Researchers at the Gene Editing Institute at ChristianaCare have been moving forward with an effort to use CRISPR-directed gene editing technology in the clinic.
ChristianaCare’s Helen F. Graham Cancer Center & Research Institute, which appears to be the first and only NCI Community Oncology Research Program site conducting research focused on CRISPR, started its gene-editing research in 2015.
Not quite eight years later, the institute has published a study in Gene Therapy, which shows that, in vitro, CRISPR-directed gene editing can successfully knock out a chemoresistance gene in non-small cell lung carcinoma cells.
Based on these findings and animal studies, the institute has initiated meetings with FDA in an effort to obtain an IND for testing the technology.
“The average time is around 20 years,” Petrelli said to The Cancer Letter. “We picked that up a little bit, but in a community cancer center with that collaboration with the clinicians, this could occur in less than a decade.”
In a conversation with The Cancer Letter, Eric Kmiec, executive director and chief scientific officer at ChristianaCare’s Gene Editing Institute, and Nicholas Petrelli, medical director of the Helen F. Graham Cancer Center and Research Institute (HFGCCRI), described their research program and the initial FDA guidance meetings for the technology.
We were pretty excited because at the time, in the gene editing world, it was really still a pipe dream to see if it would actually ever reach patients. So, to have someone who had a foot in both research and a clinical application actually meant a lot to us, who were essentially dreaming that someday, these bio tools would be converted.
Eric Kmiec
The therapy utilizes CRISPR to target and disrupt the chemoresistance gene Nuclear Factor Erythroid 2-Related Factor 2 (NRF2). The NRF2 gene has been implicated in chemoresistance in many cancers, including lung cancer.
The study, led by Kelly Banas, showed that the CRISPR-directed gene editing was able to target and damage the NRF2 gene and affect response to chemotherapy in human lung cancer cell lines. The institute has demonstrated this effect in multiple animal models and is now finishing the final trials under guidance from the FDA, including a chemoresistant NSCLC patient-derived PDX mouse models, which implants human tumors into mice for testing.
Kmiec joined ChristianaCare’s Cawley Center for Translational Cancer Research at the HFGCCRI in 2015, just as CRISPR technology hit the mainstream. He had previously been working with gene editing precursors of the famed “molecular scissors,” including bioengineered molecules like TALENS and zinc-fingers.
Petrelli and Kmiec said the research continuously benefited from feedback from the ChristianaCare HFGCCRI clinicians, the IRB, translational researchers, and research coordinators.
“Those meetings with our clinicians were not the prettiest for me,” said Kmiec, a basic scientist. “I got up there, and they handed me my clinical butt in a couple places, and it could not have been better.”
CRISPR technology promises revolutionary treatments, but the clinicians encouraged Kmiec to focus on more practical matters. “We would’ve been saying things that were so ridiculous that nobody would’ve believed us,” Kmiec said.
Thanks to this input from clinicians, the team “never looked at this as a cure for cancer,” Petrelli said.
“Standard of care is tough and tough on the patient, but it can work,” Kmiec said. “So, if you can think about a way to augment standard of care therapy, chemotherapy, radiation, immunotherapy, and make it work more effectively, that’s really the step you want first.”
ChristianaCare last week founded a commercial biotechnology private start-up company, CorriXR Therapeutics. CorriXR Therapeutics (from Galician meaning to correct or edit) will use CRISPR technology to develop clinically relevant oncologic therapeutics in areas of unmet medical need, starting with squamous cell carcinoma of the lung.
The new start-up company has received $5 million in seed financing from ChristianaCare and Brookhaven Bio, an investment firm.
Kmiec and Petrelli spoke with Paul Goldberg, editor & publisher of The Cancer Letter.
Paul Goldberg: Well gentlemen, thank you so much for meeting with me to talk about your CRISPR system, and I think, correct me if I’m wrong, you are the only community cancer center that has one of those. How did this happen?
Nicholas Petrelli: You’re absolutely right, Paul, and, actually, if it happens in other [community] centers, at least we can say we were the first, but at the moment, unless Eric knows, I know that right now, we’re still the only community cancer center.
There’s about 1,500 or so [American College of Surgeons] Commission-on-Cancer-accredited community cancer centers in the country, and I believe right now we’re the only one. Certainly, we are the first. I can start, then Eric can chime in.
Eric Kmiec: Absolutely.
