SQZ Biotech’s Unique Technology Squeezes Cells to Transform Them into Therapeutics

Innovation That Matters

SQZ Biotechnologies’ technology platform aims to tap into cells to create the next generation of commercially viable therapeutics with the potential to have an impact treating a broad range of diseases.

Unlike current gene and cell therapies, which use viruses to engineer cells for therapeutic purposes, the company’s Cell Squeeze® platform disrupts the membranes of cells to deliver materials that arm them to treat diseases.

The company recently received approval from the US Food and Drug Administration (FDA) to begin clinical trials of a cell therapy aimed at activating patients’ immune systems to attack solid tumors caused by human papilloma virus (HPV) infection.

SQZ founder and CEO Armon Sharei, Ph.D., explained, “What we have been starting with is this mechanism around antigen presentation. What we do is take PBMCs (peripheral blood mononuclear cells) from the patient’s blood and use the SQZ platform to load them with tumor antigens. We are starting with HPV positive tumors.”

The cells, loaded with HPV positive tumor antigens, are injected back into patients, activating the immune system’s killer T cells to attack the cancer. The clinical trials will test the therapeutic cells as a monotherapy and in combination with Roche’s checkpoint inhibitor. SQZ is working with Roche in a collaboration to develop antigen presenting cells to treat cancer.

In discussing SQZ’s technology, Sharei observed, “I’m excited about the platform. We think it can overcome a lot of the fundamental issues in the cell therapy field and potentially create a whole host of new products that can make a big impact for people.”

As part of an exclusive series spotlighting the insider perspectives of thought leaders on topics shaping the future of new medicines, WuXi AppTec Communications spoke with Sharei about his company’s technology and the challenges facing cell and gene therapies.

Sharei founded SQZ Biotechnologies in 2013 and has served as the CEO since January 2015. He earned his B.S. from Stanford University and Ph.D. in Chemical Engineering from the Massachusetts Institute of Technology.

WuXi AppTec: How has research in gene and cell therapies progressed over the past 20 years? Do you anticipate a wave of new approvals coming over the next 5 to 10 years?

Armon Sharei: Gene and cell therapies have advanced by leaps and bounds over the past 20 years and really have started to show the impact people were hoping to see with these concepts.

If you think about historically what we’ve done with therapeutics, we had small molecules and then we had biologics. Gene therapies have the potential to be a quantum leap above that relative to what has existed so far, and that is with things like CAR-Ts (chimeric antigen receptor T-cells). With the adoption of some of these AAV (adeno-associated virus) therapies we are starting to see differences in patients that are just a huge delta relative to what was done before in those fields.

CAR-Ts having north of a 70 percent response rate in patients who really had no chance of survival at that point is really dramatic. It’s very different from when you have a chemotherapy or targeted therapy come out and give patients a month of extra time versus this, which works to actually completely change your biology, potentially allowing patients to go into remission.

When it comes to the next 5 to 10 years that’s where I would start to distinguish the gene therapy and cell therapy definitions a little bit differently.

For therapeutics that use viruses—a lot of the gene therapies today administer a virus in vivo—that’s an area that we work less on, but from what I can tell it looks like people have really started to figure it out in a way that’s going to be therapeutically meaningful quickly in the next 5 to 10 years across a few indications.

That’s amplified by companies like Novartis and Roche going into this field. After a period of refinement and development, these virus-based therapies are coming into their own and most of their applications are in these rarer genetic disorders.

Now for cell therapies I would say we’re still very much at the beginning of what’s possible. Comparatively speaking, injecting a virus in vivo can do an interesting set of things beyond what a biologic could do. But a cell can do more things, by far, than a virus can do.

With these cell therapies right now, due to a lack of tools, people use viruses to engineer them. That’s why this whole category of cell and gene therapies has been blurry because so much has relied on viruses to get this far. CAR-Ts, for example, are made with viruses.

But ultimately what you can do with a cell is not restricted to genetic change, and I think that’s exemplified by what we’re doing at SQZ. Our platform lets us go after much more diverse biologies within cells, like the program we have partnered with Roche. We don’t make any genetic changes to these cells. We deliver, in this case, peptide materials that leverage these cells’ physiological systems and induce immune responses. Those immune responses have shown a lot of potential pre-clinically and we’re very optimistic about what they’re going to do in the clinic.

In contrast to gene therapies, we’re at a point where you are going to see these cell therapies become more commonplace and accepted, and useful across diseases. We’re going to start to see more interesting things happening over the next few years, but it’s going to be decades until cell therapies really reach the height of their impact because I think they can apply to so many more diseases and patients.

WuXi AppTec: When you are referring to viruses, you’re talking about the delivery systems, correct?

