Development of Personalised Cancer Vaccines

0:47 

OK, so maybe we can briefly introduce ourselves. 

 
0:51 
My name is Elisa Scarselli. 

 
0:54 
As mentioned by Ben, I'm the Chief Scientific Officer of Nouscom. 

 
1:00 
I'm MD by education, but I've been working in research and development in pharma, moving from big pharma to biotechs. 

 
1:10 
And I mean the main focus of my activities over the last 30 years been vaccine development, both for infectious disease and cancer. 

 
1:18 
So I hand it over to Laura. 

 
1:21 
Donna. 

 
1:22 
Yeah, thank you, Lisa. 

 
1:23 
So my name is Loredana Siani. 

 
1:25 
Nice to meet you. 

 
1:26 
I'm the VP of Technical CMC Development at Nouscom. 

 
1:31 
I'm biochemistry by education, but I have more than tenure of experience in GMP manufacture for viral vector both for infectious disease and cancer field on large scale, but also on the small scale. 

 
1:45 
So I got my Master in Business Administration recently and happy to steer this discussion related to the cancer vaccine development. 

 
1:57 
OK, Yes, thank you, Eliza. 

 
2:00 
So my name is Eric Halioua. 

 
2:02 
I'm the CEO of President of PDC Line Pharma. 

 
2:06 
PDC Line Pharma is a cancer vaccine company based in Belgium and France using a specific cell line of subset of dendritic cell called the plasmacytoid dendritic cells from the blood of a patient having leukaemia affecting this specific populations and very high population of dendritic. 

 
2:26 
And we are currently in clinical trial in Phase 2 in non-small cell lung cancer with a team of 42 people now. 

 
2:34 
And we just have established a GMP unit that is running now. 

 
2:39 
Thank you. 

 
2:40 
And I'm very pleased to be with you. 

 
2:43 
OK, So maybe I can start by sharing a brief presentation just to introduce the field. 

 
2:54 
Can you see the presentation? 

 
2:57 
Yes, OK. 

 
3:00 
So I mean it's really a pleasure to introduce this field of cancer vaccines and where we can position cancer vaccine. 

 
3:12 
I think that after the success in oncology of immunotherapies, there is still a high medical need and we like to place the cancer vaccine in this area. 

 
3:25 
And on the right part, you can see there are two showing the way that we believe the cancer vaccine may help the treatment of cancer and these by amplifying the existing and inducing novelty cells with the capability to infiltrate the tumour and to destroy the tumour. 

 
3:51 
So this brings me to share with you the recent success in the field of cancer vaccine that has been shown at big conferences, ACR and ASCO and published by the two company Moderna and BioNTech. 

 
4:15 
So I just would like to briefly comment on the results. 

 
4:19 
So Moderna just showed in the Melanoma patients results in the randomised trial by using in an adjuvant setting in Melanoma patients personalised vaccine in combination with the checkpoint inhibitor. 

 
4:39 
It's not been compared to checkpoints. 

 
4:41 
So this is really although preliminary the first set of statistical power data to show that cancer vaccine can help on the top of the checkpoint treatment in Melanoma. 

 
4:54 
I think that also data that were presented by biotech by using a similar platform again vaccine are quite interesting. 

 
5:05 
They are in a really tough indication that this pancreatic cancer again in the other one setting after surgery and they were able to show that there was a clear separation in the relapse free survival by comparing patients with an induced vaccine using your response to those without an inducing response. 

 
5:27 
So this set of data sets the ground for this interesting field and I mean help me underline what we as a community believe this crucial for cancer vaccination. 

 
5:45 
And from one side, we have the platform that I mean I say genetic platform, it's not only genetic platform, it's something that maybe even the cell line or something different from protein vaccination clearly can do. 

 
6:04 
So it's important to keep in mind that the vaccination that we are used at with protein or peptides in the field of infection, this is in mainly using antibodies, why in cancer vaccine we want to sell. 

 
6:19 
So that's why we need to shift to a new platform and then the type of antigens. 

 
6:26 
I think these are the two key aspects for the success of cancer vaccine and the type of antigens are new antigens. 

 
6:35 
New antigens are coming out from mutation present in the tumour and therefore they are tissues that are exclusive for the tumour compared to the normal tissue and they are seen by the immune system as different from the wild type cells and therefore they can in use a very important response. 

 
7:01 
So these are the two aspects and just to tell you a bit more of what we are doing, we are using genetic vaccines in the format of viral vector. 

