased dosing, longer dosing and enhanced antigen pep mix along with checkpoint blockade, with various options including anti-PD1/PDL1, VISTA, LAG3, CTLA4 among others). I think this immuno/chemo combo is really the best hope I have seen that can make a serious dent in PC. The CR with Folfirinox is a very good sign though not confirmatory of activity just yet.
As usual, spot on. We all know dilution is hanging over our heads, so it's a game of chicken with the CEO whether he has something else brewing with which he could stun the market (e.g. partnership, TPIV200 data, other solid tumor or hematologic malignancy responses, another PC CR pending, etc.) It's clear that this treatment works, both from the clinical responses in heavily pretreated patients and the correlative immune response data. A cancer treatment that works with no side effects! Hmmm If this was a charity, I give them money. For now, I'll just buy the stock. Easy decision at this level.
The reason I'm invested in marker is quite simple. I think the evidence for activity for Multi-TAA is essentially unassailable in hematological malignancy and suggested but not yet confirmed for pancreatic cancer. With the low cost and absence of side effects, I just don't see how Multi-TAA cannot become an important addition to many cancer treatment regimens, particularly combination treatments. If immunotherapy is ever going to work for the majority of patients, it will likely take multi-targeted strategies, without compiling side effects. Multi-TAA fills that niche beautifully. We now know it can be used with a multi-dosing strategy with chemotherapy and chemotherapy apparently does not suppress in vivo expansion or epitope spreading, or at least suppression can be compensated for with multi-dosing. We don't know yet how this will perform with checkpoint blockade, but it certainly makes sense to expect some degree of synergism. I think it's time for a full court press and if raising capital is the problem because the market has not rewarded MRKR with a reasonable SP, the CEO should immediately pursue one or more strategic partnerships. I'd be surprised if he is not already doing so.
I think the low cost of manufacture is well known. I think the revenue potential comes from this being used in both metastatic disease and as an adjuvant. A lot of patients fall into those categories. Take melanoma. Currently adjuvant therapy for stage 3 disease is anti-PD1, which has serious side effects (IRAE). Many of the anti9gens MRKR uses in pep mixes are expressed on melanoma. If Multi-TAA is better than anti-PD1 in an adjuvant setting for stage 3 disease or it can be used for earlier stage disease because of absence of toxicity, there is a large patient number that might be treatment candidates. Same case in other high, or even moderate risk patients rendered NED by surgery.
Almost all biotechs at this MC range go through wild gyrations in SP for no good reason. Here we have clear evidence of efficacy in lymphoma with 5/15 durable CRs in heavily pretreated patients. Amazing really. This correlated with expansion and antigen/epitope spreading.
Same with the responders in in the PC trial, though IMO the PC data is has not yet reached absolute certainty with regard to efficacy, as opposed to lymphoma where IMO it has.
All this with no Multi-TAA adverse events. Also Amazing.
I'm not sure what it will take for the market to decide this is the real deal. Obviously we're not there just yet. Maybe one or two more CRs in PC will do it? Maybe the market just doesn't believe you can have a treatment that works with no side effects. I mean all drugs are poisons and you have to balance dosage between therapeutic effect and toxicity. How can it be that Multi-TAA has no side effects if it is working? Maybe that's part of the source of skepticism.
Biotech stocks at this stage really can't be valued in the traditional way, so we expect huge volatility and SP manipulation. Only when it's clear to almost everyone that Multi-TAA works as advertised will we see the rapid and sustained rise in SP.
