Chris Spivey is director of Industry Relations and Strategic Partnership, MJH Life Sciences.

Chris Spivey

® spoke with Carl Allenspach, director of business operations, manufacturing, science, and technology organization at Bristol Myers Squibb about expectations and significant benefits to be gained at this year’s INTERPHEX, to be held at the Javits Center in New York City on April 16–18, 2024.

Allenspach’s background includes solids formulation and processing, with more than 20 years of experience in formulation development. Much of his experience involved hands-on work with equipment, operations, and processes formulations. Allenspach has also moved into the biologics space, gaining exposure to biologics drug substance, drug product, and packaging.

About this year’s INTERPHEX, Allenspach remarks on the addition of scientific-focused sessions, stating that, “INTERPHEX is well known and established for bringing in an impressive array of pharma vendors—covering all aspects of the industry. So, attendees already go there to meet with the vendors to see the new equipment, the new materials, and processes that are available. So, adding on the scientific content really adds another aspect to the meeting. The [meeting] brings in an international audience because of the location; it's a place where scientists can collaborate and exchange ideas.”

“By adding in this—the learning lab that INTERPHEX is offering—it's going to give [attendees] this curated scientific content that the attendees will really be able to benefit from—getting the information on these technologies, processes, regulatory changes—that they can then bring back and utilize in their daily life,” he adds.

The collaborative spirit at INTERPHEX offers the opportunity for experts from different fields to meet and engage, which significantly helps accelerate different innovations as well, Allenspach points out. “We hope that attendees will gain some actionable strategies that they'll be able to apply. I think everybody that attends a conference goes in there with some problem that they're having, something that they want to know more about, and [most of the time] by talking to the other people there and by listening to presentations, by asking questions … I've taken something back that I've benefited from. So … we really hope most people who go there get inspired from listening to some of these talks, and they're going to leave with some excitement and enthusiasm that will be able to give them a boost in their career,” he explains.

Carl Allenspach, director at Bristol Myers Squibb discusses the interactive and collaborative important of INTERPHEX.

 Bristol Myers Squibb’s Director of Business Operations for MSAT, Carl Allenspach, Highlights Collaboration and Interactive Exchange at INTERPHEX 

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Carl Allenspach, director of business operations, manufacturing, science, and technology organization at Bristol Myers Squibb discusses the interactive and collaborative important of INTERPHEX.

Bristol Myers Squibb’s Director of Business Operations for MSAT, Carl Allenspach, Highlights Collaboration and Interactive Exchange at INTERPHEX 

Fabian Gerlinghaus, co-founder and CEO, Cellares

The number one priority for every early-stage biotech is speed to clinical data. Standardizing processes and regulatory paths are an overarching priority for the commercial cell and gene therapy (CGT) field, as this not only advances timelines, but also encourages further investments. The Office of Tissues and Advanced Therapies (OTAT) at FDA currently lists 35 approved CGT products (1). Clearly this is an amazing success story for saving many lives, but some of these products have a troublesome future commercially, while others have a difficult road ahead in terms of manufacture and mechanical deployment. However, all faced regulatory uncertainty alongside a burdensome filing requirement to become “products”, and all of those that follow (currently numbering into the several thousands) are subject to the same pressures, uncertainties, and requirements.

According to Fabian Gerlinghaus, CEO of Cellares, companies today typically generate on the order of 400 pages of paper-based batch records for every individual patient. “They're writing a book for every single patient. That doesn't scale well,” he says with some exasperation. “Try and do that manually, paper-based, for hundreds of thousands of patients every single year. It's a nightmare. However, our interactions with the FDA have been incredibly positive, and we view FDA as a very collaborative partner.”

Cellares was extended an FDA Center for Biologics Evaluation and Research (CBER) Advanced Technologies Team (CATT) meeting resource. The scope of these gatherings pertaining to advanced manufacturing technologies “focus on novel technologies that can have a significant impact on product development, manufacturing process and control strategies, and may also have regulatory implications. This includes manufacturing and analytical methods for those products or classes of products for which the center has limited experience with the manufacturing or development process” (2).

https://www.pharmtech.com/view/cellares-expands-agreement-with-bristol-myers-squibb-for-second-car-t-program

“FDA understands that they need automation the standardization afforded by this automation, Gerlinghau continues. “Peter Marks has been very outspoken about what we want, what the cell therapy industry needs, is effectively a soda machine where you press the Coca-Cola button and out comes Yescarta, and you press the Pepsi button and out comes Breyanzi. And that is what we have built. And moreover, Congress at this point has actually given directions to the FDA to standardize the processes. The FDA has since implemented this direction from Congress, and they came out with the Advanced Manufacturing Technologies designation, which is really an effort to standardize a cell therapy manufacturing technologies.”