 
7:12 
But what is important is that the vaccine is processed inside the cells and therefore the antigen is downloaded on the Class 1 and Class 2 to induce T cell immune response. 

 
7:27 
Different from antibodies and now few additional words on the type of antigens, the neo antigens. 

 
7:38 
I think that it's important to underline that although that are exceptional and actually Nouscom is pursuing also and off the shelf vaccine based on shared new antigen. 

 
7:52 
The vast majority of mutation are exclusive for a single tumour. 

 
7:56 
That's why you need the personalised approach. 

 
7:59 
And this is the layer of complexity of having a vaccine based the on a personalised medicine for each patient needs its own specific vaccine. 

 
8:10 
And here I am the lying what is commonly done by using the platform. 

 
8:17 
So you need the tissue from the tumour and from the blood that you need to run a sequence to identify mutation, to build your skin, to manufacture the vaccine and release it and then to give it back to the patient. 

 
8:32 
So this requires time and this is adding a complexity to the clinical design to the way you want to use this personalised vaccine approach in the clinic. 

 
8:47 
I mean, I just selected the one set of data that we obtain as many others by using models. 

 
8:55 
And this is underlying that the vaccine would require different forms of activity if you are working in an established tumour setting with the large tumour or you are working in a more preventative setting, like for example, the adjuvant setting that I've shown before. 

 
9:19 
So if you have the back two more there, then you likely need to be more strong and to have the combination with the checkpoint as in this experiment. 

 
9:30 
In animals, the vaccine can work if it's combined with the checkpoint, while in a prophylactic setting there is room to use the vaccine as standalone. 

 
9:41 
This is was our starting point. 

 
9:44 
I mean with this very high level information, I think that we can share the topics that we would like to discuss with you. 

 
9:54 
And one is about the clinical setting indications for the personalised vaccine. 

 
10:01 
So which is the space in which the personalised vaccine can work better? 

 
10:07 
Which are the strategy to have a more effective vaccine in terms both of your immunogenicity and effectiveness? 

 
10:15 
And then we have Loredana in the panel and Eric in the panel to we focus also on the challenge that are linked to the personalised and the others that are linked to the personalised production release the supply chain, everything that is needed to give back this personalised therapy to the patients. 

 
10:42 
So I think that with these, I can leave the floor maybe to Eric to or if there are specific question from the audience, we can try to address it starting from the clinical design and settings. 

 
11:02 
OK. 

 
11:03 
Any questions Ben because we cannot see them, but I could thank you Eliza for this very nice and very comprehensive introductions. 

 
11:12 
But I think provide a good understanding of where we are and the value propositions with the antigens based cancer vaccine. 

 
11:22 
So if we address the first topic which is identification of the clinical setting or indication for personal life cancer, I would build on what you have presented already. 

 
11:33 
You know, so a lot of clinical trial has been ongoing on different line of treatments from new adjuvant up to a third line of metastatic you know patients. 

 
11:46 
So and today what, where we have seen a study of positive clinically significant power and study with a controlled arm, it is in low tumour burden in adjuvant setting. 

 
12:01 
So it's the study that you have presented with the one that everybody mentions and finance by Merck and Moderna on adjuvant in Melanoma, where here the tumour has been removed because it's in adjuvant and where in general, we have chemotherapy to remove any residual disease. 

 
12:23 
And it's in this specific setting that we have observed a benefit. 

 
12:27 
So the question now that everybody is asking is it the right and the only positioning for cancer vaccine? 

 
12:37 
So today it's I think it would be too early to make final conclusions. 

 
12:41 
But definitely we can observe that in low tumour burden, we have at least in Melanoma something that seems to work. 

 
12:49 
Of course it's still a phase two. 

 
12:51 
Why it's not a confirmatory or pivotal study. 

 
12:54 
Yeah, I know that they are they want to launch or they have launched already. 

 
12:58 
They announced to launch a phase three pivotal study and they want to go to the lung. 

 
13:03 
And so it which is an over indications and why Melanoma in the lung because in general it's the hot what we call the hottest tumour. 

 
13:12 
So where you have the most mutations in general, most mutations even according to the PDL 1, you can segment for the lung the level of mutations. 

 
13:27 
But it's the it's mutations where there is high tumour induced immunosuppression in general where the checkpoint inhibitor of the labelling and where the vaccine could definitely play a role. 

 
13:41 
But on the other one, if you see the pancreatic cancer, you show the study of BioNTech pancreatic is quite cold down tumour and it looks like even if it's small populations and so it's difficult to complete anything. 