NP: I met Eric a while back, Paul. Even before we had the Cawley Center for Translational Cancer Research (CTCR) at the HFGCCRI, when I first got here to Delaware, wanting to start a translational program and Eric had a lab at the University of Delaware, and I’d heard about his reputation, especially with training of young investigators. There wasn’t much connection between Christiana and University of Delaware with research.
And so, when I met Eric and looked at the work that he was doing, I think originally with oligonucleotides, we had a couple of clinicians. One in particular in thoracic, who was very interested in translational research and actually worked with Eric for a while, and that started it off, and I’ll let Eric comment on that and then I’ll tell you how it happened—how I got him to come here .
He’ll tell you why he came to a clinical entity, but Eric, anything that I missed when we first met at UD?
EK: No, that was it. I had joined the University of Delaware, and was plugged into the Delaware Biotechnology Institute, and I actually interviewed Nick when he came through, after he was offered the position, and from the beginning I think we just hit it off really well. It was an opportunity to work with someone of his caliber who has an extraordinary track record of success in clinical research and medicine in the cancer field.
We were pretty excited because at the time, in the gene editing world, it was really still a pipe dream to see if it would actually ever reach patients.
So, to have someone who had a foot in both research and a clinical application actually meant a lot to us, who were essentially dreaming that someday, these bio tools would be converted.
I think that was 1998, 1999, some time in that frame. So, Nick and I decided to start off a new millennium with this relationship. I’m sure that was the main focus. But yeah, Tom Bauer was the thoracic surgeon at the HFGCCRI, and Tom had stepped in to run a statewide program that supported research, and, boy, what a choice! Great guy, very innovative, forward-thinking, and that really got us to appreciate right away the importance of having a clinician in the mix as you develop research programs.
And you didn’t have any clinicians before?
EK: No, absolutely not.
You were just editing genes from whatever it is you could find.
EK: Yeah.
Getting samples wherever you could, right?
EK: That’s right, and we were really just doing very basic research on tissue culture cells and trying to figure out the mechanism of how these sort of primitive tools, like oligonucleotides, were working, and at the time, that was kind of it. And there were probably only 10 to 15 labs in the country that were working on the gene editing side of gene therapy.
A lot of people were focused on adding the correct gene to a patient, where, if you had a dysfunctional gene, they would use a virus to package it and send it in, and that was the University of Pennsylvania’s big program that ultimately had some serious issues.
But we felt that correcting the gene or at least using the tools to either correct the gene or destroy it was really the only way to do this, adding more genes to a genome that has been undergoing some pretty good evolution for several billion years. I thought that we’d done a pretty good job.
So, we felt that just tinkering with what nature had given us was really the right way to go, but Nick was one of the few guys that I think from the clinical side was willing to listen to that aspect of things. So, that started off this relationship.
So that predates CRISPR technology.
NP: Well then what happened was that some time passed, Paul, and Eric was looking and the CAWLEY CTCR at the HFGCCRI when it opened in 2009 had space he was looking for and I said, “You know Eric, we have the CTCR at the Cancer Center we have a couple of scientists in it, but what we also have are clinicians who are interested in translational cancer research.”
We hadn’t started the Wistar partnership yet. It was just after that, I think. Eric may be able to correct me.
EK: I think that’s right.
NP: Yeah, and so I said, “Look, okay, so we’re not what you’re used to, a full-time academic center with a dean down your back.” I think I might have even said that’s an advantage to you, Eric.
EK: Definitely, and it has been.
NP: I said, “You’ll be surrounded by clinicians. As a matter of fact, the CTCR is right smack across the hall of the clinician’s offices. So, why don’t you think about coming over.”
I’ll never forget this. It was July of 2015 when he came over with himself and only two other people, that really started it off.
The scientists that he brought—the two—were very talented. He has a tendency to attract very young talented scientists. If you ever saw his CV, it’s very impressive of how he mentors them and then sends them off to really powerful labs. And so, the clinicians were very excited about this and that was July of 2015.
And by now, CRISPR exists, the current technology.
NP: Well actually, Eric was really talking to me about TALENs and zinc fingers, and I said, “Yeah. Oh great.” And then I think once he got here.
EK: It hit the mainstream.
NP: Wasn’t that when CRISPR came out?
EK: It did. So, it’s like anything. Nick is exactly right. It’s amazing how you remember that—TALENs and Zinc Finger Nucleases.
We discovered some of the forerunners of the CRISPR system and were working on others, fundamentally molecular scissors that had been around quite some time, but in 2015, we began to turn our attention to the CRISPR system.