“On the topic of standardization, we talked about the benefits of standardization for the drug sponsors, for the FDA. If there is a manufacturing standard, it means less work, less effort for the drug sponsor to create their regulatory filings and less work for the FDA to review those regulatory filings. If you can just reference a standardized self-manufacturing technology.”

Watch part 4 of our interview with Gerlinghaus below:

Can Cellares deliver on the goal to meet total patient demand for cell therapies globally? CEO Fabian Gerlinghaus discusses.

Automation of Clinical Data Key in Meeting Cell and Gene Therapy Demand

Approved Cellular and Gene Therapy Products

Cellares CEO Fabian Gerlinghaus discusses the nuts and bolts of counterflow centrifugal elutriation and electroporation innovations and optimization.

Cellares Cell Shuttle is More Valuable Than the Sum of the Value of the Individual Parts

Standardizing workflows for system components and process steps is both a challenge and a goal for cell and gene therapies (CGT) scale up and commercialization. Counterflow centrifugal elutriation is employed for white blood cell enrichment and platelet removal. In addition, Cellares is using this technology for concentration steps and buffer exchanges. Gerlinghaus believes the key to appreciating the importance of their counterflow centralfugal elutriation feature is that it is but one of many technologies integrated into a fully-closed, fully-automated cartridge. The sum of all of those technologies put together in a closed and automated system is much more valuable than the sum of the parts; the whole system is worth more than the value of the individual technologies. Simply, automation solves the cost problem and closing the process solves the contamination problem. All of these technologies in and of themselves had to be at a similar efficacy level as technologies used in the current market, so Cellares generated a data set to show that that is the case. Gerlinghaus pointed out that in many cases, Cellares’ implementation of these technologies actually outperforms what's out there in the market; its electroporator achieves higher electroporation efficiency than many of the top electroporators used by professionals in the field. This can be seen as an underappreciated strength of Cellares’ technology platform.

Analytically speaking, it’s important to understand that the cell shuttle system handles purely the manufacturing of a cell type product; it does not handle release testing of the cell therapy products that come out of the platform. Gerlinghaus hinted, however, that there's a much bigger story coming soon. During the actual manufacturing process that is conducted on the cell shuttle, Cellares’ team does a lot of in-process testing. Cellares has integrated a fully automated biochemistry analyzer that can run up to 16 different assays on a tiny sample. It provides cell count, density, viability, and metabolite and nutrient data and it's fully integrated fluidically, mechanically, and from a software perspective. Gerlinghaus outlined the cell shuttle process: technicians decide ahead of time at which frequency they want the cell shuttle to take a sample and which assays they want that platform to run on the cell shuttle. Then, with the support of offline assays, the cell shuttle can take a sample, a human can pick it up, and the sample can be analyzed on any other third-party instrument. In future iterations of the cell shuttle, Cellares plans to go through an entire design-build test cycle roughly every year and a half. Moving forward, the company aims to integrate even more in-process analytical capabilities into the cell shuttle, promising that there is yet more to come.

Cellares CEO Fabian Gerlinghaus discusses the nuts and bolts of counterflow centrifugal elutriation and electroporation innovations and optimization, while hinting at big news on future release testing of products, as a product itself.

A trade imbalance between the supply and demand sides of the advanced therapy medicinal products (ATMP) field sees demand for these often-curative 

 far outstripping supply, manufacturing being one of the main bottlenecks.

Processes that have progressed farthest have been modular, semi-automated processes that still contain manual handling steps. “This style of process is inherently limiting,” Peter Yates, director of Product Management–Personalized Medicine, Cell and Gene, Lonza, told 

 (1). “These processes may work well in early clinical trials where the numbers of doses produced is relatively small and demand can be handled with a specialized manufacturing team. However, the problems become abundant when trying to increase throughput.”

One company trying to open that bottleneck is San Francisco-based Cellares, a self-titled

Integrated Development and Manufacturing Organization (IDMO) that provides

cost savings, scalability, and drug product quality improvements versus traditional manufacturing techniques.

, Fabian Gerlinghaus, CEO and co-founder, Cellares, recalls walking the exhibit floors at cell therapy conferences in 2018, noting that “there was just nothing on the market that I thought would actually be able to solve the scalability and the cost and the quality problems. And at that point, Omar and I teamed up to start Cellares, and build a technology platform that actually does solve all three of these issues.”

