Perry Rearick: Our next presenter is from MaxCyte. He is Dan Miller, MaxCyte’s field application scientist for the Central United States. He’s going to introduce us to high-efficiency cell engineering with the MaxCyte electroporation platform, from concept to clinic. Welcome, Dan.

Dan Miller: If you've heard of MaxCyte, wonderful. If you haven't, we get that somewhat frequently. We’re an electro coordinator for non-viral cellular transfection, but since the beginning, we have been focusing on clinical electroporation. So we came out of the Harvard Institutes of Blood. Spun out from there. And their original goal was to be able to transfect blood tissue, human blood tissue, back in the 2000s.

This was before cell therapies are where they are at today, and so we were a little early to the technology space and we hung in there. Around 2008, our active users started asking us if they could use us for things that weren't cell therapy, like CHO and HEK and Jurkat transfections to get their cargoes in and get their testing done.

We, of course, said yes. Back in 2002, we released an FDA master file because we had our eyes on the clinic all the way back then. This allows our customers to file their INDs with a letter of authorization from us, and that allows the FDA to just go through our books and have that part of the process already done for them.

Late in 2019, we introduced our ExPERT™ system. This was basically a remodel of the system. There used to be a laptop that went with it, but we wanted to reduce its size as much as possible because we know that we're going into GMP suites where every square foot is important. And so now it is about the size of a desktop computer with integrated touchscreen and the entire operating system just works on board.

And then last up here, we show the two most important things that have happened in our recent history, and that is that one of our partners, CRISPR and Vertex, got their full FDA approval for a cell therapy that uses the MaxCyte platform, and we will be talking about that today. Next up is that early this year, we acquired SeQure DX to help us expand our offerings in the cell and gene therapy space.

Next slide please. Our platform can be introduced into many parts of a cellular process as it uses an electric field to open up cellular pores to get your cargo in. So really size is our limitation and not cell type, until you get into something like a bacteria with a cell wall. What we're going to focus on today is the cell therapy space, because that's what these talks are about.

Next slide, please. Okay, so these are our instruments. One instrument, the GTx™ here, this one near the middle, was invented all the way back at the beginning. This allows for our Flow Electroporation^® technology to do its best. This unit can go from 100,000 cells all the way up to 20 billion cells with an unbroken line of processing assemblies, basically the consumable that goes with it. This really allows you to focus on what your process is going to look like instead of having to make it fit what our plastic is designed for.

As the years went by, we found a need to have a more entry-level device. This was the ATx™ for academics. What I love about the engineering around these devices is you'll notice that they look nearly identical, and that's because what they did is instead of reinventing the box, they simply took some components out and stopped building it in a GMP environment, and that allowed them to bring the price down to make it more suitable for academics and process development [PD] groups.

This means that when you use an ATx, up to 700 million cells, you can immediately scale to our GTx and expect it to behave the same because the internal components are the same. And that's what I love about the system is that I am never having to troubleshoot different units’ operations.

This is that unbroken line demonstrated, so from 100,000 cells all the way up to 20 billion cells in the beginning of our line, we have a lot of process development processing assemblies. So there are our 25x3 and our 50x3. I love these because they allow you to put in three samples into one transfection so that you know that that electrical field went across all three samples identically. We envision this as process development and raw research. You put in your control in well number one, and then variable one and variable two, and you know that all three of those were treated identically inside the system. And so that really allows you to do a lot of your PD a lot faster and see how true the system can hold to its electroporations.

And then as you scale up, they move into more and more process development, getting into that clinical scale. The last one that fits on the ATx goes up to 700 million cells, and that one is basically one of our bag systems without the bags. That is so that you can test something on our ATx and know that it's going to work on our GTx because it's the same exact chamber; it's just that we've added bags to it to allow you to do multiple runs.

So you'll see that your cells hang on the left side here in a bag, and we move them in and out of this electroporation chamber, three and a half mils at a time on our CL-2. And then after they've been electroporated, they get moved over to a collection bag. Most important thing I'd really like to point out here with this video is that your cells are never touching the parasol pump. In this system, we're about to deliberately tear open a hole in the cellular membranes to let your cargo in, and so adding sheer stress right before that will add a huge amount of variability depending on your upstream cells, right? Because patient cells are also variable. And so the engineers engineered their way around that. There is a sterilized airbag that you can barely see down here on the bottom left. It is in that little holder you can see on the bottom left picture. That is used as a bladder: The parasol pump pulls air out of the chamber, creating a vacuum to pull your sample in, and then pushes the sample back out to collection with the air from the bladder. And so it's sterile air the whole time moving around your cells, not the pump.

This slide simply demonstrates that we can slot into most workflows that are out there. Many, many cell therapies require some form of edit if Cas9 is involved, Cas12a we're seeing a lot recently, all the way up to knocking in CARs and larger payloads into some of our fibroblast cells. This technology really can slot into your current technology, and we find it replacing virus in a lot of steps. It de-risks the process as you no longer need that as part of your step. You use pure DNA or pure mRNA, and it removes an entire two-week process from your cell therapy.