 
13:54 
But it looks like even in this category of tumour it could work. 

 
14:00 
So, but I will not provide a clear answer of the setting. 

 
14:04 
I think you need to do some assessment of where your product could be positioned, where the time you know to needle to make the vaccine make sense. 

 
14:16 
Of course, when you're in a driven setting, you have more time and that when you are metastatic and you need to go very quickly to avoid that the mutations go out and the new mutation appear. 

 
14:28 
But all this element need to be to taken into account to define your right populations. 

 
14:34 
But what I would like to add, but please Loredana and Eliza, if you want to comment on the first topic, I could comment on the two others afterwards. 

 
14:42 
Yeah, thank you. 

 
14:43 
Eric. 

 
14:45 
I don't know if there are specific questions from the audience on this topic of clinical setting and I fully agree with Eric. 

 
14:55 
So I mean from the theoretical point of view that the place for the vaccine to work is in prevention, this we know very well. 

 
15:04 
And so preventing relapse is something that certainly fit to what we know about vaccine even in the field of infectious disease. 

 
15:18 
Having said that, I think that there is still room to consider personalised vaccine also for leather setting may be combined with other agents. 

 
15:34 
And yet there is really complexity to run the clinical trial in which you need to rely on another component while you are preventing the vaccine because you cannot leave the patients untreated and then add on the top the vaccine. 

 
15:54 
So you really need to try to understand how the multiple components of treatment that could synergize and of course related to these, I think that's very important to have biomarkers that can help you understanding what's happening from the clinical point of view before reaching the let's say survival endpoint. 

 
16:25 
So the more you can do it can use biomarkers like cell free DNA to understand the monitor the fact of the vaccine and we are in certainly in a better position in terms of clinical indications for the vaccine. 

 
16:45 
I think that this is also related to the positioning the vaccine from the commercial point of view. 

 
16:55 
These activities are at the moment quite expensive and complicated from several point of view and including the manufacturing and the supply chain. 

 
17:08 
So maybe we can move to this aspect if you agree with the help of Loredana trying to the way we have done it because we have produced some personalised vaccine, our own internal experience and how this compare with what has been published in the field of RNA and the challenges that we and other encountering in this area. 

 
17:38 
So thank you, Lisa. 

 
17:39 
So I would like to start the building on top of what Eric was saying that of course it's important depends in which field you are is if you are in advanced settings or in metastatic settings. 

 
17:51 
But overall the timing of producing a vaccine play a role. 

 
17:56 
Because of course, especially if you are in the metastatic settings in which you need to administer your vaccine before that mutation can occur again, then of course you need to have a platform that allow you to manufacture and release successfully and injecting patient within a defined needle to needle time. 

 
18:19 
And this is actually what we did, what we experienced in Nouscom since we have been able to produce and to vaccinate patient in a very short time from the biopsy till the manufacturing the final release. 

 
18:34 
Of course before starting and guiding you deeply in what we did the related to the manufacture of our vaccines. 

 
18:42 
I think that it's useful also to compare different platform that are at the moment, of course that are playing a role in the personalised cancer vaccine. 

 
18:52 
And since we compared with Moderna, I think that we should make an effort in order to compare viral vector versus mRNA because also of course, mRNA platform is playing a very role within the personalised cancer vaccine. 

 
19:11 
So we did this exercise in order to compare the two platform. 

 
19:16 
And because essentially our question was, are the viral vector, is the viral vector platform scalable? 

 
19:24 
Because of course all of us, we want to start, we started with the first one. 

 
19:29 
But now the next step is this platform available and also cost effective from a cost point of view if compared the with the mRNA platform. 

 
19:42 
And I would like to guide you through the answer. 

 
19:46 
So and to answer to these questions, of course we should compare the manufacturing step head to head manufacturing step of the viral vector. 

 
19:56 
So of course viral vector to be produced the needs to grow up in the packaging cell line and what is not this is not required. 

 
20:05 
From the mRNA vaccine in which of course the upstream is based on in vitro prescription and but except for this difference that play a huge role in terms of the release and we will see later on the downstream process of the viral vector and the mRNA base, the platform is almost the same. 

 
20:26 
So both rely on chromatography and then tangential full filtration for the formulation. 

 
20:33 
What we would, what I would like to point out here is that for the viral vector the formulation. 