Most people use CRISPR because it is a naturally occurring system found in bacterial cells, whereas all of the other genetic tools are engineered or manipulated. So, this is why this technology has gained everybody’s attention, because it’s naturally occurring, and you might be able to scale it up fairly readily.
We were working with some early sort of, I would say forerunners of the CRISPR system that there were these types of molecular scissors that had been around, and in 2015, we began to turn our attention to the CRISPR system.
And most people use it because it is a naturally occurring system found in bacterial cells, whereas all of the other genetic tools are engineered or manipulated. So, this is why this has gained everybody’s attention, because it’s naturally occurring and you can scale it up fairly readily.
Now, no biomolecule therapy’s easy to scale up. That’s just not true, but there’s some hope that because we know so much about this system, pushing it forward and amplifying it up and scaling it up enough to manufacture enough to treat patients is definitely possible.
[In] 2015, we entered the Cawley CTCR at the HFGCCRI, and it is the best decision of my entire career, because all of us who were working at the bench in the molecular basis of gene editing always had the dream of having a clinical [application]. I mean, that’s why we actually do this stuff.
It isn’t just about getting grants and writing papers. That’s all well and good, and you’re a scholar, but you hope to kind of leave something behind, where you can set the stage for young clinical, innovative clinicians to use your stuff, or at least combine it with something else that either works better or can work in an augmentative fashion.
So, Delaware is unique. I could go see someone like Nick Petrelli. Maybe in New York or something, you don’t have easy access to people like him on a daily, often an hourly basis.
It was one of the great things. It gets someone of that level and to be in a community cancer center with NCI clinical trials funding.
So, we just jumped in with both feet, and built a lab that went from essentially three or four people to now 26, and a lot of that attraction, as Nick mentioned, is because we do have a clinical output into our projects
When the three of us were in professional school, we wanted it just for the sake of medicine. Today, you have to attract young people with either some social cause, which they do like, and they talk about, and that’s appropriate; but also, they want to work on something important.
So, I am quite sure that because we have this clinical direction and are able to talk to surgical and medical oncologists, we are able to attract people who wouldn’t normally come to a lab in Delaware, frankly.
NP: Before I forget this thought. Eric brought it up to his credit. He and I talked about this and we formed a clinical partnership for Eric’s lab made up of thoracic surgeons and medical oncologists.
When we’d meet and Eric would present—and still does today—where his research is, we’d have the chair of the IRB there, we’d have our translational research people there, to give input.
Clinicians, as Eric will say, they weren’t stingy in telling the scientists, “Look, we don’t think this is going to work. It looks great in the lab, but it’s not going to work in a patient.”
And I think that partnership was critical for where Eric is today, and is already what has allowed two passes through the FDA already for the trial that we talked about a while back, Paul.
Well, so, basically, in 2015, Eric comes to Christiana, and what about the machinery, the CRISPR technology? What does it cost? How do you get it?
EK: So, it’s amazingly simple. We can engineer it in the lab, and in a very standard molecular reaction.
It’s very inexpensive, which is again, another reason why people are so attracted to it, and the way you can actually use it is when you get near a clinical trial, and we’re moving down the road, we will have to license the technology from the Broad Institute at MIT, and that’s because the United States Patent Office has awarded them the patent for CRISPR after a brutal and probably continuing fight with Berkeley.
And we’ve been fortunate, because with a good senior counsel at ChristianaCare, Richard Dashefsky and Nick. Richard encouraged us to sign a few deals, licensing the CRISPR patents for other purposes, like education and teaching, and MIT was very helpful in that and very open to doing that.
So, we established a good line of communication following Richard’s thought process, which positions us quite well now for when we are ready to actually use it in patients, and then you do have to develop a license.
From a practical molecular construction standpoint, it really is just a bunch of little test tubes and some solutions. There’s no Wayback Machine. There’s nothing big, and introducing it into cells is done the same way that it’s been done for 50 years. So, it’s very inexpensive, right? The expensive thing is the license.
MIT, I think, recognizes the value of this technology, but to actually do the experiments, it’s extremely inexpensive, and you need no special equipment, which is what’s been astonishing for this, and I think that’s why the world has exploded around this, just in an amazing way.
NP: I think, Paul, Eric would agree there does come a time and I know he is going to smile where there is expense for, translational cancer research, but I’ve mentioned this to you, before it started, almost the first week I arrived in Delaware, the community here in Delaware has been unbelievably supportive of research.
