Category Archives: Cell Therapy

The biotech IPO market has been hot for the past few years, but it set all sorts of new records in 2021. A total of 399 companies priced IPOs in 2021, raising $142.5 billion, according to IPO research firm Renaissance Capital. Those figures made this year the busiest by deal count since 2000, and the biggest ever in terms of proceeds raised.

Healthcare, which includes biotech, was the busiest sector, accounting for 36% of the IPO activity, Renaissance said in its 2021 annual review. The biggest biotech IPO of the year belongs to Seattle cell therapy developer Sana Biotechnology, which was able to upsize an IPO that raised $588 million.

While Sanas IPO total is eye-catching, the sum is also notable because its the largest ever IPO for a company that has yet to reach the clinic. Not so long ago, biotech companies typically waited until they had clinical data before turning to the public markets. Even early dosing data reduces the investment risks.

Sana still doesnt have clinical data. What it does have is a cell and gene therapy technology and leadership from two former Juno Therapeutics executives who steered that company to a $9 billion acquisition by Celgene in 2018. Sana said it is preparing to file multiple investigational new drug applications in 2022 and 2023. That means investors must wait another year or more before the company produces data that could move the companys stock price.

Other cell therapy developers that went public this year include Lyell Immunopharma, Caribou Biosciences, Instil Bio, Talaris Therapeutics, and Achilles Therapeutics. Most of the biotechs in this group had reached at least early clinical testing at the time of their IPOs.

Recursion Pharmaceuticals had the second biggest biotech IPO of 2021. The Salt Lake City, Utah-based company raised $436.4 million to continue clinical development of drug candidates discovered by its AI platform. Similar to Recursion, Exscientia has an AI-based drug discovery platform that it uses to develop drug candidates for partners as well as its internal pipeline. The Oxford, U.K.-based company raised $304.7 million from its IPO. Absci, which uses its AI platform to produce proteins that become drug candidates for its pharmaceutical industry partners, raised $200 million in its stock market debut.

According to Renaissance, IPO filings increased for the third straight year; the 495 IPOs that were filed in 2021 through Dec. 20 is a more than 94% increase compared to the same period last year. The $142.5 billion raised is an 82.2% increase over last years total.

The year was also marked by a surge in companies going public by merging with special purpose acquisition companies (SPACs). Renaissance counted nearly 200 companies such deals. Biotech companies that went public in 2021 via SPAC deals include Nautilus Bio, Humacyte, Ginkgo Bioworks, and Pardes Biosciences.

As we head into a new year, the hot IPO market appears to be cooling off. While the market wont turn completely cold this winter, Renaissance doesnt think investors should expect a repeat of 2021s IPO activity.

Looking forward, we believe the 2022 IPO market will have a slow start and fail to match the past years record pace, but ample IPO candidates are ready to take the leap once conditions improve, the firm said.

Photo: Spencer Platt, Getty Images

Link:
Cell therapy, AI drug discovery highlight 2021's record year in biotech IPOs - MedCity News

Megan Olsen, MPH, principal at Avalere, discusses the role that value assessments are expected to play in the future pricing of gene and cell therapies.

Megan Olsen, MPH, principal at Avalere, discusses how the impact of small patient populations and other limitations may influence payer conversations about gene and cell therapies.

Transcript

What role will value assessments play in payer decisions on pricing for cell and gene therapies?

It's going to play an important role. And I think it already is today, to some extent. We've done some survey research with payers at Avalere and found that most payers are already doing their own valuations for products in this space. We've also seen other entities like [the Institute for Clinical and Economic Review] be referenced as a key stakeholder at informing valuation of various products in this space. When you have an introduction of a high cost potentially million dollar therapy, with the potential for the benefit over many years, it's going to get a lot of attention you'll want to understand what is the true value of the product relative to price. So, there are a lot of different frameworks under consideration for how to measure that and how to adapt various methodologies or framework specific to the cell and gene therapies, given the uniqueness of the asset.