 
20:40 
So the final production is well established since viral vector have been produced and the we have and there are a lot of stability data in a very simple buffer. 

 
20:53 
And this is not the case of at least up to now of the mRNA vaccine in which the production of the lipid nanoparticles offer the major challenge within the manufacturing of this platform. 

 
21:07 
Both platforms can produce and release within the same, more or less within the same time. 

 
21:14 
We experienced 7-9 weeks and that is the same that Moderna did. 

 
21:20 
That's so far with the mRNA vaccine and also the COGs. 

 
21:26 
So the cost of goods to manufacturing vaccine for viral vector or using the mRNA platform are in the same order of mind. 

 
21:37 
The challenging related to the viral vector is related to the release panel of tests since because using a packaging cell line, of course some tests like the that are related to the adventitious virus needs to be performed. 

 
21:54 
And this is the main you know, differences between the two platform. 

 
22:01 
So in order to answer the previous questions. 

 
22:04 
So if the both platform are scalable, it can reach a commercial scale always in the field of personalised cancer, I would say yes, the two platform are head to head. 

 
22:18 
So they can compare very well. 

 
22:20 
To me it will be a matter of efficacy. 

 
22:23 
So which platform will be will show the best efficacy data. 

 
22:27 
But from a manufacturing point of view, we can say that we are very close to the mRNA platform. 

 
22:36 
I would stop here just to see if there are some questions related to this important comparison because we know now it's the moment is for the mRNA. 

 
22:45 
Thanks also for the COVID. 

 
22:47 
And the usual question that we receive from investor or from a different layer is how the two platform compare each other. 

 
22:59 
And as you can imagine, I mean you have to scale down the production because of course this is for only one individual. 

 
23:08 
But the release, the panel of release test, it's very similar to the one that is requested for an off the shelf vaccine. 

 
23:19 
And we had interesting discussion with the Regulatory agency to reduce and to make it feasible because I mean some are indeed needed that other they may be less important than and also the quality request is linked to the type of indication if you are in a more advanced setting or not. 

 
23:44 
So I think there is an open discussion on this and maybe Eric can give us his perspective by for the production of the saline and deputy saline. 

 
24:00 
That's something yeah, because we're a bit different from what you have mentioned. 

 
24:05 
But I think, the quite the kind of question the investor asking you is the same for us. 

 
24:12 
So how you compare with RNA or the viral vector. 

 
24:16 
So and we did the same exercise the one of the slight difference we have here in our case, you know to produce the cell line where we are in bioreactor today and we started first we've shared antigens, we are in clinic currently. 

 
24:31 
We shared antigens in non-small cell lung cancer. 

 
24:33 
So we have the full manufacturing and QC system in place and we could use any kind of shared antigen for any kind of indication. 

 
24:43 
One of them, you know, because we can develop tools adapted to be able to release, at least for potency test any kind of personalised vaccine, you know. 

 
24:53 
So that is a big point I want to underline. 

 
24:56 
But we can do because we have just to add one shared antigen that makes sense for the indications. 

 
25:02 
And we know that there is coverage for shared antigens and that help in fact to have something from a regulatory point of view, which is good, fine, good, which is something they understand. 

 
25:15 
I understand they mean they want to have a full release to show potency test, to source, to show safety, to show the phenotype of the identity story of the yeah, the identity. 

 
25:29 
And something that we can do identity by FACS. 

 
25:33 
It's done easily. 

 
25:35 
And potency test or if you use a specific antigen all the time, that's fine. 

 
25:41 
You know, you can say, OK, it's true for this one, it should be true for the others anyway. 

 
25:47 
It's true that the timing needle to needle is a challenge for everybody. 

 
25:50 
So everybody claim including a marine time, but are extremely short. 

 
25:56 
So I'm not saying it's sometime difficult to see how it's possible to be so quick. 

 
26:04 
But once again, it depends of the level of release you're doing and the level of the characterization of the product you want to reach. 

 
26:11 
We have an opinion on what we believe makes sense. 

 
26:14 
So that is one of the elements. 

 
26:16 
But in our case what we do, we just take the vial from master cell bank and we do we have from the cell line of the patients having the leukaemia, you know the pDC leukaemia. 

 
26:26 
We have developed primary cell bank, master cell bank and working cell bank to amplify just to have a big mass of supply of cells. 

 
26:36 
And from when we want to launch manufacturing campaign, vaccine manufacturing campaign, we just have to see the single use by your reactor. 

 
26:46 
We have a vial of the working cell bank and in nine days we have productions of billion and billion of cells. 