So this is my favorite part. I am the field application scientist. I travel all over the country and go to my customers’ labs and troubleshoot their problems. I also do the demonstrations, and so I'm doing electroporations every single week in a different lab. And these case studies come out of our customers and not out of our internal R&D, and that's my favorite part about them.

My first one comes from CRISPR and Vertex. This is the HSPC and RNP delivery. We are using a CRISPR Cas9 to attack the BC11A enhancer region that will disrupt the production of adult hemoglobin and allow the production of fetal hemoglobin, rescuing the sickle cell phenotype. These samples are from some of the first patients ever dosed and what they demonstrate is that after this transfection and these cells are healthy enough to be reintroduced to a patient population, they can then take over the circulating bone marrow and produce fetal-expressing hemoglobin at near a 100% rate. And this is what's rescuing that phenotype.

I really like to talk about Victoria Gray. She was the first patient ever dosed and she has done several interviews, so we've gotten to hear her speak about her experience, and it's been really powerful. These patients often end up in the ICU for pain crises on a regular basis. Victoria speaks about that. This was happening several times a month and she couldn't trust herself to go and travel. Sometimes she couldn't go to her son's games. So she really wanted to get on top of this and volunteered for this therapy. As the first patient ever dosed, she has been symptom-free to this day, and I believe we are currently somewhere near the eight-year mark. It's amazing to have a therapy that works that successfully.

This is part of my favorite piece of dataset. This is from the University of Minnesota and Catamaran Bio. This group is working with peripheral blood NK cells, which are notoriously hard to grow and expand, and they needed to get in four cargos simultaneously—they're trying to knock in a CD70 CAR, an anti-CD70 CAR, and knock out the native CD70 to prevent fratricide. And they're able to do this in a single step on the MaxCyte platform. They're using a Cas9 mRNA, a Cas9 guide of transposon minicircle and a transposase, and getting an 86% integration rate and 100% knockout of the gene of interest in a single step. This is allowing them to then expand these cells significantly, so in further decks, which you can contact us to see, you'll see that these cells expand 40- to 60-fold, and they can do so over two different rounds of expansion. This is critical for our NK folks because they need to expand these to critical cell therapy doses, and this allows that to happen after the electroporation.

This is our bread and butter. This is an example of a T cell therapy done on our platform. This group was originally using virus and they came to us to see if they could introduce a transpoCART as a workaround from the virus. Using a Sleeping Beauty transposase mRNA, as well as a minicircle. These minicircles and nano vectors are two different pieces of new technology where they have a plasmid with the bacterial components removed. These have proven to be incredibly effective in these transfections and keeping viability and efficiencies quite high.

The best part about these two slides, you'll notice that these two sets of graphs, data look near identical. The top left is a process development set of data, so this happened with patient cells and healthy donors, and this was in the PD labs working with us. You'll see that we got a 40% to 60% integration rate and that these cells are highly cytotoxic after their electroporation. We have up to a 15:1 kill ratio, and we have up to 40-fold expansion. So they're quite healthy in both the patient and healthy donor populations.

Meanwhile on the bottom right, this is a spinout to two different CDMOs. So part of the MaxCyte mentality is that we will help you do your tech transfer. We will go to your CDMOs, we will go suit into your GMP suites and make sure the things that we work with you in your labs that work there will work in your new labs. And that way, you don't end up with either the telephone game or process drift causing you delays in your clinical trials. This bottom set of graphs is at two different CDMOs, completely different sets of hands, that have been trained by MaxCyte staff. And you'll see that we have leveled off that variability between the subpopulations. We've not just hit the 40%, but actually at the 60% mark, and these cells are still healthy, expanding and cytotoxic. So this is a great set of data that shows our capability of allowing us to go from that concept to clinical trials and keep the process true. This is a large amount of extra data available, so at any point you can take a screenshot of our QR codes and go pull up extra data. You can also go to our website. It was redesigned, I think a year or two ago, and the new website is amazing. It’s really easy to navigate. There are tons of data in there, lots of white papers, custom testimonials. I really encourage you to go there. There's a lot of stuff there and it's easy to contact us through there.

This is my last slide and it kind of covers everything we've talked about. I'd like to focus on MaxCyte support. I think it's one of the things that really has changed us over the years. As one of the hands in the field, there are dozens of us that get to go into labs every single week and do experiments, and through those experiments and troubleshooting with the staff, on the ground, we have learned a lot about this very small part of the process. It's a 90-minute window most of the time to get your cargo into your cells, but it is often the critical work step, as you will. Most of the rest of the time you're simply growing the cells and moving them around, expanding them, bringing them into new vessels. This is the one time we're actively doing the something to the cells, and we will come into your labs and work with you to help you get that to work as well as it can the first time. When you get a MaxCyte, you get an FAS to go with it. There's one of us in every single territory. We come out and we do hands-on training when you get an instrument, and we will come back and do that hands-on training anytime you ask us. This is so that when you get a new set of grad students, when you get a new set of texts in your GMP suite, when these things happen and turnover happens, we can make sure that nothing changes about the process so that these clinical trials go forward correctly.