There's a lot of evolving in the value-based space in the private market, but also in the policy sphere as well. We're seeing the new Biden administration emerge with its priorities in health care and I think value-based care is going to be at the top and we've heard references in the drug pricing arena on interest in tying prices to value in some way or leveraging or standing up a value assessment entity to really measure value and potentially have a role in informing price as well. So, I think a lot more to come there. And this whole swirling interest in innovative financing models is based on value and wanting to determine net pricing based on the value that the product is delivering to the patient, to the health care system, to the payer, etc. So, needing that data to to make those determinations but also using the data that is derived from these arrangements to inform future value conversations as well.

Read more:
Avalere Analyst Weighs in On How Value Assessments Will Influence Gene and Cell Therapy Pricing - AJMC.com Managed Markets Network

Sexton Cell Processing tools and CryoStor cGMP Freeze Media Incorporated in Cell and Gene Therapy Workflows

BOTHELL, Wash., Jan. 4, 2022 /PRNewswire/ -- BioLife Solutions, Inc. (NASDAQ: BLFS), a leading supplier of class-defining bioproduction tools and services for the cell and gene therapy and broader biopharma markets, today announced an extended collaboration with Seattle Children's Therapeutics, a venture at Seattle Children's, bringing cutting edge, curative technologies and therapies to defeat pediatric cancer and other diseases that impact children. The collaboration will focus on establishing best practices in biopreservation and closed-system manufacturing with the introduction and integration of Sexton's AF-500 for closed-system processing for cell therapy manufacturing and viral vector delivery that will be used in Seattle Children's Therapeutics new lentiviral vector manufacturing facility called VectorWorks.

BioLife Solutions New Logo 2021 (PRNewsfoto/BioLife Solutions, Inc.)

"This expanded collaboration is an exciting step for Seattle Children's Therapeutics as we work towards developing closed-system processes for cell therapy manufacturing," said Matt Selley, Director of GMP Manufacturing at Seattle Children's. "Lentiviral vector manufacturing is a critical component of the cell production process."

Seattle Children's has utilized BioLife's CryoStor cGMP freeze media for several years, as an optimized excipient for improved post-thaw viability and functional recovery of cells used in clinical applications and trials. As cell and gene therapy manufacturers move toward closed-system processing, it is vital that upstream critical excipients and ancillary materials, such as viral vectors, are manufactured and packaged in containers suitable for closed-system integration. While some upstream bioprocesses have been successfully automated, the final steps of downstream bioprocess, namely fill-finish, are often performed manually in open systems with associated risks of contamination and user error. Furthermore, current packaging for viral vector intermediates demands that therapy developers operate in higher grade environments due to the open nature of this manufacturing step.

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This continued collaboration will combine the Sexton off-the-shelf automated fill-finish system, AF-500, with Seattle Children's Therapeutics' expertise in viral vector manufacturing. Sexton's rapidly deployable AF-500 is capable of filling and sealing up to 560 CellSeal vials in 90 minutes. The goal is to utilize the AF-500 to initiate high throughput fill-finish of vector intermediates. Vectors will be filled into Sexton's proprietary vials, CellSeal and CellSeal Connect. CellSeal Connect builds on the original CellSeal cryogenic storage vial, which has been incorporated as the final drug packaging in commercial cell therapy products. The new version allows closed-system retrieval of intermediate products, such as viral vectors, thereby negating the need for therapy developers to operate in higher grade manufacturing suites for delivery of vectors and cargo.

The collaboration will result in detailed workflows, demonstrating the suitability of the CellSeal platform as a packaging container and closed system automation for viral vectors. It will include an assessment of the vial and fill system's usability and compatibility with high throughput fill-finish of viral vectors. In addition, post-fill activities such as high-density storage, shipping, distribution, thawing, and closed system retrieval will be assessed. As Seattle Children's Therapeutics will be the end-user of the viral vector product, the workflow resulting from the collaboration will cover the movement of viral vectors from the point of packaging to the point of transduction and patient administration, when applicable.

"The development of these closed connection processes in small volume aliquots has the potential to streamline this element of cell therapy manufacturing," said Sean Werner PhD, Chief Technology Officer, Cell Processing at Biolife Solutions. "Developing tools to meet the unique needs of this emerging industry is the best way to bring these life changing therapies to patients."