Delaware used to be number one for cancer mortality. It now hangs around number 16 or 17. The community has supported the cancer program here. They supported translational cancer research, the Cawley CTCR, then the Gene Editing Institute.
A couple of years ago, two years ago, Eric and some of the scientists joined me in visiting philanthropic individuals to present their research, and we raised $5 million, and our president and CEO, Janice Nevin, MD chipped in another $5 million. So, the cancer translational research program is endowed here at the Graham Center, and that really started with the community and has continued from the first week I arrived, and I’m sure Eric would confirm that.
EK: Absolutely. It’s been the keystone events. Even though the CRISPR molecule itself is easy to work with, there are these things called animal studies, transgenic animals, and since very few people actually do those particular studies well, especially with us being guided now by FDA protocols, we have to seek out places that do them outside. Places like Covance or Charles River. Some of the main animal houses, and it really becomes a challenge to pay for that.
So, because of the philanthropy coupled to our federal grant support, we are enabled to be much more flexible and get things done right away. The NIH and National Science Foundation, where we have funding, can be a bit slow to respond because of the bureaucracy surrounding the grant process.
This is a funny problem, Paul, I think you’ll find Nick knows this well, that if you don’t act quickly enough to enter the queue for FDA-approved animal testing, you can be delayed for months and months because of a serious back up; in the gene editing world, there are a lot of people are jumping on this. So, the line can be long.
Nick established a really strong philanthropy program and frankly, helps to be based at an NCI-funded clinical trials program, believe me. Again, the fact that we have flexibility in how to move money within these philanthropic grants, which are competitive, allows us to establish a strong foothold in a timely fashion.
It’s not just, you know, handed to you in a check; we have to think through and provide a strong rationale; there are serious reporting structures and presentations and today, people are much more tuned to quality research than they have been in the past.
Because of this support, which can carry out our own extensive animal work at the University of Delaware in an approved and well-controlled facility, we use that university lab as a pilot lab to test out some of our molecules. That provides us with a snapshot of toxicity and safety data prior to providing a document for the FDA to review.
Particularly in the gene editing world, there are a lot of people jumping on this, so you have to really get in the queue right away and if you have to wait for a grant to be funded or a change in your budget to be approved, that’s just a simple, practical problem.
How much do you go through in the year? Your lab with 26 people?
EK: You mean animal wise or overall budget? Oh, we’re probably operating about a $3 million-a-year budget. Most of that, we have grants and support for, and frankly, probably 25% of that are animal costs. Just animal upkeep and that. So, yeah, it’s a serious dollar that needs to go through, but that would include everything.
NP: Paul, Eric mentioned the NCI, you know about how we were just talking about Dr. Monica Bertagnolli. You know about our NCI clinical trials program (NCI Community Research Program (NCORP) and the recognition we get actually.
We received two awards at the Alliance meeting a couple of weeks ago. Greg Masters, MD is the PI of our NCORP but also one of the clinicians in the group that advises Eric and his team. So, our track record on accruing patients to clinical trials also attracted Eric to our place.
EK: Oh yeah.
NP: Because that’s where we’re headed. That’s where the team is headed, with the trial with CRISPR and the NRF2 genes. So, that was really critical getting that NCI recognition. Paul, you know that since 1987, the cancer program at Christiana has been supported by the NCI with clinical trials, and now that it’s an NCORP, that has really helped—and I know it helps when Eric has to go to the FDA and he’s getting ready to put a trial together.
Oh, speaking of FDA, can we talk about FDA for a moment?
EK: Sure.
Usually, you have an IND. How does that work?
EK: No, not yet. So that’s what we’re working toward exactly.
So when you’re working on patient material, how does that work in terms of regulatory…
EK: That’s a great question. So there are three meetings, three formal meetings that you have to go through to get approval to launch a clinical trial.
The first one is called the INTERACT meeting, and then there’s kind of a second informal meeting that reflects on just guidance, how you’re kind of doing it, and remember, the FDA meetings are supposed to be guidance meetings.
So, they’re trying to help you get through this, but they’re not really telling you what to do. It’s kind of funny. You ask things as if you were in a court. Would it please the FDA if we did things this way? It’s a really odd way to go and so we’re through a major formal meeting and then a bunch of these informal meetings that Nick said, through multiple rounds of discussion.
