Tell us about your background.

Brian: As a teenager, the loss of my grandparents to different cancers influenced my scientific journey. In college, cancer research became a focal point. My career started in strategy-focused management consulting, advising life science companies. Notably, I led the team that advised the merger of Invitrogen with Applied Biosystems. My interest in entrepreneurship grew from family history and helping lead a project funded by Coca-Cola and the Gates Foundation in Kenya and Uganda. Returning to the US, I pursued an MBA at UC Berkeley, where I met Dr. James Lim, my scientific co-founder, at an entrepreneurship event.

James: I earned my Ph.D. in Biophysics from the Scripps Research Institute, focusing on single-cell analysis and cancer cell metastasis. Afterward, I did a postdoc at Harvard Medical School, where I identified and expanded rare circulating tumors. With varying degrees of success, I was able to demonstrate that we can keep these rare tumor cells alive and dividing ex vivo. My interest deepened in understanding how different microenvironments impact cancer cells. Later, I joined Lawrence Berkeley National Lab, and the collaboration with Brian led to the founding of Xcellbio.

How did you go about founding Xcellbio?

James and I founded Xcellbio within the Berkeley ecosystem. We also secured partnerships with a local cancer center and UCSF's genitourinary cancer research group provided initial data sets. These collaborations, along with biotech and pharma partnerships, led to a $5M seed investment in 2016. Our business model evolved based on partner feedback, focusing on selling workflows to pharmaceutical and academic customers.

What got you interested in cell therapies?

When we started Xcellbio, our focus was on growing tumors from patients. Our early work highlighted to us the importance of immune effector cells at keeping tumor cells at bay. We saw firsthand that you can engage and arm immune cells to target tumor cells with a high degree of specificity and effectiveness. It was incredible to observe the effectiveness of T cells killing tumor cells. This solidified our belief in the potential of cell therapies.

What was the need you saw in cell therapies?

Early collaborations with CAR-T cells revealed their efficacy in screening conditions mimicking the solid tumor microenvironment. We observed that CAR-Ts would get exhausted under low oxygen and hyperbaric screening conditions, compromising their effectiveness. This led us to question how we could enhance cell therapy potency in these immunosuppressive environments, ultimately resulting in the creation of the Avatar™ family of cell culturing and analytical systems.

What was the first application Xcellbio went after?

Initially, we aimed to enrich disseminated tumor clusters (DTCs) from cancer patient blood. We shifted focus to insights into TME-associated tumor cell and therapeutic cell performance, which was an area where several partners were offering to pay us to provide insights.

The company gained traction with this enrichment idea; can you tell us a bit more about that aspect?

Early collaboration with Thomas Krahn from Bayer Healthcare was pivotal. Running a blinded pilot study, we demonstrated impressive results, leading to paid partnerships and the first sale of our technology platform. Recognition of the importance of hypoxia-regulated pathways and pressure sensing receptors further boosted our efforts. Studies with Merck exploring lymphocytes in solid tumor specimens steered us towards repositioning our technologies for immune cell therapy.

You recently signed a partnership with Labcorp. What caught their eye?

Labcorp sought to expand their service offerings in gene and cell therapy (CGT) development. They were interested in technologies modeling the tumor microenvironment. Our collaboration involves applications providing more relevant tumor models and reprogramming immune effector cells for enhanced efficacy. The partnership expanded to include our GMP cell therapy manufacturing system, bridging preclinical research to scaled-up autologous patient data.

Why are these tools to modulate conditions necessary? What might it do from a potency perspective?

Conventional in vitro settings often show excellent cell therapy performance. However, the challenge arises in the suppressive solid tumor microenvironment.   What’s apparent from our early investigations into cell therapies, is that only a small subset of the immune/effector populations exhibit targeted tumor killing. So, the question becomes how can you select or enrich for the active cell populations?   Our systems provide a more relevant predictive readout, accounting for factors like low oxygen tension, high interstitial pressure, and low nutrient levels. The cells that survive or flourish in these conditions are “super killers”, having been conditioned in this environment.

And the process of cells’ reactions to these conditions have been studied for some time and recently received Nobel Prize recognition, right?