 
26:52 
You know, 7 to 9 according to the director, where, which sides of bioreactor are you going to see the at the first passage? 

 
27:01 
And then of course you need to re amplify the cells. 

 
27:05 
Yeah, is what I was about to say. 

 
27:07 
We start with one litre after for the shared antigens, not for the personalised 1 litre should be enough, but we can go up to 10 litres and even 40 litres and we have 40 litre single use bioreactor. 

 
27:20 
But it's for the off the shelf. 

 
27:21 
Of course if you are an off the shelf, you have a lot of advantage for the logistic, for the cost, for the reproductivity. 

 
27:29 
I mean there is no it's a no brainer if you want to go and we have decided as well to go in personalised is because you believe the clinical benefits you know of this vaccine will be a lot better than the short antigens. 

 
27:44 
OK, So the new data that has been provided up to 2018 I would say seems to go in these directions. 

 
27:54 
But there is we've neo antigen something that happened. 

 
27:58 
But once again, I we believe that shared antigens, our mix of neo and shared antigen could make sense, you know to optimise the mixture. 

 
28:08 
And so in and why I'm saying that because the second point is how to announce vaccine immunogenicity. 

 
28:16 
What I we have seen and I don't know if ELISA has the same understanding, it's the when you screen with the different algorithm, the neoepitope, the number of neoepitopes that are really immunogenic are not so big. 

 
28:32 
You know, it's difficult to know which, how many, but it looks like it's not so much. 

 
28:38 
It's between 1% to 10% according to the publication. 

 
28:41 
At least I've been able to see and publicly. 

 
28:45 
And the way to improve that would be to find a way to improve the algorithm or to have tools to assess the immunogenicity of the new epitope before infusing to the patient. 

 
28:56 
And where it's here again, we can play because with the cell line, we can definitely do the potency test in two weeks, you know, and we could, if we have time, of course, assess, you know, the immunogenicity of any kind of epitope before using to the patients. 

 
29:15 
So, but I think this game of improving the number of really immunogenic are really effective because immunogenicity is just one of the aspect really clinical clinically benefits an epitope is extremely important and will be in the future a way to improve the vaccines. 

 
29:36 
That's what I can tell you briefly, we can spend hours on this topic. 

 
29:40 
It's a complex one, but it's an interesting one. 

 
29:46 
But once again, I think according to the characteristic and the attribute of each technology, maybe there is a different place where you can play. 

 
29:54 
So it's something that need to be think through anyway, association with checkpoint inhibitor is a must. 

 
30:04 
And as I said, Eliza to look for really CD8 T cells expansion is a must. 

 
30:11 
OK, of course, I've seen a lot of different publication recent thing. 

 
30:15 
There's a role of CD4. 

 
30:18 
OK. 

 
30:19 
I mean, it's interesting, but today the real effector of the immunity, at least from 20 years of experience is the CD8 T cells. 

 
30:27 
Awesome. 

 
30:31 
There's a question in the chat, which is just asking how about adjuvants such as saponin, I believe, if anyone wants to address that. 

 
30:41 
Could you repeat, Ben? 

 
30:42 
I didn't understand the question. 

 
30:43 
He wants to know if the same applied to adjuvants such as saponin adjuvant. 

 
30:53 
So we don't in OK, maybe Eliza you can answer to this question. 

 
30:57 
We don't use any adjuvant in our case, the cell line is the adjuvant. 

 
31:00 
So maybe Eliza you can answer yes, no, I can certainly touch on the story of the other one. 

 
31:07 
So we know again from conventional vaccine that you can use adjuvants to have the induction of immune response. 

 
31:17 
But in this field these are not vaccine based on protein. 

 
31:23 
And so the well known conventional adjuvant albumin, squalene, that have been used in the past, for example for the influenza vaccine, it's not the right choice. 

 
31:40 
And we have tried a lot with our platform to combine with something that can improve the new response. 

 
31:49 
We believe that this is not really mandatory because the platform is already powerful, but maybe a nice swap for elderly people, very sick people to have something more that can help index the new response. 

 
32:07 
LNA has in this intrinsic lipo-particles has the capacity to induce in immunity to announce the adaptive T cell immunity in use by the vaccine. 

 
32:21 
This is the field in which many people are working is still at the research level and trying, for example, to encode something else, not only the antigen can further improve on the induction in new response. 