And what’s interesting is that we’ve heard anecdotally that to get into the queue, about one in three applications are getting in the queue. So, we’re in there now, which is great, and then you go through a pre-IND meeting and then ultimately an IND meeting. So, we’re getting very close to our pre-IND meeting, and this is where we present all our animal data and what they require, interestingly, is an outline of the clinical trial you intend to support.
So, Nick was exactly right, and he won’t say it, but I will. Without ChristianaCare and the NCI clinical trials experience, we probably wouldn’t have this anywhere, because they recognized, number one, it’s a community cancer center of excellence.
It’s not just the cancer center of excellence, and that, in our world today, appropriately so, is very important, because we’re looking at patients of all socioeconomic levels and that impacts all patients. Christiana had that baked in for a long time including the cancer center.
And then once we get through the pre-IND with all of the protocols, then the distance between the pre-ID and IND can be months. It’s usually maybe four months, six months. It depends on what we have left to do. So the process is well regulated and then once you get to the IND, you actually start on patients, but you asked about patients.
So, actually, all of our animal models are generated using a patient sample. So, we have tumors from lung patients that are now implanted into mice, and that’s called a PDX. It’s patient-derived xenograft. We do all of our testing on those. We really are working on patient samples, and of course, that’s all been cleared and approved.
And so, that is not inexpensive, because in those mice, the tumor has to be moved from mouse to mouse. There’s a lot of surgery involved in that, and that’s really where, again, all the support goes, but that particular PDX model is a requirement by the FDA.
They ask specifically for those, and ironically, you’ve got to wait for a patient to donate their tumor to generate that. So, again, being associated with the clinical cancer center helps in getting those samples, including even from the NCI because they recognize you’re for real, you’re not just mashing things up in a university lab.
I see. So, basically, right now, you’re pretty close to the pre-IND meeting. How many months do you think that’s going to take?
EK: I would say this spring of 2023 if everything goes well.
We could go now, but the queue to get in there is hard. Again, the FDA is understaffed, and a lot of people are using CRISPR. Although, what we’re being told now was we are pioneering the use of CRISPR for solid tumors, and it wouldn’t give me any greater delight to be one of the first to test it at the HFGCCRI ChristianaCare in a unique approach to solid tumors.
Nick has always educated me that it’s important to be safe—not first. So, we’re moving along, and I just want to comment on something Nick mentioned. And he’ll smile when I’ll say this. As I said before, those meetings with our clinicians were not the prettiest for me. I got up there, and they handed me my clinical butt in a couple places, and it could not have been better.
It was the best meetings I’ve been at, because it really helped us shape how we do experiments and how we think about experiments. Don’t do the experiment for scientific sense, but think about the long-term impact, and without, again, that team of clinicians, I’m pretty sure we wouldn’t have chosen our target, or we wouldn’t have had an impact.
So, in fact, when we go to the FDA and we talk about this, they can’t believe it. They thought you have clinical impact already? And so, it helps in our credibility frankly, just to be associated with Nick’s team at the cancer center.
What kind of clinical impact can you have, because you’re taking a patient’s tumors and planting them into PDX mice, and the patient just goes along on their way, as to proceed with whatever is happening.
EK: Well, it changed the way we thought about things. When you work in a really exciting innovative field, and we’ve actually contributed a lot to CRISPR on its own, and a lot of the discoveries about CRISPR, you always think you could just go in and destroy solid tumors. So, a couple things come to mind right away.
Standard of care is tough and tough on the patient, but it can work. So, if you can think about a way to augment standard of care therapy, chemotherapy, radiation, immunotherapy, and make it work more effectively, that’s really the step you want first.
You want to be able to demonstrate that your approach does not cause any harm and is relatively safe. And then the second thing we really educated on is think about your clinical outcome. What is it you want to achieve?
And it could be something as simple as reducing the size of the tumor so the surgeon can now resect it or remove it. So, when you come out of a basic laboratory that’s doing quite innovative work on gene editing, you’re thinking the world is ours, and then you get to the reality of how you actually have to treat solid tumors and what these patients go through.
Just the frailty of a patient that’s been on chemotherapy for a year, it’s taxing and what is your endpoint there? And where do you think about doing the intervention? Most patients with lung squamous cell carcinoma present maybe stage II, stage III.
So, think about something you can do there to extend their lives for a period of time, rather than reversing the entire metastatic tumor pattern.
So, just educating us on endpoints and the reality of what we can actually impact early on, it was a game changer frankly. We would’ve been saying things that were so ridiculous that nobody would’ve believed us. So I think a reality check is kind of the final answer on that.