The only thing we know with certainty from the pancreatic cancer trial is that Multi-TAA expands in vivo and generates epitope/antigen spreading even in the face of ongoing multi drug chemotherapy. This is something we did not know before the trial and is likely required for clinical benefit. This is incredibly important because if we can prove clinical benefit in pancreatic cancer, it is likely that the treatment (with antigen adjustment) will enhance other chemotherapy regimens in other tumor types (e.g. lung, colon, cervical, ovarian, prostate, brain, etc). The question of clinical benefit has not yet been answered definitively but we have some hints it is present that include 1) a CR, which is rare on chemo alone 2) reversal of tumor growth in two patients when cells were added and 3) no progression in any responder while cells were being given. 4) Multi-TAA (MAPP) is also clearly active in lymphoma generating 5/15 CRs thus far in heavily pretreated patients. Stand alone activity is very important to see when considering a treatment for a combination therapy
The market has responded as if the data was a total bust. It wasn't. One more CR in pancreatic cancer and this turns totally around unless the market is totally blind to probability.
Agree. I hope the CEO goes with a synergistic partnership at this juncture. The PC data may not have impressed the street, but a BP may bite based on the unexpected CR and the correlative immune response data, which was quite impressive.
Of course Multi-TAA works. Look at all the CRs as a stand alone treatment in heavily pretreated lymphoma patients. Same product as used in pancreatic cancer. Considering just pancreatic cancer, the chance of a CR with Folfirinox alone was 1/171 in the largest trial for metastatic disease. You can do the math but we have had thus far 3 patients progress on Folfirinox + multi-TAA in group A, 2 after cells were discontinued after the sixth dose,, and 1 CR thus far. Even given that group A was selected for SD on folfirinox (70% will be stable), the chance of seeing a CR in 4 patients was fairly small (~1/30). Now consider what we might have seen if we started cells after the first dose of folfirinox and then continued dosing until a CR was achieved or the patients progressed. Then consider what we might see when we actually include several antigens in the pep mix that are expressed on pancreatic cancer in high concentration. Also drugs are usually increased in dosing to optimize response until dose limiting toxicity is reached. We are using very low dosing relative to other cell therapies and have seen no toxicities of significance.
Bottom line: Anyone who studies the totality of the data (including the immunological responses) should come to the conclusion that this works in lymphoma and probably in pancreatic cancer, and there is also ample opportunity for enhancement.
Ditto.
Without a doubt, MRKR will be going forward with development of a product for pancreatic cancer. That was clear from the cc. Now if the data didn't support that, they would have buried it or PR'd it with a simple dismissive that there was not enough efficacy to proceed further with Multi-TAA in PC and they would focus on the cancers where it is clearly working. Listen to the Q&A and you can sense the optimism of the researchers and clinicians. Are they just trying to put lipstick on a pig? I don't think so and neither did AACR, that put them on the podium.
I'm virtually certain Multi-TAA is working in some hematological malignancy indications and I think there's a good chance (not yet 100%) that it's synergistic with chemo in pancreatic cancer. Lung cancer data has proven that chemotherapy can be synergistic with immunotherapy (anti-PD1). Chemo can enhance the TME in multiple ways (suppresses T-reg, MDSC, enhances MHC expression) and oxaliplatin specifically (in Folfirinox) can produce immunogenic cell death. These facts along with the in vivo product cell expansion, antigen/epitope spreading, and tumor infiltration of T-cells along with the low probability of CR with chemo alone, suggest the CR we saw with Folfirinox in arm A was not chance. Data in a few more patients may confirm that thesis.
The market has dismissed all this evidence and knocked this back down to the SP lows. No big surprise really. It happens in biotech after a run up, if the data does not far exceed expectations. The market focus is on dilution and time to the next "catalyst". This is the time where the momentum gamblers get squeezed out, but if you think Multi-TAA works in at least one cancer, it makes sense to own more shares.
Ultimately, the decision will be made by the FDA. Question is what they will require to approve Multi-TAA. Usually, a prospective randomized trial is necessary, comparing the new drug too SOC. However, to run such a trial ethically, you must have equipoise, that is you can't know with certainty which treatment is better. I would assert that if we see another CR or even two in group A, it would prove Multi-TAA is synergistic with chemo, since CRs are so rare with chemo alone. Would the FDA accept this evidence. I don't know. They could grant accelerated approval and then follow more patients to be sure the CR rate holds up and that translates to OS.