 
32:38 
As far as concerned the efficacy, I mean, I think that as mentioned by Eric, synergy with other molecules like the checkpoint is important to be investigated because maybe you can have a better vaccine just because you combine it with the right molecule in your combination treatment. 

 
33:00 
I just wanted to underline that I fully agree with Eric. 

 
33:06 
So on many topics, that's the importance of CD8, although maybe CD4 also relevant, but CD8 are important. 

 
33:14 
This we know very well and the focus of this discussion is on new antigens. 

 
33:21 
New antigens are important, but I'm pretty sure that in the future we will listen more on two more specific antigen. 

 
33:30 
The old ones that didn't work at first maybe because that I mean that they were not deliver with the right platform and that certainly could synergize with the new antigen. 

 
33:44 
So I believe that maybe in the future we will see more personalised, including also the old fashioned antigens because they can in selected cases be the one that are also responsible for the outcome and the new response. 

 
34:05 
And as far as concerned the challenges, I think that also in our case it was really good to have both of the shelf and personalised approach because we could transfer some learnings from of the shelf that is much easier. 

 
34:22 
For example, the potency I say that we develop for the of the sharp and transfer it to the personalised approach. 

 
34:28 
So I think that you need to have your platform in your hands and know it very well and adjust the request from the regulator on the specific platform to try to go through the adults. 

 
34:45 
I think there is one last topic that we have not touched. 

 
34:49 
This is very general and probably applied to all platform and is about the supply chain. 

 
34:56 
And so as shown in the cartoon at the beginning, it's very complex. 

 
35:01 
You need the biopsy, you need the blood from the patient. 

 
35:04 
You have to transfer to a facility that is sequencing, then maybe a different facilities building the products and then you have to ship it back to the patient. 

 
35:13 
Sometime you have the custom. 

 
35:15 
So I think that there is a big complexity around this on which we have to think about and find another solution to deliver the vaccine at the bad side, let's say a less complex and cumbersome way, maybe a solution is to prepare the vaccine somewhere else. 

 
35:40 
I think that can contribute with some ideas to this. 

 
35:44 
Yeah. 

 
35:46 
Because this is another question that we asked ourselves. 

 
35:48 
So what is the best for the next future, for the future of the personalised vaccine? 

 
35:53 
So are we thinking to produce vaccine close to the hospital in order to reduce at the minimum what is the supply chain at least related to the, you know, to do delivery of the final product to the patient? 

 
36:06 
Or I think to have a satellite production over the world that can deliver that can ship in a very short time in order to reach patient all around the world. 

 
36:17 
Of course at the moment we are investigating and we are thinking which is the best solution. 

 
36:24 
This is also needs to take into account other different aspect that are related not only to the viral vector platform, but also to other platform that are the stability data that you have your in your hand and the four, as Eliza was mentioning, once you want to approach developing a cancer vaccine in the personalised field, you need to know very well your platform not only from stability point of view, but also from a manufacturing point of view. 

 
36:54 
Because it seems that I'm seeing the obvious. 

 
36:56 
But if we want to stay in a very short timeline, then we need to avoid any deviation, any problem that maybe we'll request some investigation. 

 
37:07 
And then this can cause a delay or maybe this can fail in the production of the final the product that at the end the product does not reach the patient and also the supply chain remain a very challenge. 

 
37:26 
As for this kind of field, are the cost related to the manufacturer and essentially the cost are of course based on two different dimension. 

 
37:39 
We did a very good discussion with McKinsey in which we asked them how in which are the cost driver for a personalised cancer programme. 

 
37:51 
And of course the cost, the major cost driver are the facility, then the COGS and also the personnel. 

 
37:59 
So these are the major challenges that we are facing in our programme. 

 
38:06 
The cost of goods, of course, are related to the manufacturing process. 

 
38:10 
And it's our goal to as much as possible streamline the manufacturing process in order to avoid to use too much disposable, too much reagents that this can bring the cost of the final vaccine down. 

 
38:26 
And of course negotiate with the Regulatory agency in order to speed up the release panel of tests and by keeping, of course, the safety always at high level. 

 
38:38 
But maybe and there needs to be a very a good interaction with Regulatory agency in which also regulators needs to compromise with the name of the timing the release of this vaccine. 

 
38:55 
And then of course, release is always to the challenging and the cost. 

 
38:58 
The second first driver is the facility. 

 
39:01 
So the CD mode, the manufacturing space that is going to produce for a personalised vaccine needs to be agile. 

 
39:10 
And we are thinking different solution. 