It’s interesting, because I read your publication. Congratulations, by the way.
EK: Thank you.
Is about resistance to chemotherapy. So, maybe we could talk about that a little bit because you’re doing safety studies, not in patients; right?
EK: No, it’s still in animal; using patient human tumors implanted in animals. It’s still all animals. It’s actually looking at the tumor we would be treating in a patient, but in an animal, and hopefully, if that goes well. Yeah, and that’s it, who knows. It’s not in its environment, and so, you learn all this.
So, our thought was that there are genes. So what we know is that a series of genes, well documented and discovered by other people, actually contribute mightily to the development of chemoresistance, in just about all patients. Lung cancer patients are one of them and that the needle moves in lung cancer patients. We had some really excellent oncologists.
We’ve been told about 25% of those patients will probably always need chemo, because they don’t have the right biomarkers. It’s important that we’re not restricting our approach to only chemotherapy and established chemoresistance. Our target genes are those that confer resistance to radiation therapy ,immunotherapy and even targeted therapy. This is a key part of our overall program; our goal is to improve the quality of life for people undergoing cancer therapy no matter what the therapeutic regimen is.
And even though there’s a lot of hope for immunotherapy and more biomarkers, the fact is that there’ll be a cadre of patients there. So, we found a CRISPR, sort of this molecular scissors approach that can destroy the master gene of chemoresistance in lung cancer cells.
The game is to destroy it, and then allow the chemotherapy to do its job at a lower dose and better, and that’s the entire approach, and as Nick mentioned, our first target is NRF2, but we can move into KRAS, and EGFR, and all the more traditional driver mutation targets to allow chemotherapy or radiation or others to work better.
That’s the beginning, and again, that’s probably the third area, be realistic about what you can really affect in cancer care, and that comes from Dr. Petrelli directly.
And the IND is going to be in this.
EK: That’s exactly right.
So, what does it look like? The submission if you were to kind of give it a title now, what would it be called?
EK: I think it would be CRISPR-directed gene editing for solid tumors.
NP: Eric and I have talked about this. It’s the equivalent to a phase I or a feasibility study.
So, what we’re really looking for in the first phase in that clinical trial is really, what will be the toxicity?
As you know, as you move further and further in a feasibility or a phase I, you’ll get to a point where you may know whether there’s a response to the tumor, but the real issue with this gene editing in humans now is what’s the safety of this, and I’ve told Eric, even if there’s a failure in a response to the tumor at the end of that feasibility study, you’re going to learn a lot on that failure, maybe more than a success.
And there’s one other thing that Eric mentioned. We never looked at this as a cure for cancer. We really never did. He mentioned something that’s important. Maybe this will allow a patient to undergo a less of a dose of chemotherapy, which subsequently translates into a better quality of life, and that’s critically something we always think about when we’re thinking about the trial.
But you will probably be doing exactly the technology that’s in the paper.
EK: Yes. The approach has been the same actually for about three-and-a-half years.
Chemoresistance!
EK: That’s right.
Just knock out the NRF2.
EK: And what’s funny about it is this is why the pre-IND FDA meeting is so critical. In the IND, they sort of back up and just make sure that you’ve done what they’ve requested and there’s no toxicity. Obviously, that’s really critical, but that’s the stuff that’s done by outside animal, but for the pre-IND, you need to have your molecule.
You need to tell them this is what I’m going to inject and this is the overall design of the clinical trial, and the fact that we can go to the Graham Center under Nick is enormously powerful, because the FDA actually wants to be sure you’re going to do this. They’re spending a lot of time helping you. They don’t charge you for this, but they’re also looking at feasibility. So, that’s why two-thirds of the applications never make it into the pipeline.
That used to not be the case. It used to be that you throw something in and people look at it, but there’s so many crazy ideas out there, including some, frankly, with gene editing tools that they can’t do it.
So, they tend to do a triage, and we were actually positioned in to go for review, which I’m sure was a bit of a surprise to them, because here comes ChristianaCare, the Graham Center, with an organically grown, new therapeutic approach using CRISPR for solid tumors and sitting probably in front of us is the University of Pennsylvania and then MIT and Hopkins.
But the people who came and have been visiting with us online about our approach are directors of the FDA, associate directors of the gene therapy branches, because they’re so fascinated how a community cancer center program could actually move along.
Is FDA handling this through the device arm?
EK: No, it’s through CBER. It’s the biologics arm.
Through the biologics.
EK: Right.