TACTOPS is a suboptimal trial for assessing the therapeutic potential of Multi-TAA + chemo in pancreatic cancer for several reasons:
1) Multi-TAA was started AFTER multiple cycles of chemotherapy. Especially in the case of Folfirinox, where oxaloplatin induces immunogenic cell death, the most chemosensitive cells likely died in the early rounds of chemo and we may have missed the opportunity for maximum immune response to non Multi-TAA antigens
2) Only 6 monthly doses of cells were given. 2 patients on Folfirinox, the best chemo, progressed only after cells were discontinued. No patient in the trial who responded progressed while on cells
3) Only Survivin of the 5 antigens in the mix is expressed in vivo in high concentration on pancreatic cancer.
4) The dose of cells was quite low.
Even with these short comings, there was 1/4 CRs in patients treated with Folfirinox (the best chemo therapy) and cells. 2/4 Folfirinox patients progressed only after cells were discontinued and 1/4 had a mixed response. The expected CR rate to Folfirinox alone is 0.6%. Group A is a select group that responded to Folfirinox (70% do). Therefore the Multi-TAA/Folfirinox response rate is on the order of ~20% after accounting for the selection of responders into group A. 20% vs 0.6% and that's for a sub optimal study testing the impact of Multi-TAA. So is the market logical when it dismisses Multi-TAA for pancreatic cancer? I don't think so. Sure the CR could have occurred by chance, but then you also have to dismiss the epitope/antigen spreading as further evidence that this treatment is working in pancreatic cancer.
I think to get another CR in the remaining patients for group A, which will essentially prove treatment effect, we should select patients responding to Folfirinox. It's likely the combination of a chemosensitive tumor plus Multi-TAA cells that will yield the highest chance of another CR, which is what's need to close the book on the debate over Multi-TAA efficacy in pancreatic cancer IMO.
So the SP decline is a combination of the shelf dilution option hanging over our heads and the pancreatic ca data which did not wow the market. The big question is will we see more impressive data from MRKR, either in hematological cancers, TPIV200, or even another CR in group A in TACTOPS before the CEO decides he needs to dilute. He certainly seems to have time to make that decision. Alternatively, he could be working on a partnership that might allay the need for dilution.
Even though the market was not wow'd by the data, a BP might be. They would be able to take a closer look at the data and decide whether to bite.
Well said. I sense this is going to be a great ride but, as with most budding companies that will eventually make it, investor conviction will be repeatedly tested by the market, which we all know is subject to considerable manipulation in biotech. If you don't believe Multi-TAA really works, why invest? If you do, hold on or add more on declines, depending on your circumstances. Forget about the short term gyrations. They are often brutal in small/micro biotech and are often engineered to shake out "dumb money".
In the early days of immunotherapy, it was thought that chemotherapy would likely suppress an anti-tumor immune response. That is likely true to some degree but we now know that this is a double edge sword. Chemotherapy can induce immunogenic cell death, increase MHC expression, eliminate T-reg and MDSC. However it can also dampen T-cell responses. That is the beauty of MRKR's therapy. The immune response against multiple TAAs is generated ex vivo in a G-Rex incubator while the chemo kills tumor cells and prepares the tumor microenvironment. Then we hit the tumor with fully primed healthy T-cells, which then also clearly initiates further immune responses to other tumor associated antigens, likely those we have measured along with neoantigen responses that we have not measured.
I think that is the source of the responses we are seeing to date in pancreatic cancer. Raising the dose of cells, the number of doses and the antigens targeted may further amplify the impact of Multi-TAA.
I think we're all in for an exciting ride.
Congrats to those who are holding on and supporting this company. I think this company is about to change cancer medicine in a big way.
Start dosing cells as close to initiation of chemo as possible and keep dosing cells with chemo as long as tolerated. Modify chemo dosing if needed until you drive it to CR. Then continue with both for a bit longer to consolidate the response.