About BioLife SolutionsBioLife Solutions is a leading supplier of class-defining bioproduction tools and services for the cell and gene therapy and broader biopharma markets. Our tools portfolio includes our proprietary CryoStor and HypoThermosol biopreservation media for shipping and storage, the ThawSTAR family of automated, water-free thawing products, evo cold chain management system, high capacity cryogenic storage freezers, Stirling Ultracold mechanical freezers, SciSafe biologic storage services, and Sexton Biotechnologies cell processing tools. For more information, please visit http://www.biolifesolutions.com, http://www.scisafe.com, http://www.stirlingultracold.com, or http://www.sextonbio.com and follow BioLife on Twitter.

About Seattle Children's Seattle Children's mission is to provide hope, care and cures to help every child live the healthiest and most fulfilling life possible. Together, Seattle Children's Hospital, Research Institute and Foundation deliver superior patient care, identify new discoveries and treatments through pediatric research, and raise funds to create better futures for patients.

Ranked as one of the top children's hospitals in the country by U.S. News & World Report, Seattle Children's serves as the pediatric and adolescent academic medical center for Washington, Alaska, Montana and Idaho the largest region of any children's hospital in the country. As one of the nation's top five pediatric research centers, Seattle Children's Research Institute is internationally recognized for its work in neurosciences, immunology, cancer, infectious disease, injury prevention and much more. Seattle Children's Foundation works with the Seattle Children's Guild Association, the largest all-volunteer fundraising network for any hospital in the country, to gather community support and raise funds for uncompensated care and research. Join Seattle Children's bold initiative It Starts With Yes: The Campaign for Seattle Children's to transform children's health for generations to come.

For more information, visit seattlechildrens.org or follow us on Twitter, Facebook, Instagram or on our On the Pulse blog.

Cautions Regarding Forward Looking Statements

Except for historical information contained herein, this press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. These forward-looking statements include, but are not limited to, statements concerning our extended collaboration with Seattle Children's and the results of such collaboration. All statements other than statements of historical fact are statements that could be deemed forward-looking statements. These statements are based on management's current expectations and beliefs and are subject to a number of risks, uncertainties and assumptions that could cause actual results to differ materially from those described in the forward-looking statements, including among other things, those factors described in our risk factors set forth in our filings with the Securities and Exchange Commission from time to time, including our Annual Report on Form 10-K, Quarterly Reports on Form 10-Q and Current Reports on Form 8-K. We undertake no obligation to update the forward-looking statements contained herein or to reflect events or circumstances occurring after the date hereof, other than as may be required by applicable law.

At the CompanyTroy WichtermanChief Financial Officer(425) 402-1400twichterman@biolifesolutions.com

InvestorsLHA Investor RelationsJody Cain(310) 691-7100jcain@lhai.com

Cision

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BioLife Solutions Collaborates with Seattle Children's to Improve Viral Vector and Cell and Gene Therapy Manufacturing - Yahoo Finance

ATMPS Hataali is a secure data sharing platform, specially designed as a scalable system for advanced therapies. The developer describes it as a vein to vein, blockchain based, cell orchestration platform, providing full chain of custody, identity, and condition information.

It allows multiple stakeholders - hospitals, manufacturers, couriers - to communicate and coordinate their activities in real time, thereby increasing efficiency, ensuring patient safety and regulatory compliance, Raja Sharif, CEO of ATMPS, told us in May last year.

Assurea, which specializes in navigating the complex regulatory pathway for advanced therapies, has already begun working with ATMPS on a number of collaborative projects, including one for a UK based phase I biotech focused on CAR-T.

The partners want to target pre-clinical companies heading into the IND stage, as well as well providing data rescue systems for therapies already undergoing trials. The latter issue, they said, is a growing area of concern as many biotech companies realize that, as key regulatory touchpoints approach, they dont have a robust enough platform to stand up to intense regulatory scrutiny.

This collaboration enables biotechs and innovators to have regulatory-ready, decentralized data records that have integrity built-in by design.

"Its a completely different way of tackling compliance and provides investors with increased confidence in the results gained and initial valuations.

"Looking further ahead, it also means they can have confidence that trials are progressing as they should, with data available in near real-time and, crucially, have the ability to scale quickly, said Sharif.

Using this blockchain system means even the smallest companies can now operate a continual state of audit readiness, rather than scrambling for records as an audit or inspection approaches, said the partners.