That’s right. The 2019 Nobel Prize in Physiology or Medicine was awarded to teams for discovering how cells sense and react to low oxygen levels. Then in 2021, the same prize was awarded to Ardem Patapoutian and David Julius for discovering receptors for sensing temperature and touch. So, these are no small discoveries by any means and explains how these external stimuli can result in changing cell phenotypes. 

Are there discernible phenotypic differences between those cells that kill cancer and others? What makes them more efficient in targeting and ultimately killing cancer?

Our working theories suggest that conventional activation and exhaustion markers are poor predictors of effector cell potency. We combine cell-based killing assays with targeted immunophenotyping to identify persistent and potent effector cell subpopulations. These cells, exhibiting anti-tumorigenic properties under challenging conditions, often display unique metabolic profiles.

Is this the critical step to enable cell therapies to target solid tumors? What else might be needed to unlock that space?

Maintaining optimal differentiation status during in vitro CAR T cell manufacturing is crucial. However, the suppressive solid tumor microenvironment presents additional challenges. Metabolically conditioning cells through transient nutrient depletion and lowered oxygen tension produces fitter cell products. This conditioning enhances cytokine secretion, cytotoxicity, and metabolic rewiring, potentially translating to better efficacy at the tumor site. We think these functional outcomes in preclinical models will translate to better trafficking to the tumor site and better efficacy at the tumor site than current approaches offer, hopefully achieving higher complete response rates in patients.

So how would a biotech go about applying your technology to their programs?

Our technology spans the biotech value chain. The Avatar™ and Avatar AI™ instruments serve preclinical research, screening conditions, and assaying antitumor function. The Avatar Foundry™ enables fully closed transduction (optional) and expansion under GMP conditions for improved gene editing efficiency and greater potency for use in clinical trials and cell therapy commercialization.

Do you think a one-size-fits-all approach will work for cell therapies?

Unlikely. Cell therapies vary in source material, cell types, dosing regimens, and desired phenotypes. Bespoke manufacturing workflows tailored to specific therapies are necessary.

Is it feasible to think about bespoke manufacturing workflows? How might this look?

Yes, bespoke workflows are crucial in cell therapy manufacturing. Tailoring unit operations to each therapy's specific requirements involves optimizing steps for consistency, throughput, and quality. This approach accommodates diverse therapies with unique manufacturing processes.

You’ve been doing some work along these lines as well. Can you speak to these efforts with Cellular Origins?

Our focus on cell quality includes efforts to automate and reduce human interactions in our workflow. The partnership with Cellular Origins aims to create solutions for automation around our proprietary workflow, connecting upstream cell selection and downstream operations.

So, a platform could be automated with, in theory, any unit operations desired to create the best process for one’s cell type or indication?

Yes, we favor a modular approach where unit operations are optimized for each therapeutic strategy. Modules can connect in a sterile manner, enabling technicians or robots to perform the workflow with minimal manual manipulation.

How important generally is an offering like this to the cell therapy field? What does automation and breaking the process down into unit operations allow for?

This automated, modular approach is essential for modern cell therapy manufacturing. Automation increases efficiency, reduces costs, and ensures consistency. Breaking processes into unit operations minimizes batch-to-batch variability, making results comparable across batches and sites. It also allows for use of best-in-class technologies for delivering new or more powerful capabilities to the field, i.e., the Avatar Foundry’s emphasis on delivering improved capabilities around[CS1]  transduction, expansion, and potency improvements.

What other parts of the manufacturing workflow do you think can be improved? Are there specific unit operations you think are critical to further optimize?

Genetic modification of therapeutic immune cells is critical and can be improved. While lentiviral transduction is common, it comes with complexities. Nonviral approaches, such as electroporation, show promise but need refinement to enhance efficiency and reduce cytotoxicity.

So, what’s next for Xcellbio?

We recently launched our beta program for our GMP cell therapy manufacturing instrument (Avatar Foundry), with Elevate Bio announced as one of a number of top-tier beta sites utilizing our platform to optimize the metabolic fitness of their (clients’) cell therapy candidates for solid tumor indications.

That’s terrific. Brian and James, thanks so much for chatting with us. We wish you a productive Advanced Therapies Week!

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