Look at IOVA, 10% CRs in melanoma and cervical. 3.2B valuation. Give me another CR in group A at some point and I'll make the case we should have a MC at or greater than IOVA. Why? because the scalability is much greater and the opportunity for combination treatment is much greater. We will be able to treat many more cancer types and will not be restricted by neoantigens and tumor mutational burden.
I think one thing to keep in mind is we are seeing the responses (including a CR) with a relative low dose of cells (in the 10 million range). CAR-T are given in a 1-2 (and even 3)orders of magnitude greater dosing. They talked about increasing the dose and giving more doses, which makes obvious sense. You normally push a P1 until you see toxicity. We have seen no toxicity but we are seeing responses, so push the dose .
Simple axiom: If a little is good, more is better (until you get prohibitive toxicity).
Yes those 3 CRs turned heads. Fortunately our Multi-TAA has no side effects so the treatments could be easily combined I presume.
The halozyme trial is interesting and IMO this could be synergistic with Multi-TAA.
In this one case they apparently weren't successful at making more.
PS I believe the purpose of this trial was really to see if they could achieve antigen/epitope spreading in pancreatic cancer in the context of heavy ongoing chemotherapy, like they have in hematologic cancer in a stand alone setting (along with safety). I think they were genuinely surprised by the responses, especially the CR.
The way I understand it, they only prepared 6 doses max. I think that's because they didn't expect much here. I believe after the 6 doses they can continue chemo alone, which may or may not contuse to drive the patient into CR. They should have more doses and I'm sure they will in the future. Just look at the spider plot for patient #1 who only got 2 doses. He might have been on his way to a CR., but no more cells.
My guess it will be a pivotal event and will come with a PR. Just my guess.
I believe that's 14mm and 40mm. But, yes the larger lesions may take more time to progress to a CR on CT. Look at the article I just posted where it took 16 mo to drive the patient into a CR. The big lesions have moore storma and may take longer for the reticuloendothelial system to digest after the tumor cells die. It would be interesting to know if the tumors in the SD or PR patients are metabolically active on PET scan. The tumor cells could be already dead.
We obviously need longer dosing. For example, Patient #1 responded beautifully after receiving cells initially but only received 2 doses of cells after which the patient bounced back to a stable disease pattern, progressing after one year. What would have happened if he had received cells over that one year period? Maybe another CR (Look at the spider plot)?
Read this if you want to appreciate just how rare a CR is with Folfirinox. We have one CR with the first 5 evaluable patients in arm A treated with Folfirinox and one more SD in the evaluable 5 treated that has yet to progress.
This very unexpected finding plus the antigen/epitope spreading strongly points to Multi-TAA synergism with chemotherapy. This is akin to the synergism seen between chemo and pembro in lung cancer. We don't have 100% certainty yet, as if we did this would today be a multibillion dollar company. However, we're coming close to that and the market continues to to yawn. It will wake up soon. One more CR in Group A in the remaining patients dosed who have not progressed or waiting to be dosed and we reach certainty IMO. That's your near term catalyst and it could come any time. The CR in the article took a couple of years but ours took only a few months with cells.
http://www.alliedacademies.org/articles/a-3year-disease-free-survival-in-a-patient-with-metastatic-pancreatic-adenocarcinoma-following-folfirinox-chemotherapy-a-case-repo-10396.html
By the way, some of the questions asked yesterday were a bit redundant. They didn't accept questions from individual investors. I submitted a simple question. How much epitope/antigen spreading are they seeing in non responders? That was not shown in the data, only a statement that there was a correlation and it was clear that all the responders had impressive antigen spreading. If this phenomenon is indeed restricted to responders primarily, it strengthens the cause/effect relationship. That would be a stronger selling point to the FDA that the treatment works as advertised.