This joint approach will lead to higher valuations, increased security and potentially better returns for biotechs as the immutable records will back up every claim and data point with an irrefutable record, providing greater trust for an industry that has seen a number of prominent data scandals in the last few years, they continued.

This collaboration means that biotechs can reduce costs and increase trust. It takes away so many of the problems these therapies face as they progress through the clinic to commercial. For example, the ability to alleviate silos in the supply chain while providing an end-to-end solution to track and trace for patients and in near real-time is potentially a game changer for the industry in how quickly and [data integrity] issue free they can accelerate towards patients, commented Tanya Sharma, co-founder of Assurea.

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ATMPS and Assurea team up to ensure audit readiness for cell and gene therapy innovators - BioPharma-Reporter.com

- GC Cell seeks to expand global availability of Immuncell-LC for liver cancer

- Rivaara Immune to lead development and commercialization in India

YONGIN, South Korea & MUMBAI, India--(BUSINESS WIRE)-- GC Cell (KOSDAQ:144510) and Rivaara Immune Private Limited today announced that they have entered into an exclusive licensing agreement, pursuant to which Rivaara Immune has agreed to develop and commercialize Immuncell-LC in India, Sri Lanka, and Bangladeshi. Developed by GC Cell, Immuncell-LC is a patient-derived autologous T-cell immunotherapy for liver cancer, which was approved by the Korean MFDS back in 2007.

Under the terms of the agreement, Rivaara Immune has obtained the exclusive right to develop and commercialize Immuncell-LC within India for liver cancer. In return, GC Cell is entitled to receive an undisclosed upfront payment, as well as payments for the achievement of commercial milestones, with royalties based upon the sales.

In addition, GC Cell will also receive a partial stake of Rivaara Immune and exclusive rights to supply media which is essential for the production of Immuncell-LC.

The number of cancer patients in India is more than 1.3 million, about 6 times that of Korea, and India's liver cancer market is 2.3 times that of Koreas. Notably, 5-year liver cancer survival rate is 4%, which is very low compared to 37% of Korea, so new treatments are urgently needed.

Immuncell-LC's overseas expansion is based on its domestic success, pushing for technology transfer by country, and signing contract with Rivaara Immune in India is the first outcome, said Dae-woo Park, CEO of GC Cell. Both companies will cooperate in a win-win strategic partnership, and are also closely discussing with a number of partners in China and other countries in the Middle East.

Rivaara Immune is pleased to partner with GC Cell, a leader in Immune Cell Therapy in Korea. With this partnership we will be among the first, to bring to the Indian market, customized solutions to cater to the unmet needs of the liver cancer sufferers, said Syd Daftary, Director of Rivaara Immune.

About Immuncell-LC

Immuncell-LC is a customized anti-cancer drug that is made from a patients blood. Professionals extract a sample of a patients T-cells from the blood and genetically modify it into a robust immune cell that has maximized anticancer functions and is incubated for about two weeks before they infuse it into the patient. Immuncell-LC received approval for the liver cancer immunotherapy from the Korean MFDS in 2007. It also received FDA Orphan Drug Designation for the Treatment of liver cancer, brain tumor, and pancreatic cancer. More than 7800 individuals have been treated with Immuncell-LC which recorded the highest selling of anti-cancer immune cell therapy in Korea.

About GC Cell

GC Cell is an integrated corporation created through the recent merger of Green Cross Labcell and Green Cross Cell, and is focusing on the development and production of treatments using immune cells and stem cells. In particular, it has a variety of pipelines for autologous and allogeneic cell therapies. It also has global competitiveness based on platform technology and experience throughout the entire period from the initial research stage to the commercialization stage.

About Rivaara Immune Private Limited

Rivaara Immune is a part of the Bharat Daftary group of healthcare companies and aims to be the leading and trusted provider of specialised cell therapy/Immunotherapy for patients with cancers and offer them an improved quality of life.

This press release may contain forward-looking statements, which express the current beliefs and expectations of GC Cell's management. Such statements do not represent any guarantee by GC Cell or its management of future performance and involve known and unknown risks, uncertainties and other factors. GC Cell undertakes no obligation to update or revise any forward-looking statement contained in this press release or any other forward-looking statements it may make, except as required by law or stock exchange rule.

