Armon Sharei: Origins of SQZ Biotech and the Future of Cell Engineering (Nucleate Insights #3)

Welcome back to the Nucleate Insights program.

Nucleate is a student-led nonprofit agency for future biotech leaders. Among our educational initiatives is Insights, which invites life sciences trainees to engage in deep-dive discussions with company founders who transformed academic projects into thriving biotechnology companies.

In these journal club-style discussions, we uncover what helped founders fully realize and grow the commercial potential of their original academic projects.

Background

Armon Sharei, PhD: CEO and Founder of SQZ Biotech

Insights’ guest for this session was Armon Sharei, inventor of the Cell Squeeze® technology. Armon earned his ChemE PhD from Massachusetts Institute of Technology under Profs. Klavs Jensen and Robert Langer, where his invention premiered in a 2013 publication in PNAS: A vector-free microfluidic platform for intracellular delivery”. Armon completed a postdoc in immunology from Harvard Medical School with Uli von Andrian. Armon has since been named in Forbes 30 Under 30 and Endpoints 40 under 40.

Scientific Context

The successful merging of engineering and biology is a remarkable event. When done right, we get breakthrough innovations from the macro to the micro scales: medical imaging technologies, prosthetic limbs, engineered organs, nanoparticles, molecular tools for DNA editing and the list goes on. The topic of this Insights session is a technology which acts at the cellular level in a surprisingly mechanical way.

Armon Sharei was a Chemical Engineering PhD student at MIT where he was working on developing a micro-fluidic “gun” which was meant to shoot materials of interest into a cell. This could be a promising technique for introducing exogenous genes, drugs, or other molecules of interest into a cell as a means of engineering the cell’s biology. Armon found that the gun was unsuccessful in delivering materials to the cells. Instead, the cells would respond to the gun by simply and unceremoniously deflating. In an attempt to avoid this mechanical reaction of the cells, he pushed the cells right up against the gun so that they were fixed in a microfluidic space and…the method worked! The cells were able to take up delivered materials. But a simple follow-up experiment revealed the true innovation in the approach; Armon turned off the gun completely, re-ran the experiment, and…it still worked! It turned out that physically squeezing the cell disrupts the membrane and allows materials to enter, independent of the gun. The cell repairs its own membrane and holds on to the cargo.

Armon and colleagues published this work in 2013 in PNAS, describing “A vector-free microfluidic platform for intracellular delivery.” At the time, existing approaches for exogenous material delivery primarily relied on viral vectors, which harness the biological properties of a virus to introduce genes of interest to a cell. Existing physical approaches relied on chemical or electrical disruption of the cell to sneak cargo past the cell membrane. The existing techniques came with various challenges with respect to cellular toxicity and off-target effects. Armon’s new microfluidic approach avoided placing the burden of innovation on the biological side of delivery and instead focused on the physical and mechanical properties of a cell membrane. As the cell passes through a 30–80% cell diameter constriction, the cell membrane incurs transient holes through which various materials can enter. The group was able to demonstrate a range of delivery materials including carbon nanotubes, proteins, and RNA into 11 different cell types, including ones that had been classically challenging to transfect.

The idea of turning the cell squeezing technology into the basis for a company flourished through Armon’s experience of the flood of collaborators who were interested in using the technology for a wide variety of applications. SQZ Biotech was founded later in 2013. The technology itself evolved into a sophisticated microfluidic chip with 1000 channels, capable of squeezing and delivering molecules to 1 billion cells per minute. SQZ Biotech is now a clinical-stage company with several cell therapy pipelines across oncology, auto-immunity, and infectious disease applications. In partnership with Roche, SQZ developed its lead program, SQZ-PBMC-HPV, which targets HPV-positive solid tumors using their “SQZ-APC” platform. In this approach, a patient’s own immune cells are squeezed with tumor-specific antigens to create SQZ-APCs (SQueeZed Antigen Presenting Cells). The modified APCs are delivered back to the patient where they are able to present the specific tumor antigen to CD8 T cells through a MHC-I / T Cell Receptor “handshake”. The educated T cells go on to kill the tumor target. SQZ Biotech anticipates clinical data in the second half of 2022.

Key Insights

1. Just Listen

Scientists Talk, Collaborators Listen: Coming from a chemical engineering background, Armon had a bit of an outsider’s perspective when it came to the biology side of things but it seemed to work toward his advantage. He had an attitude of openness to discussion. Instead of pouring over endless papers — which Armon found to simply regurgitate the same supposed challenges and problems ad nauseum — he went to the lunchroom. There, he met with many scientists who were eager to collaborate and use the cell squeeze technology for a wide range of applications. They inspired Armon and his group to think about what would be the most fruitful and interesting biology for the technology to address. The therapeutic applications appealed most to Armon, which pushed him to take a postdoc position at Harvard Medical School, dive into immunology, and nudge the technology toward the therapeutic direction.