NP: So, Paul, when was the last time you heard a scientist and a clinician talk together and say there’s a presentation to the FDA where you were targeting squamous cell carcinoma, the lung, and after the presentation, the FDA says, “You know what? You can expand this out to other tumors because the NRF gene is also present on other solid tumors …”
EK: Everywhere.
NP: So, that was mind blowing to me.
Well, that’s fascinating. And when you’re talking about the molecule, what is the molecule? Because I thought you’re editing molecules. It’s not like a drug.
EK: Yeah, so it’s actually the CRISPR itself. It’s actually two pieces of RNA. It’s an mRNA, which codes for the Cas part of the CRISPR molecule and the CRISPR. CRISPR is basically a piece of RNA that’s folded in a unique site, and combining with the protein, the Cas protein, together that complex then goes and identifies the NRF2 gene and breaks it and knocks it out.
So, that’s it. It’s two components and strangely enough, the delivery vehicle we’re going to use is a non-viral particle, a complex using a similar formulation that’s been used in the COVID vaccines.
We are optimistic that it won’t cause any huge negative impact on patients themselves. We ran down the line with a viral delivery system, but for really practical reasons and the potential for immune responses that are just going on and on, we switched over to the non-viral particle.
It’s a nanoparticle called a lipid nanoparticle, LNP, and that’s kind of the hot delivery vehicle now. They’re having nice success, using it in patients and so far, although the numbers are low, there haven’t been any sort of adverse effect.
This is not a new field. Like with CRISPR, non-viral delivery particles have now entered the mainstream of biological systems as new advances may have produced particles that work.
So we jumped on top of that, and we have mounting confidence that it will be well tolerated because that’s the particle with the same general formulation that goes into the COVID vaccines both in Canada and the United States. So, it’s just a bit of luck there that all kind of came together right in front of us.
NP: And Eric, I told Paul that the viral vector you had worked initially with was with the team at Wistar. So, that was important for our partnership with Wistar also, and, Paul, the Gene Editing Institute was made a core facility for Wistar. So, Eric, as director of the Gene Editing Institute, was a core facility for Wistar. Still is today.
So, this is kind of a part of the Wistar collaboration.
EK: Oh, it has been in fact, actually, Wistar made our viral vector brilliantly. It was wonderful. I’ll tell you the reason we actually went away from it was almost not really scientific.
The manufacturer of viral particles, biological material is so expensive and takes so long that the entire field has been waiting for a non-viral option, and by the way, the viral particles work great. We’ve got PDX models where lung cancer’s been completely arrested using this approach, and we’ve delivered it with adenovirus.
So, the old standard and that approach will be developed in parallel no doubt, but the decision of the delivery vehicle actually sometimes comes down to scientific reasons or impacted by the cost of manufacturing.
Problem is that there are still big questions about adenoviruses. We would’ve pushed forward on it, but ultimately when you start to ask companies, “Can you make enough of this to go into patients?” They say “Well, it might take a year-and-a-half to do that. And it’s $3 to $4 million to treat three patients.”
So, it was really a practical side… Plus there’s also been a lot of activity very recently in the non-viral world that made us think it was useful in humans. A couple of clinical trials have been quite successful now and shown no toxicity. So, we shifted gears and we save ourselves a lot of money and a lot of time in this. It’s just growing. Who knows, right?
I mean everybody wants to deliver these biomolecules with viral vectors, but, honestly, it’s a challenge. It’s just a practical side of making it, and how is the patient going to respond when you put 10 to the 12th viral particles in their body? It’s hard to believe there won’t be a pretty significant immune response.
Oh, it’s fascinating. Is there any aspect of it that we have not touched upon, anything we missed?
EK: No, this has been great. The whole reason for this talk is just the impact of how practicing oncologists can have on the development of the anti-cancer innovative therapies. These are not people that would normally be doing translational cancer research projects, but their knowledge about what patients really need, and the reality checks that they give us on a routine basis, this continues.
We never looked at this as a cure for cancer. We really never did. He mentioned something that’s important. Maybe this will allow a patient to undergo a less of a dose of chemotherapy, which subsequently translates into a better quality of life.
Nicholas Petrelli
Now I do think that they’ve kind of turned the corner and they think this might work. They’re still cautiously optimistic, which is exactly where we want them, because we need them to be critical as we go forward in, and without this relationship, this would’ve been disastrous.
The one thing I like about the clinicians at Graham Cancer Center, unlike maybe some others, they don’t really have a stake in the game.