Armon Sharei: Yes, exactly. At the end of the day, for these applications, it comes down to what can you make a cell do; and viruses are pretty limited in what kind of cargo they can bring in and also what kind of cell type they can transduce.

But if you are relieved of those constraints, there is a much broader range of what you can do. What illustrates that is most AAV vector gene therapies are being used for relatively rare genetic diseases.

WuXi AppTec: What scientific advances are needed to make these therapies more effective? 

Armon Sharei: On the viral gene therapy side, one of the biggest things right now is repeat dosing and pre-existing immunity. That is something where people are trying to figure out how to shut down those immune responses against these viral vectors so that you can enable repeat dosing. That has been a challenge so far.

In the context of cell therapies, it goes back to those elements we were talking about where right now people are really limited in what they can engineer. Improvements in cell engineering are really going to drive that big differentiation down the line. That’s where you need these newer technology platforms, which can alter many different functions within cells to create these therapeutics.

Now to layer on top of that, I would say the challenge is manufacturing. Right now manufacturing for both gene therapy and cell therapy, and particularly for cell therapies, can be really impractical in the sense that it is quite expensive and, from a patient perspective, takes too long. If you are a cancer patient on your last legs, you don’t have a month to just wait for your cell therapy to be prepared.

With the SQZ system, for example, our manufacturing process for our program that’s already in the clinic now is under 24 hours. So it is by far faster and more cost effective than what people have been able to achieve so far with cell therapies. And I think these kinds of manufacturing improvements are going to really determine the accessibility of these therapies down the line.

A final point on the cell therapies is safety. Right now within cancer there is significant tolerance for safety challenges. CAR-Ts are not safe-based products. They tend to have significant side effects that are currently manageable, but they are still substantial. You can’t tolerate those kinds of side effects as you go into earlier lines of treatment in cancer, or if you go into indications that are not going to be terminal for the patient.

Going back to cell engineering, that is the main advance needed. As you can access different biologies, you can start to create therapies that can be really effective, but also are a lot safer because they stay closer to natural physiology in how they work and don’t inadvertently trigger a host of other responses that drive toxicity.

WuXi AppTec: Will cell therapies ever be commonplace? Will they become more commonplace than small molecules and biologics?

Armon Sharei: I think cell therapies can be a much more rational biological approach to many diseases because you are using a complex biological machine to go and create your treatment as opposed to a relatively simplistic small molecule or biologic.

That being said, it will always be easier to swallow a pill than to get an infusion of a cell therapy. So for our more serious diseases cell therapies can become commonplace and will usher in a new era where you can treat terminal illnesses with few side effects. They will be the most meaningful therapeutic modality. But when you can take a pill to ease your joint pain you’ll probably do that over a cell therapy.

WuXi AppTec: How far away are we from that day?

Armon Sharei: I think we are over a decade away from (cell therapy) being that commonplace. Over the next 10 years people are going to have to show that future world is possible. By taking the dramatic progress made already in cell therapies and starting to implement cell therapies across more diseases, in a safer way, with much faster manufacturing, that will be the tipping point which can lead to a proliferation of cell therapies across many disease areas. It will take a while to get there, but it will be a very interesting world when we do get there.

WuXi AppTec: What are the risks and limitations of these therapies?

Armon Sharei: For gene therapies, which you are delivering with viruses, the limitations are that there are not that many diseases that will ultimately be addressed by that kind of the therapeutic strategy. There are some very serious diseases that relate to a genetic deficiency, but there are many diseases that are not rooted in that kind of cause. Gene therapy will certainly have an impact for patients who really need it, but it’s not going to be a huge proportion of the population.

For cell therapies, the limitations right now are those points we talked about. They are limited in what diseases they can be used for, there are safety issues, and it’s very impractical to administer them. And as we improve on methods of how to engineer these cells and have new platforms that can engineer a much broader range of function in a quick and practical way, you will start to see significant change, which makes this a lot more accessible.

WuXi AppTec: How does your cell therapy work and what diseases are you targeting?

Armon Sharei: Our company is built around this platform where we have shown that by squeezing cells at high speeds in a microfluidic channel you can disrupt their membranes and enable the delivery of all kinds of different materials.

This has really opened up the doors as far as what cell types you can use and what you can engineer about them while implementing a simple, rapid, and cost-effective manufacturing format. We think this can ultimately be used as the basis for creating many different cell therapies. Our goal for the company is to create that next wave of much more impactful cell therapies.

What we have been starting with is a mechanism around antigen presentation. We take PBMCs (peripheral blood mononuclear cells) from the patient’s blood and use the SQZ platform to load them with tumor antigens. We are starting with HPV (human papilloma virus) positive tumors.

When we load these cells with the tumor antigens, what they’re going to do once we inject them in vivo is present those antigen components on their surface. That will activate the patient’s own endogenous CD8 T cells, which are the killer T cells, and they will proliferate and try to destroy the tumor.