View source version on businesswire.com: https://www.businesswire.com/news/home/20220103005504/en/

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GC Cell Inks First Licensing Agreement for Immuncell-LC With Rivaara Immune Private Limited in India - BioSpace

Boca Raton, Florida, Jan. 04, 2022 (GLOBE NEWSWIRE) -- INmune Bio, Inc. (NASDAQ: INMB) (the Company), a clinical-stage immunology company focused on developing treatments that harness the patients innate immune system to fight disease, today announced that management will participate in two upcoming investor conferences and a medical meeting. Details of the event are as follows:

LifeSci Advisors 11th Annual Corporate Access EventDavid Moss, Chief Financial Officer, will participate in a panel discussion at the LifeSci Advisors 11th Annual Corporate Access Event. Title: News Voids: How to Keep Investors and Strategics Engaged During Data DesertsDate: Thursday, January 6, 2022Time: 10:00am 10:55am EST

Interested parties may register for the event here.

H.C. Wainwright Bioconnect ConferencePresentation Date: Monday, January 10, 2022Presentation Time: 7:00 AM Eastern Time

Please contact your representative at H.C. Wainwright to schedule a virtual one-on-one meeting.

Allogeneic Cell Therapies Summit Europe (Virtual), Professor Mark Lowdell, PhD, CSO/CMO, InMune Bio, will chair a session at the Allogeneic Cell Therapies Summit Europe (Virtual). Title: Academic to Commercial Development of an Off-the-Shelf Allogeneic ATMP: Three Clinical Trial Case StudiesDate: Wednesday, January 19th, 2022Time: 4:00pm-5:00pm CET / 10:00am-11:00am EST

Dr. Lowdell said, Im so pleased to have been invited to present the background to our first in human trial of INKmune to this specialist group of allogeneic cell therapy developers. INKmune is a unique cellular medicine in having been designed from the very concept as an off-the-shelf and affordable therapy which can be scaled to many thousands of doses. Companies often overlook the real-world challenges of getting cell therapies into hospitals, and we developed our INKmune platform to solve many of the commercialization challenges of cell therapies.

Interested parties may register for the Summit here.

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About INmune Bio, Inc.

INmune Bio, Inc. is a publicly traded (NASDAQ: INMB), clinical-stage biotechnology company focused on developing treatments that target the innate immune system to fight disease. INmune Bio has two product platforms that are both in clinical trials. The DN-TNF product platform utilizes dominant-negative technology to selectively neutralize soluble TNF, a key driver of innate immune dysfunction and mechanistic target of many diseases. DN-TNF is in clinical trial to determine if it can treat cancer (INB03), Mild Alzheimers disease, Mild Cognitive Impairment and treatment resistant depression (XPro). The Natural Killer Cell Priming Platform includes INKmune aimed at priming the patients NK cells to eliminate minimal residual disease in patients with cancer. INmune Bios product platforms utilize a precision medicine approach for the treatment of a wide variety of hematologic malignancies, solid tumors and chronic inflammation. To learn more, please visit http://www.inmunebio.com.

Forward Looking Statements

Clinical trials are in early stages and there is no assurance that any specific outcome will be achieved. Any statements contained in this press release that do not describe historical facts may constitute forward-looking statements as that term is defined in the Private Securities Litigation Reform Act of 1995. Any statements contained in this press release that do not describe historical facts may constitute forward-looking statements as that term is defined in the Private Securities Litigation Reform Act of 1995. Any forward-looking statements contained herein are based on current expectations but are subject to a number of risks and uncertainties. Actual results and the timing of certain events and circumstances may differ materially from those described by the forward-looking statements as a result of these risks and uncertainties. INB03, XPro1595, and INKmune are still in clinical trials or preparing to start clinical trials and have not been approved and there cannot be any assurance that they will be approved or that any specific results will be achieved. The factors that could cause actual future results to differ materially from current expectations include, but are not limited to, risks and uncertainties relating to the Companys ability to produce more drug for clinical trials; the availability of substantial additional funding for the Company to continue its operations and to conduct research and development, clinical studies and future product commercialization; and, the Companys business, research, product development, regulatory approval, marketing and distribution plans and strategies. These and other factors are identified and described in more detail in the Companys filings with the Securities and Exchange Commission, including the Companys Annual Report on Form 10-K, the Companys Quarterly Reports on Form 10-Q and the Companys Current Reports on Form 8-K. The Company assumes no obligation to update any forward-looking statements in order to reflect any event or circumstance that may arise after the date of this release.