Recently, the company announced that its first Cell Shuttle has been deemed current 

Good Manufacturing Practice (cGMP)–compliant

, marking a major milestone as it prepares for clinical readiness by the end of 2024. 

Watch Part 2 of our interview with Gerlinghaus below to learn more about Cellares’ Cell Shuttle platform and how they are innovating in a complex and highly regulated space.

Cellares CEO Fabian Gerlinghaus discusses automated cell therapy manufacturing using the company's Cell Shuttle platform.

Cellares CEO Fabian Gerlinghazc CEO Fabian Gerlinghaus us on Automated Cell Therapy Manufacturing

Small Footprint Automated Closed Production Platforms for CAR-T and Other Advanced Therapies

In an interview, Fabian Gerlinghaus of Cellares outlines a paradigm change in both hardware and software, regulatory expansions, and some positive cost outcomes for the CGT field.  

Software Advances Mass Customization for Cell and Gene Therapies 

There’s no doubt that things are moving quickly in the field of cell and gene therapy. Less than a decade into market availability, there are more than 10 FDA-approved cell therapies available (1), including first-in-class tisagenlecleucel (Kymriah; Novartis), which was approved in 2017 for the treatment of acute lymphoblastic leukemia in children and young adults. Soon after, three more CD19-specific CAR T-cell therapies were approved by the FDA for the treatment of different B-cell malignancies, namely axicabtagene ciloleucel (Yescarta), brexucabtagene autoleucel (Tecartus), and lisocabtagene maraleucel (Breyanzi), and more continue to come to market for 

An August 2023 report from market research firm Roots Analysis (2) revealed that “over 1,000 cell and gene therapy candidates are currently being investigated for the treatment of various disease indications.” The report went on to say that “in order to ensure the optimum use of their resources and augment their revenue generation opportunities, a number of cell therapy companies engaged in this market offer contract services, in addition to their in-house manufacturing capabilities. In recent years, several big pharma players have undertaken initiatives, including establishing strategic partnerships, seeking investment from venture firms, and carrying out expansion projects, in order to enhance their capabilities.”

One of those companies leading the charge is San Francisco-based Cellares, a self-titled Integrated Development and Manufacturing Organization (IDMO) that provides cost savings, scalability, and drug product quality improvements versus traditional manufacturing techniques. In an interview with 

, Fabian Gerlinghaus, CEO and co-founder, Cellares, set the stage to understand what it took to innovate in a fiercely complex technology and tightly regulated space.

In the first segment of this interview, Gerlinghaus describes the scalability achieved with the Cell Shuttle platform and integrated consumable cartridge automated platform. All unit operations take place inside the single-use consumable cartridge. Cellares can load up to 16 cartridges into the Cell Shuttle, running up to 16 different processes simultaneously. According to Gerlinghaus, the Cell Shuttle reduces the amount of labor required by about 90% due to the automation, saying “it’s equivalent to about 100 different bench top instruments in one machine, in a very compact, tight space [requiring] about 90% less facility space. So, you put those two things together, a 90% reduction in labor required.” He goes on to emphasize that this results in about a 50% lower price per batch compared with conventional CDMOs. In a complex set of manufacturing operations, full automation can apparently “reduce process failure rates by about 75% compared with open and manual cell type manufacturing methods based on bench-top equipment” by greatly reducing both contamination and operator error.

Watch part 1 of our interview with Gerlinghaus below:

Fabian Gerlinghaus of Cellares discusses the company's innovative cell and gene therapy platform.

Fabian Gerlinghaus on Cellares' Platform Innovation

(1). Approved Cellular and Gene Therapy Products. US Food and Drug Administration. Updated February 21, 2024. Accessed March 6, 2024. https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/approved-cellular-and-gene-therapy-products
(2). Top 10 Cell and Gene Therapy Companies. Roots Analysis. August 2023. https://www.rootsanalysis.com/key-insights/10-leading-cell-and-gene-therapy-companies.html

Cellares CEO Fabian Gerlinghaus shares how an automated, closed-production platform with a small footprint can dramatically impact cost savings and scalability for cell and gene therapies.