The only stake they have is patient care. A lot of other places have research teams themselves. They’ve got five companies they own, they’ve got patents on everything, and so they’re going to kind of steer the direction a little bit on their own opinion. The opinion of the oncologists we use is to better care for their patients—period. And when they think you’re off base, they’re more than happy to tell you about that in a very no nonsense way
I’ve had my clinical ass handed to me a few times, Paul, which has been, and Nick has always reminded me. Nope, they love you. I’ll say, “Jesus, I guess they love me.” But they did. So yeah, I’ll let him comment on that.
And I think Paul, just one last thing, I think the reason they actually came to the first meeting is because of Nick. He’s been right about a lot, “We’ll go down to that meeting and listen to those crazy guys.” And after about two years, I think we turned it around a little bit.
What kind of meeting is it? Is it a meeting of the entire faculty? Or how does that work?
NP: It’s a meeting with the medical oncologists, the thoracic surgeons. We have translational people there, the ones that collect the tissue, the ones that collect the data, and as I said, we’ve had representatives from the IRB there.
EK: Yeah, that was important.
NP: We’re staying on track. I think, Paul, if you think of this, you’ve been doing this a long time interviewing scientists and clinicians, but think of this. Eric has been in the gene editing business, his whole career. He arrived here in July of 2015.
When CRISPR first came out, he started from square one with CRISPR; okay? Started from square one, is still in the preclinical, but think about this. He could potentially, with clinicians and the HFGCCRI support, have a clinical trial in less than a decade.
I mean he’s right there for the pre-IND, and when was the last time, remember now, started the preclinical? Usually, you have a scientist come to you after 10 years and say, “I got this now, let’s roll with this.” And it takes another period of time.
You know, the average time is around 20 years. We picked that up a little bit, but in a community cancer center with that collaboration with the clinicians, this could occur in less than a decade.
It’s amazing. Well, that’s a very interesting story. Thank you for walking me through it. It’s very complicated, but I think I’m starting to understand it.
EK: Well, if you need, just reach out anytime. I mean Nick knows this so well because he’s basically engineered it. He’s put the pieces together and without that orchestration, it just doesn’t work. It’s critical to have the attention of medical oncologists like Greg Masters, MD and Michael Guarino, MD. Mike unfortunately passed away recently, and Mike was probably more impactful than he’ll ever know, and his hand has really kind of guided us.
He was a big immunotherapy guy, and he really forced us to keep defending what we were doing, but they’re not going to come down to me. They’re very pleasant individuals, but I think initially, Nick brought them in, and we did hook a couple of them and they’ve been along for the ride all along. But if you need to reach out to either of us, I’m more than happy to fill in any gaps.
Yep. At what point do you have to start paying the Broad?
EK: That’s a very good question. Paul, you’re very good at this. I don’t know. There’s a debate going on. So, one argument is that you try to cuddle up to them now and say, “Hey, we’re looking good, and we really like you and they’ll give you a good price.” The other thing is why do that? Wait till you see it works, and then license it. Of course, if you see it works, they’ll see it works, and their price is now 10 times what it was. So, the answer is we don’t know. It’s an interesting question.
We’re talking about an institution that’s been in litigation on this topic forever and is winning. So, my bias is to probably get it late pre-IND/IND timeframe in there. Once we’re confident it’s safe, that’s really going to be, as Nick mentioned, what we’re asking. It’s a proof of principle safety trial and we’re confident that we will move on to efficacy shortly thereafter.
Could you tell me about the firm you just founded?
NP: The next phase in the Gene Editing Institute’s evolution is CorriXR Therapeutics, ChristianaCare’s first commercial biotech spinout that will use CRISPR gene editing technology to develop new, clinically relevant oncologic therapeutics in areas of unmet medical need, starting with squamous cell carcinoma of the lung.
CorriXR Therapeutics will license technology from the Gene Editing Institute and work closely with its scientific researchers and clinical oncologists at ChristianaCare’s Helen F. Graham Cancer Center & Research Institute.
The startup will take advantage of the Gene Editing Institute’s unique set of CRISPR gene editing tools capable of disabling the genomes of a tumor cell while leaving intact the genomes of surrounding healthy cells, which allows for precise target selectivity.
CorriXR Therapeutics has been boosted with $5 million in seed financing from ChristianaCare and Brookhaven Bio. The CorriXR team includes experienced biotechnology executives and world-renowned scientists and clinicians and is led by Eric as CEO.
Well, thank you so much.