INmune Bio Contact: David Moss, CFO (858) 964-3720DMoss@INmuneBio.com

Investor Contact:Chuck PadalaLifeSci Advisors(646) 627-8390chuck@lifesciadvisors.com

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INmune Bio, Inc. to Participate in January Investor Conferences and a Medical Meeting - Yahoo Finance

The Breakthrough Therapy Designation was granted based on data from the dose escalation portion of 2 expansion cohorts of a 3-cohort phase 1 study.

Officials with the FDA have granted Breakthrough Therapy Designation to patritumab deruxtecan (HER2-DXd; Daiichi-Sankyo) for the treatment of patients with metastatic epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) with disease progression on or after treatment with a third generation tyrosine kinase inhibitor and platinum-based therapies.

Patritumab deruxtecan is comprised of a fully human anti-ERBB3 (HER3) immunoglobulin G1 monoclonal antibody attached to a topoisomerase I inhibitor payload via a stable tetrapeptide-based cleavable linker. It is currently being investigated across multiple cancers as both a monotherapy and in combination with other anticancer treatments.

HER3 is a member of the EGFR family of receptor tyrosine kinases, which are associated with aberrant cell proliferation and survival, according to a press release. Approximately 25% to 30% of lung cancers have an EGFR-activating mutation, including approximately 83% of all NSCLC tumors. Currently, no HER3 directed medicines are approved for the treatment of cancer.

According to the press release, lung cancer is the second most common form of the disease and the leading cause of cancer-related mortality globally, with 80% to 85% of diagnoses classified as NSCLC. Although the efficacy of targeted therapy with EGFR tyrosine kinase inhibitors is well-established in the treatment of advanced EGFR-mutated NSCLC, the development of a broad range of resistance mechanisms commonly leads to disease progression.

After failure of an EGFR tyrosine kinase inhibitor, platinum-based chemotherapy has a limited efficacy with progression-free survival (PFS) of approximately 4.4 to 6.4 months, and subsequent salvage therapies have PFS of between 2.8 and 3.2 months.

The Breakthrough Therapy Designation for patritumab deruxtecan acknowledges the need for new treatment approaches to overcome resistance and improve survival in patients with metastatic [tyrosine kinase inhibitor]-resistant, EGFR-mutated non-small cell lung cancer, said Ken Takeshita, MD, global head of research and development at Daiichi Sankyo, in the press release.

The Breakthrough Therapy Designation for patritumab deruxtecan was granted based on data from the dose escalation portion of 2 expansion cohorts of a 3-cohort phase 1 study. The dose expansion part of the study is evaluating patritumab deruxtecan at 5.6 mg/kg every 3 weeks in 3 cohorts.

Cohort 1 includes patients with locally advanced or metastatic EGFR-mutated NSCLC who experienced disease progression after taking 1 or more EGFR tyrosine kinase inhibitors and 1 or more platinum-based chemotherapy regimens. Cohort 2 includes patients with squamous or non-squamous NSCLC without EGFR-activating mutations following platinum-based chemotherapy and following an anti-programmed death cell 1 (anti-PD-1) or anti-programmed cell death ligand 1 (anti-PD-L-1) antibody regimen. Finally, cohort 3 includes patients with NSCLC with EGFR-activating mutations including any histology other than combined small cell and NSCLC.

The primary objective of the dose expansion part of the study is to assess the efficacy of patritumab deruxtecan as measured by confirmed objective response rate. Secondary endpoints include overall response rate, safety, and pharmacokinetics, according to the press release.

REFERENCE

Patritumab Deruxtecan Granted US FDA Breakthrough Therapy Designation in Patients with Metastatic EGFR-Mutated Non-Small Cell Lung Cancer. News release. BusinessWire; December 23, 2021. Accessed January 3, 2021. https://www.businesswire.com/news/home/20211222005517/en

Link:
FDA Grants Breakthrough Therapy Designation to Patritumab Deruxtecan for Metastatic EGFR-Mutated Non-Small Cell Lung Cancer - Pharmacy Times

Adeno-associated virus (AAV) vectors are a versatile and appealing gene therapy delivery platform, capable of targeting a wide range of cell types. However, AAV must be produced in a living system, and issues with scalability and high production costs have so far limited the widespread adoption of the technology.