“When you’re talking to people in those fields, you hear the real problems much faster…in the lunchroom you can learn very quickly what the problem is.”

Innovators Challenge: As the number of collaborations ramped up, Armon and his group found themselves working in roles similar to customer support, helping their collaborators troubleshoot, and implementing modifications to suit a wide variety of applications. What frustrated the inventors was that they felt like they had “invented an airplane but all people want to do is drive it on the highway at highspeeds instead of flying it”. In essence, collaborators were using the technology primarily for the purpose of expediting or incrementally improving biological applications that already existed. This was when Armon and his colleagues realized that it was time for them to take the technology in their own hands and develop the therapeutic applications themselves. 1.5 years into SQZ Biotech’s formation, Armon committed to his full time CEO position at the company to drive therapeutic development.

“We think we’ve invented an airplane but all people want to do is drive it on the highway at high speeds instead of flying it.”

2. Now Prove It!

To Yourself: There are no prescribed proof-points to demonstrate that a technology is ready to graduate from “academic tool” to something worth investing in as the basis for a company. That distinction is often quite fuzzy and challenging to discern. Armon emphasizes the importance of proving the value of your technology to yourself as a starting point. Then it’s a matter of figuring out how to position the data, improving how you present that position, and really tapping into an understanding of which data matters to whom.

To Partners: For example, Armon mentioned that securing the partnership with Roche was an important step in the company’s trajectory toward its therapeutic focus. Roche was interested in seeing a comparison of the squeeze tech relative to other vaccine mechanisms. SQZ was able to show that a typical vaccine mechanism encourages APCs to endocytose an antigen and primarily present it on MHC-II surface molecules which can interact with CD4 T cells. By contrast, squeezing the cells allows the antigen to bypass the endocytosis mechanism. The APC discovers the antigen already on the inside and presents it on MHC-I surface molecules which primarily activate CD8 T cells. These cytotoxic CD8 T cells are effective killers when they encounter the antigen in a tumor context. This particular proof-point was important to securing the Roche partnership but may have been an extraneous data point for other parties or investors. SQZ was intentional about which proof-points they chased early on and the value of those to their future success.

3. Navigating the Options

Incremental vs Unique: As Armon puts it, “the blessing and the curse of ‘squeeze’ is that there are so many things you can do with it!” Of all the things you can do, the big question for an emerging company is — what should you do? For SQZ, a network of collaborators and seasoned Scientific Advisory Board members helped them navigate this decision through the lens of two questions: 1) Does SQZ want to go after something that makes an incremental improvement on something that already exists, or 2) Does SQZ want to go after something that does not currently work but which SQZ may be uniquely positioned to address.

“The blessing and the curse of Squeeze is that there are so many things you can do with it!”

Incremental: The incremental improvement approach can be attractive because it can be seen as a safer investment — the biology has already passed certain proof-points and there are known benchmarks to improve upon. Going after CAR-T therapy, for example, could have positioned SQZ to improve on the efficiency of CAR delivery to T cells, speed of production, viability of cells, point-of-care workflow, or other factors where CAR-T approaches could stand to improve. As SQZ saw it, the downside of the incremental path was knowing that if you are working on “version two” of something, so are many other groups. Distinguishing your approach among a sea of others can be challenging. This approach may also leave the technology under-used or under-challenged (remember the airplane metaphor?)

Unique: Going after an unsolved problem can be seen as a risky undertaking — one that investors and stakeholders may need extra convincing to get behind. On this path, you either emerge with a ground-breaking and awesome solution, or you fail with much disappointment and loss. SQZ saw an opportunity to position their technology toward addressing a bold, as-of-then unsolved, and somewhat risky challenge — cancer vaccines. As described above, a major challenge of cancer vaccines was getting APCs to present antigen on their MHC-I versus MHC-II surface molecules in order to get a robust CD8 T cell response. When facing this “incremental vs unique” decision point, Armon recalls himself and his team having to make a best judgment call. They took the unique path. Within the cancer vaccine space, they decided to go after an immunologically well-defined, and robustly studied tumor, landing on HPV+ solid tumors. Cancer vaccines had previously failed for this indication, but SQZ saw their technology as capable of facing the biggest obstacle to success.