Cellares Innovates With Automated Cell and Gene Therapy Platform

Wide-scale resources have increasingly been deployed to find, characterize, validate, bank, and file patents for cancer neoantigens. It has been a biological landgrab echoing the single nucleotide polymorphism (SNP) fervor at the turn of the century. In a conversation late in 2023 with Maravai’s chief innovation officer Kate Broderick and Accuitas’ CEO Tom Madden on future applications for messenger RNA (mRNA)-based therapeutics, the notion came up as a potential lynch pin. Broderick commented that, “there was a beautiful study that came out of a large group in the UK [United Kingdom] called the TRACERx Study where they actually monitored people's cancers over time and fairly frequently, and within a matter of a month, some of these tumors had completely changed their neoantigen profile. So, to [Madden]'s point, the need to have really unprecedented speed to make this, the promise of personalized vaccines prominent … is absolutely key now” (1). However, lacking in mature and effective tools and equipment, activities have been labor intensive and, for the most part, produced only halting successes.

. from the La Jolla Institute for Immunology with a new platform approach described in a February American Association for the Advancement of Sciences (AAAS) paper (2). This new approach appears to work well on cancers pictured as evading patients’ immune systems, in part because these cancers do not carry many mutations. However, while these cancers are not infiltrated by cancer-fighting immune cells, the tumors do appear to trigger some cancer-fighting T cells and can perhaps be entrapped, thus “heating up” cold cancers.

The first principles that follow might seem complex, but some amount of future therapeutic target tractability may well require basic understanding of those principles. From the paper’s introduction “the genetic instability underlying neoplastic transformation can also provide tumor-specific targets for host T cells. These include function-altering mutations in so-called ‘driver’ genes, which endow the tumor with growth and survival advantages, as well as tumor-specific variants of ‘passenger’ genes that lack an obvious protumorigenic function” (2).So far so good; cancers behave and interact differently from regular tissue in ways that leave characteristic biological trails that can be tracked. Along this trail researchers recognize mutated peptides bound to the surface of human leukocyte antigen (HLA) molecules for recognition as neoantigens by patients’ CD8 and CD4+ T lymphocytes. Researchers have been aware of neoantigens for some time and have wanted to target these tumor specific targets; however, it has been a substantial challenge to do so.

A typical traditional neoantigen discovery setup relies on next-generation sequencing (NGS), complex algorithms/databases, and a certain distrust regarding the utility of the eventually upturned somatic nonsynonymous mutations (NSMs). The process is expensive and slow. A second method assesses T cells in peripheral blood or tumor-infiltrating lymphocytes (TILs). This can be “technically challenging or require specialized cellular reagents, such as autologous dendritic cells, thus limiting their utility in routine neoantigen screening using nominal clinical samples” (1). The La Jolla team set out instead to forge an “unbiased and HLA-independent strategy for the functional validation of spontaneous neoantigen-specific CD4+ and CD8+ T cell responses that uses NGS-guided selection to nominate NSMs for functional recognition testing in a short-term culture of autologous peripheral blood mononuclear cells (PBMCs), which reports on both T helper cell 1 (TH1) and TH2 cytokines. Using this approach (herein referred to as ‘IPV’ for identify-prioritize-

validate), we now show that preexisting CD4+ and CD8+ T cell responses can be identified and the T cell receptors (TCRs) that mediate them can be isolated at rates that are about 10-fold higher than class I HLA binding–based predictive approaches across a spectrum of tumor types and degrees of tumor mutational burden using routinely available clinical samples” (2). It will likely have been understood that by integrating elements of both traditional approaches, this new platform performs in a more HLA-agnostic and clinic-capable manner and is, henceforth, a healthy step ahead in terms of reliably churning out tumor target information—especially regarding low mutation tumor profiles. It is also a step toward a better understanding of tumor microenvironment interactions with an individual’s immune system, which alone makes it an effort worth celebrating.

There are some drawbacks and limitations, however, and these can be found in the discussion section of the AAAS paper. But the expectation to “routinely and reliably identify natural tumor-specific neoantigens and the TCRs that recognize them” will indeed “be crucial to the development of precisely and accurately targeted immunotherapies that can effectively offer therapeutic benefit while avoiding off-tumor toxicities” (2), which is a long-sought goal in oncology research now visibly present as a functional platform technology.

, Oct. 17, 2023.
2. Miller, A.; Schoenberger, S.; Peters, B.; Cohen, E. A functional identification platform reveals frequent, spontaneous neoantigen-specific T cell responses in patients with cancer. 

 (736), eabj9905. DOI:10.1126/scitranslmed.abj9905

Articles

Accurately targeted immunotherapies through reliable neoantigen recognition enable personalized medicine development.