Technology Networks spoke to Emily Jackson-Holmes, PhD, associate product manager, Thermo Fisher Scientific, to learn more about the benefits of AAV vectors and reasons for the growing interest in their use. In this interview, Jackson-Holmes also explains how the Gibco AAV-MAX Production System can help to overcome challenges associated with AAV production and ensure regulatory compliance.

Anna MacDonald (AM): Why is there so much interest in AAV vectors? What makes them an ideal option for the delivery of gene therapies?

Emily Jackson-Holmes (EJ): AAV vectors are an attractive and widely pursued option for gene therapy, evidenced by the three approved gene therapies (Luxturna, Zolgensma, and Glybera*) and the many others in development. Specifically, for in vivo delivery of gene therapies, AAV vectors are used for several reasons. Since AAV is non-integrating, it is preferred over lentivirus (LV) for in vivo gene therapy applications, and it also has low immunogenicity. In addition, not only can AAV transduce both dividing and non-dividing cells, but it can target specific cell and tissue types through different naturally occurring and synthetic or hybrid serotypes.

AM: What are some of the main challenges encountered when manufacturing AAV vectors?EJ: Productivity, cost, and scalability have been major challenges in the field. Low productivity is particularly a challenge when considering the amounts of viral vector required for treating diseases with large patient populations. Traditionally, for AAV production in mammalian cells, adhered-based HEK293 systems have been used. These require scaling out in order to scale up the amount of viral vector produced, which in turn requires a large footprint. The suspension adaption of HEK293 cells has enabled implementation of suspension-based production of AAV, which is more amenable to scaling. Finally, another key challenge has been the lack of fit-for-purpose and regulatory-compliant reagents that enable a path to commercialization. Examples of this include the use of cells containing the oncogenic SV40 large T antigen and the use of serum-containing reagents, which both present safety concerns.

AM: Which methods of transfection are most used? What are the advantages of transient transfection?EJ: The most common method of producing AAV is transient transfection of plasmid DNA in HEK293 cells. With helper-free transient transfection specifically, cells are transfected with three plasmids that provide the rep and cap genes, the transgene and the genes that provide the function of a helper virus. The key advantages of using transient transfection are the versatility and speed.

AM: Can you tell us more about the Gibco AAV-MAX Production System and how it can help to address challenges of AAV production?EJ: The AAV-MAX system is a complete suspension-based system for AAV production. The system achieves high AAV titers through high-density suspension culture of a clonal 293F-derived cell line in chemically defined, animal origin free medium. Helper-free triple transfection is performed using a lipid nanoparticle transfection reagent and a novel production enhancer. Each component of the system has been optimized to work together to achieve high titers in a simplified workflow, eliminating the need to optimize reagents and protocols. To enable users of the system to easily scale from research use to clinical and commercial use, the system is designed to scale from shake flasks to bioreactors, and the reagents are fit-for-purpose and regulatory compliant.

AM: The AAV-MAX system reagents are animal origin free. Why is this important?EJ: In the gene therapy space, speed to market is hugely important. A key aspect of this is making sure that AAV production systems initially used at the research stage are chosen with clinical and commercial use in mind, including the choice of reagents that are regulatory friendly. The use of animal origin free reagents reduces the risk of viral contaminants as well as reducing batch-to-batch variability.

AM: What regulatory issues do cell and gene therapy developers face? How does the AAV-MAX Production System address these?EJ: As has been mentioned, the choice of fit-for-purpose and regulatory-friendly reagents ensures a smooth transition to clinical and commercial manufacturing. The AAV-MAX system uses a clonal HEK293 cell line that lacks the T antigen and includes reagents that are all animal origin free. In addition, to complement our currently available research use only (RUO) AAV-MAX system, we will be launching our Gibco Cell Therapy Systems (CTS) version of AAV-MAX next year. Our CTS version provides a documented cell line, GMP-grade reagents, extensive safety testing, and regulatory documentation. Together, these help gene therapy developers to minimize risk and support their regulatory filings.