Just my opinion but i think Multi-TAA would be a lock for accelerated approval if we see another CR. I think the correlation with antigen/epitope spreading makes the case even much stronger.
https://undark.org/article/fda-drugs-accelerated-approval/
Great post and spot on. I count 8 more shots at a CR in arm A. 3 in already dosed patients and 5 in those yet to be dosed. If we were to see one more CR, I don't really think you could have equipoise for a randomized trial. IMO it would be unethical to give chemo without Multi-TAA. FDA many not agree or they may grant conditional approval and then track further CRs, while we enhance the pep mix. Not certain how this will go but another CR in arm A (or B) and MRKR will almost certainly get approval IMO. That can't be by chance.
If i had pancreatic Ca, right now I would beg borrow or steal to get Multi-TAA cells and I would not want to wait the 3 mo to see if I was responding to chemo. Give them as close to out of the gate as you can deliver them, I say. Best chance of success IMO.
Think of it this way. A patient presents with primary unresectable cancer or newly diagnosed metastatic cancer. There's a lag time of several week to grow cells from the time of blood draw.
During that time the patient gets chemo. If he/she responds with a PR or SD the SOC of chemo continues with Multi-TAA (Arm A). If not or the patients does not tolerate chemo, then chemo is discontinued and the patient gets cells only (arm B).
In arm C the patient presents with a potentially resectable tumor and gets chemo then gets gets cells once before and then after surgery +chemo.
MRKR will likely need to prove efficacy, either with overall survival or a surrogate endpoint (response rate or progression free survival). FDA will likely require a randomized trial, but if they can show enough of a correlation of response with immune markers and improvement on SOC considering toxicity, maybe not. Maybe we'll get some guidance here tomorrow.
Sorry about your mother. I think MRKR's treatment is a good step forward. I'll be interested to see what's said at the conference regarding the next step. Combo with checkpoint blockade is an obvious step here. More antigens in the pep mix is another. I too love the absence of side effects. Right now, if I had this disease, I would choose multi-TAA +anti-PD1/CTLA4. I'd sign up for that trial, especially if they added WT-1 to the pep mix.
Here's my take on the results:
Group A - This is a select group of pancreatic cancer patients who are responding to chemo either with SD or PR when they are treated with multi-TAA. The CR is impressive as these are quite rare with chemo and we had a small number of patients treated. Further tumor shrinkage was seen in several patients while on the combined treatment which is also encouraging but Multi-TAA effect is not proven.
Group B - Most impressive here is the patient with SD for a prolonged period following progression on chemo. Probably a multi-TAA effect but not proven
Group C - A bit early to claim any clinical benefit I think
Now to what i consider the best evidence the treatment is working. Antigen/epitope spreading was observed in the responding patients. They did not tell us whether this occurred in non responding patients but perhaps this will be addressed on Monday. What this tells us is that Multi-TAA induced an immune response against the tumor that subsequently induced recognition and response to at least several other non targeted antigens. This is proof that the treatment is doing what it is designed to do - enhance the immune response against pancreatic cancer. Now it's a matter of how to further build on that response. I noted that all the patients who responded developed a response to non targeted WT-1, which is highly expressed in pancreatic cancer and is induced by chemotherapy of various types. Would the addition of WT-1 to the mix induce more responses? Also checkpoint blockade (anti-PD1/CTLA4) can enhance responses and modify the TME. Hyaluronidase might also be synergistic in this setting.
Bottom line: There are many ways we can go from here but we have proof of concept that Multi-TAA produces an immune response to pancreatic cancer in addition to hematological cancers. It carries no side effects and is relatively cheap, so it can be easily deployed in combinations. I'm looking forward to Monday's presentation and to any future plans.
The two treatments are not mutually exclusive and could be synergistic.
PS If we can achieve a consistent 14% CR rate (e.g. 1/7) with combined treatment, this would without question be approved. Let's hope the complete responder was not just chance.
You are correct about the CR, but the devil is in the details and we don't have a lot of details. My guess is they will correlate the progression to CR with the in vivo expansion of T-Cells and antigen/epitope spreading. That would be quite convincing. That said, CRs are so rare that more probable than not the T-cells contributed to the response.