 
39:13 
There are now in this new era a lot of solution that talks in terms of GMP that there is this, you know new hire of GMP on the wheel in which a container can reach the hospital and then needs to be validated close to the hospital. 

 
39:33 
So in our experience, we are thinking that in order to reduce the cost, we should think about personalised manufacturing that are patient room that are patient dedicated. 

 
39:47 
So in which the space is not huge. 

 
39:49 
And that doesn't means that of course the validation costs are reduced at the minimum, but also the running cost of a room that is patient dedicated needs to be affordable. 

 
40:02 
And then the third, the cost driver is the personnel. 

 
40:06 
Of course, if we need 20 resources to manufacture a single vaccine, of course, this will increase the cost a lot of each batch. 

 
40:18 
And now there are these new also in this field, the new era in which the bioprocessor are thinking about automation. 

 
40:28 
Because of course as much as possible, if some step of the manufacturing process can be automated, this will have an impact not only on the space of the overall GMP that is needed to manufacturing vaccine, but also on the number of resource of personnel that are dedicated to that process. 

 
40:52 
And of course, in another, maybe in the recent future, there needs to be an effort also to think about automation related to the quality control test. 

 
41:05 
Because of course also another point in which costs can be reduced is to synchronise the assay that can of course be performed in order to release more batches in parallel and to reach more patient at the same time. 

 
41:21 
So what I would tell you is that of course this is a new field and a lot can be done in order to scale up and to make viable this kind of programme in terms of future commercialization. 

 
41:43 
And maybe the solution it could be that the solution is not a big facility producing vaccine for the entire world, but several small facility close by the hospital or in different countries to avoid this complexity of shipping so many times that the biopsy and the game the vaccine. 

 
42:12 
So I think it's as Loredana said something that needs some thinking and solution is not yet available. 

 
42:29 
I think Louis and I we are fully online in line now on what you've said. 

 
42:33 
Maybe an interesting benchmark to follow is the Karti Cell. 

 
42:36 
You know, Karti Cell is the most advanced personalised meeting because they are approved and there is several products already on the market and reaching billions of revenue. 

 
42:48 
And now you see more and more companies proposing tools and processes to automate and to do automatizations and to miniaturise as well, you know, Micro 3 **** etcetera, to be able to do exactly what you said, you know, so it's definitely something to follow the Carty cell as an it's a benchmark to inspire the person like conserve vaccine industry. 

 
43:17 
I don't say it's the only one, but it's something you should definitely follow because I've seen recently very new and very intriguing technology on this aspect. 

 
43:27 
Yeah. 

 
43:27 
And also, yeah, Eric, thanks. 

 
43:30 
And automation is possible. 

 
43:32 
Automation is possible and we know that for example, so the mRNA vaccine, this platform is this platform has been already automated for large scale at least we know and also by processor are trying to automate also on the small scale. 

 
43:52 
But yeah, you said very well, we always use Cartier's benchmark and not only in order to position in terms of price, the barrier vector batches, but also to, you know, to think how to automate at least upstream, downstream and for the film finish. 

 
44:13 
And yeah, the another challenge that at least I experienced in my scaling down the process is the, you know, the availability of the different bioprocess reagents, for example, because of course bioprocess are until now are set to support to, you know, to supplement for large scale development. 

 
44:39 
So we see that sometimes it's very easy common to find very huge bag for big bioreactor supported by cubing and philtres on larger scale. 

 
44:51 
And it's very more difficult to find something that is a scale of one litres in terms of bags, cubings and filters. 

 
45:00 
And imagine if we have to miniaturise more in order to keep the process automated. 

 
45:07 
So these are the challenges. 

 
45:09 
I know that is possible. 

 
45:10 
We are looking at the Garti as our, you know, light in order to automate also the viral vector platform. 

 
45:21 
And I'm pretty sure that this is the in the next future. 

 
45:25 
So we can produce viral vector on small scale. 

 
45:32 
I would say my dream is close to the hospital, you know, in order to reach the patient as soon as possible in the less time possible. 

 
45:41 
Yeah, everybody, I think we will go to there and to there. 

 
45:45 
We need investment from providers, you know, because it's a different kind of business. 

 
45:48 
Yes, absolutely. 

 
45:50 
Yeah, yes, providers needs to scale down, you know, needs to provide reagents that are more at the scale for personalising in terms of everything because it's very for example, Philtre, the not physics Philtre at the sides lower than so. 