4. Leading the Company

Right Role, Right People: Armon stepped into a full-time position at SQZ Biotech 1.5 years after its inception. He was coming out of his postdoc experience having managed a group of undergraduate students and felt that served as a bit of a crash course in management. In determining his role as CEO, Armon knew that when it came to decision making about company direction, he wanted to be the one to challenge the technology and see it through to the therapeutic vision that originally inspired him. The “incremental vs unique” decision described above was the type of risk that he felt he could guide the company through from a CEO position. He mentions SQZ chairwoman Amy Schulman, as an important mentor who helped him step up to the challenges of leadership. He urges the importance of well-matched mentorship in positioning a leader for success. In his own experience, a well-matched mentor may come from a completely different field but can serve to fill in the gaps in your own skills and perspective.

5. Visions for the Future

Clinical: In the near future, SQZ Biotech is expecting clinical data in the second half of 2022 from their Phase 1/2 oncology targets. As SQZ moves forward, they are aiming to address a breadth of indications, by building out variations of their existing platforms. In the long run, SQZ sees a future of cell therapies that are administered at the point-of-care as an outpatient procedure.

RUO: With a therapeutic pipeline in place, SQZ is now planning to open up their technology for the research-use-only market. In collaboration with STEMCELL Technologies, SQZ will co-develop and commercialize a bench top system for pre-clinical stage research work. SQZ anticipates that opening up the technology in this way will usher in many unexpected and innovative applications. As the applications evolve, SQZ will be positioned to partner with groups who have impactful applications and help them translate to the clinic.

Learn more

Thank you to all who participated in this vibrant discussion! To stay in the loop and apply to attend future Insights sessions, please follow Nucleate on Linkedin

Sharei A, Zoldan J, Adamo A, Sim WY, Cho N, Jackson E, Mao S, Schneider S, Han MJ, Lytton-Jean A, Basto PA, Jhunjhunwala S, Lee J, Heller DA, Kang JW, Hartoularos GC, Kim KS, Anderson DG, Langer R, Jensen KF. A vector-free microfluidic platform for intracellular delivery. Proc Natl Acad Sci U S A. 2013 Feb 5;110(6):2082–7. doi: 10.1073/pnas.1218705110. Epub 2013 Jan 22. PMID: 23341631; PMCID: PMC3568376.

Author

Jessica Roginsky is a PhD student in the lab of Dr. Susan Kaech at the Salk Institute / UCSD, where she studies immune cell interactions in the brain and its barriers.

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Nucleate is a nonprofit organization dedicated to empowering the next generation of biotech leaders, with chapters spanning 10 regions and participation from over 60 academic institutions. Nucleate identifies future biotech entrepreneurs, removes barriers, and helps founders concentrate on building transformational technologies.

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About SQZ Biotech

SQZ Biotechnologies is a clinical-stage biotechnology company focused on unlocking the full potential of cell therapies to benefit patients with cancer, autoimmune and infectious diseases. The company’s proprietary Cell Squeeze® technology offers the unique ability to deliver multiple biological materials into many patient cell types to engineer what we believe can be a broad range of potential therapeutics. Our goal is to create well-tolerated cell therapies that can provide therapeutic benefit for patients and improve the patient experience over existing cell therapy approaches. With accelerated production timelines under 24 hours and the opportunity to eliminate preconditioning and lengthy hospital stays, our approach could change the way people think about cell therapies. The company’s first therapeutic applications seek to generate target-specific immune responses, both in activation for the treatment of solid tumors and in immune tolerance for the treatment of unwanted immune reactions and autoimmune diseases.

About Armon Sharei

Armon Sharei, PhD, is the Chief Executive Officer and Founder of SQZ Biotech, a biotechnology company creating innovative treatments by transforming cells into sophisticated therapeutics. Utilizing the proprietary Cell Squeeze® technology to develop a new generation of cell therapies, SQZ is creating powerful, multifunctional cell therapies for a range of diseases, with an initial focus on cancer, infectious disease and autoimmune disease. Dr. Sharei developed the Cell Squeeze® platform during his PhD work in chemical engineering at MIT. After his PhD, Dr. Sharei was a Ragon Institute postdoctoral Fellow at Harvard Medical School. He is co-author of 18 peer-reviewed publications and inventor on over 20 patents. In 2013, he founded SQZ Biotech. As a leader, Dr. Sharei’s motivating factor for his company is to simply make the world a better place. Dr. Sharei is driven by the potential global patient impact of the novel cell therapies SQZ can create using its breakthrough technology.

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