It’s really a mechanism of trying to tell the immune system what to target in the context of cancer. If we can show success in these HPV positive tumors, it should be pretty plug and play to then implement this for many different tumor types.

And the manufacturing time for our Phase I trial is under 24 hours for creating the product, so it’s by far faster than what people currently do.

WuXi AppTec: How would you contrast your approach with that of others attempting to create cell therapies?

Armon Sharei: Our platform can address virtually any cell type and deliver any materials to alter its function. And we can do this all without otherwise causing undesirable changes to the cell function. It has broadened our ability to go after many different biologies and concepts that others can’t implement.

So the contrast I would say right now is that a lot of the field of cell therapy in oncology has been focused on CAR-Ts, which thus far have been limited to B cell malignancies (i.e. specific blood cancers) and haven’t been able to translate effectively to other tumor types. Also they are associated with significant toxicity issues.

In our case, we are from the beginning going into these solid tumors, which are HPV positive tumors, and based on the mechanism we’re pursuing we would expect a much better safety profile; certainly have a much faster manufacturing time; and know that it will be much simpler to implement in other tumor types relative to the mechanisms that the CAR-Ts have pursued.

WuXi AppTec: Will your technology be able to treat early stage cancer?

Armon Sharei: In principle, yes. Our trial is starting with later stage cancer, but the mechanism is very applicable to early stage cancers, and because we expect it to be a lot safer, it would be quite desirable to implement it in earlier stages. Whereas some of the systems that exist today for cell therapies you would not want to treat early stage cancers because the toxicity issues would be difficult to make it justifiable. But we should be able to go in earlier as well as in a broader range of cancer types.

WuXi AppTec: What major regulatory and commercial challenges do you face, now that you have begun clinical development?

Armon Sharei: We have had productive interactions with the FDA, and from a regulatory perspective I think we all recognize that this is a newer field and everybody is learning as we go.

We have a strong case. Given the simplicity of our platform, and given the types of mechanisms we go after–and our expectations for it being safer than what’s out there–we haven’t had challenges per se from the regulatory side.

There is a challenge because it’s a new field–and relatively unknown–and the regulators and companies like ourselves are trying to be thoughtful, deliberative, and creative about how we approach it.

On the commercial front, because we’ve solved a lot of the manufacturing problems, we can make cell therapy much more feasible, much more broadly implementable, and it should be successful in trials.

I think the main challenge is going to end up being that no one has been able to implement a broad cell therapy commercially right now. That’s going to be interesting because this is going to end up being different from a biologic.

Our first program uses autologous cells. You need to think about implementation at a really broad scale, tracking individual patient material and the manufacturing chain, and scheduling the patient follow-up visits. It is more complex than a biologic or a small molecule, but ultimately we believe our approach is a lot more tractable than what people do today in cell therapy.

WuXi AppTec: As with other new medicines, the prices for some gene and cell therapies generate “sticker-shock” among patients. Will gene therapies be widely accessible for patients? What changes are needed to ensure universal accessibility to these potential disease cures?

Armon Sharei: It’s a great debate that’s going on right now. We’re in favor of outcome-based pricing because these new modalities, like the gene therapies and the cell therapies, should have an impact that is disproportionate to what a small molecule or biologic could have achieved.

That would be the justification for the added cost. In the end, if you are actually making these new modalities do what they are capable of, it should actually be a net benefit and cost-savings to society because you’re treating or potentially curing diseases that previously would result in much less desirable personal and economic outcomes.

When we are used to paying for a treatment that is going to prolong your life for a month or two and be really expensive, that is one mindset. But when you’re talking about a treatment that could potentially cure the disease, that is a very different proposition.

Ultimately, I think there will be a solution to pricing that recognizes the impacts of these therapies and has an economic incentive to continue to create them.

WuXi AppTec: Have you determined how you are going to value your therapy?

Armon Sharei: We have not. It will be determined by how much of an impact we’re having. Obviously there have been certain precedents set by where CAR-Ts have been priced, but we want to see what our cell therapy does in the clinic and how truly differentiated it is before trying to figure out pricing.

WuXi AppTec: In general, what are the top 3 impediments to delivery of better medicines, faster and cheaper to patients? 

Armon Sharei: In our context, the biggest impediments are the breadth of biology people can access today. It has been limited and we feel platforms like ours can overcome this. That will make a big difference.

The manufacturing and turn-around time involved with our field right now are problems, and if we can resolve those it will really make these (cell therapies) much more accessible.

And then finally—this actually goes to your point on pricing and incentives—we do need a more rational incentive and pricing structure that motivates the right kinds of innovation and demotivates the much more incremental or repetitive pieces that might encourage inefficiencies in the system.

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