 
46:08 
And sometimes we need to over dimension our reagents. 

 
46:12 
And these of course has an impact, have an impact on the cost. 

 
46:16 
But it's because the providers needs to adjust also their market in order to fulfil and to support the personalised production. 

 
46:29 
I just want to jump in quickly. 

 
46:31 
Sorry to say we're up to just under 10 minutes away from now. 

 
46:35 
I just want to say we've had a few queries in a chat I thought I'd put to the panel quickly. 

 
46:42 
The first one from Mohammed just asks briefly about what the best timeline would be for scheduling CPI and antigens, if this would be same time CPI before antigens or vice versa. 

 
46:56 
Yeah. 

 
46:57 
So Mohammed, I think that this is an interesting question and we did train models. 

 
47:06 
It's not very different terms of both induction immune response and the effectiveness of the vaccine our hands. 

 
47:14 
If you go to the clinic, I think that the sequence must be before checkpoint and then the vaccine just because the vaccine is not really you need time to prepare it. 

 
47:27 
And unless you want to use different treatment to keep the patient while you're preparing the vaccine. 

 
47:35 
The practical optimal scale is the one in which you first have the checkpoint inhibitor, wait for the vaccine to be reduced and then introduced the vaccine. 

 
47:45 
This is the one we used in terms on induction of the new response. 

 
47:51 
I mean in models haven't seen differences. 

 
47:54 
I see there is another question that is which is the risk of using one single biopsy source of antigen? 

 
48:05 
Is this representing the maybe another metastatic sites? 

 
48:11 
Of course this can be it's very difficult in a clinical setting to request more than one biopsy. 

 
48:20 
The way we know scum try to deal with this problem is to introduce in the vaccine not only clonal mutation but even sub clonal one because we have the possibility to have a large number included by the our vaccine. 

 
48:39 
So we have 60, therefore the risk that we are not capturing some musician that is present in another tumour site, it's slightly lower, but it can be of course can have to happen. 

 
48:56 
And yes, and the last is from Mark on and logistics can be challenging, but maybe simpler than regulatory requirements for local manufacturing at the GMP when everything is full consistent approved GMP. 

 
49:18 
So I mean this is an interesting discussion and I think that we do not have the final answer. 

 
49:25 
It would be better to have GMP that is close to the side, but then you have to have authorization for each and every MP or to have a large facility that is after running with the experienced personnel and then try just to solve the shipment and logistic problem. 

 
49:47 
We all know, I think that it's working progress and we need to understand. 

 
49:55 
Yeah, if I may add something, Eliza, to what you said related to the biopsy because it's a relevant topic. 

 
50:04 
Yeah, it's true that if you do biopsy on metastatic patients, you have the risk of first having a bad biopsy. 

 
50:13 
You know, unfortunately it happens, you know, just to the collections of the biopsy or having, you know, a subset of the mutations, you know, because it's very heterogeneous. 

 
50:25 
So it's why again, when you go in adjuvants, you can go just after the surgery removing, you know the primary tumour where you have more materials and you can have more information of really relevant information on the mutation. 

 
50:43 
So it's another advantage to go early stage, it's to get more bigger piece of materials because we remove the full tumours. 

 
50:53 
OK. 

 
50:53 
So I just wanted to add this topic. 

 
50:56 
No, this is very important. 

 
50:57 
And I think the advantage of the adjuvant, it's certainly because the in the moment that you deliver the vaccine, the tumour burden, it's lower. 

 
51:08 
Maybe you have minimal residual disease, you don't have the tumour, but also as underlined by Eric, because you have the beauty of the entire surgical resection. 

 
51:19 
And maybe if the quality of the sequencing is not good enough, you can repeat it on another area that you have stored. 

 
51:29 
So that's I think it's important. 

 
51:32 
Thank you, Eric. 

 
51:38 
No other questions from the audience. 

 
51:44 
So I think we've got any other ones in the chat. 

 
51:45 
If anyone has any other questions to post, that's probably a good time as we come up to the hour. 

 
51:55 
No, I guess I've not been probably wrapped up. 

 
51:59 
Brilliant. 

 
51:59 
Thank you very much to everyone for coming. 

 
52:02 
Thank you Laura, Donna and Eric for hosting. 

 
52:04 
It's been fantastic. 

 
52:05 
I find it really informative and I hope everyone else has to. 

 
52:08 
I thank you very much. 

 
52:08 
I have put a sorry. 

 
52:10 
I'll pause the recording.