Emily Jackson-Holmes was speaking to Anna MacDonald, Science Writer for Technology Networks.

*Glybera was approved in 2012 by the European Medicines Agency but was later withdrawn from the market in 2017.

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Addressing the Challenges of AAV Production - Technology Networks

People with multiple myeloma are living longer than ever, thanks to new treatments and drug combinations that continue to emerge. Alongside these new therapies also come ways to mitigate side effects to ensure that patients live as high-quality life as possible.

From new treatments to noteworthy deaths and clinicians who go the extra mile for their patients, CURE looked back at the most-read myeloma articles of 2021. They were:

1. Treatments for Multiple Myeloma Are Transforming Lives

After receiving a myeloma diagnosis, many patients stress that the disease is incurable. However, new treatments continue to emerge for the disease, and survival times are increasing every few years, explained an expert from The University of Texas MD Anderson Cancer Center.

2. Multiple Myeloma 101: An Incurable But Very Treatable Disease

Dr. Andrew Yee from Massachusetts General Hospital explained the basics of myeloma from symptoms to look out for to staging and common demographics for the disease. He also highlighted recent research and advancements in myeloma that are helping patients with the disease live full lives.

3. Former Defense Secretary Donald Rumsfeld Dies From Multiple Myeloma

In July, Donald H. Rumsfeld, the secretary of defense for Presidents Gerald R. Ford and George W. Bush, died from multiple myeloma. He was 88. In a statement, George W. Bush said that Rumsfeld, never paled before tough decisions and never flinched from responsibility. He brought needed and timely reforms to the Department of Defense, along with a management style that stressed original thinking and accountability.

4. Preventative Kineret May Ease CAR-T Cell Therapy Side Effects in Multiple Myeloma

CAR-T cell therapy is an exciting advance for the treatment of many hematologic malignancies, but can come with severe side effects, such as cytokine release syndrome (CRS). Luckily, recent research found that patients with relapsed/refractory multiple myeloma being treated with the CAR-T cell agent orva-cel had decreased rates of moderate/severe CRS when they took the drug Kineret to prevent it.

5. The Myeloma Nurse Who Climbed a Mountain to Connect With Her Patients

For Donna Catamero, a nurse practitioner who specializes in myeloma, a hike alongside myeloma survivors, loved ones and fellow clinicians was just what she needed as an antidote to the burnout she has been facing in the midst of the COVID-19 pandemic. She climbed Alaskas Kenai Peninsula through Moving Mountains for Multiple Myeloma, a joint effort between CURE and the Multiple Myeloma Research Foundation to raise funds and awareness for the disease.

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The Most-Read Myeloma Stories of 2021 - Curetoday.com

DISCUSSION QUESTIONS

DEVA NATHAN, MD: I have different question. Are you willing to replace R-CHOP [rituximab (Rituxan), cyclophosphamide, doxorubicin, vincristine, prednisone] as the first line? Do you think at some point R-CHOP is going to be pass?

PAOLO CAIMI, MD: I think it probably will be improved upon. There are some [aspects] of R-CHOP that will stay. I still think that cytotoxics have a space for these diseases, and we have to be respectful of their role. I dont think it will be completely pass, but maybe vincristine is not the most important drug. So, its a good question. I think at some point well replace some of the parts of R-CHOP.

DIVIS KHAIRA, MD: I think its very important [to note] that the NCCN [National Comprehensive Cancer Network] doesnt put everything into 1 slot, so then youre arguing with the insurance company. Last week, I was trying to teach the insurance company person some hematology. It was an addiction specialist who was telling me how I should practice hematology. Were getting more and more insurance companies [saying] Peer review this and peer review that, and NCCN said only use 1 drug, and not 2 drugs, and thats become a nightmare in daily life. You went from maybe 1 peer review a month to 4 or 5 for everything, and youre talking to a non-oncologist on the other side.

CAIMI: When you say that they dont put everything in 1 slot, you mean that they include the drugs that you use?

KHAIRA: What they do is, they have level 1, 2, and 3. So, what the insurance company does deny is the level 2 and 3. Level 2 and 3 evidence is no evidence to them. For example, they wont give you obinutuzumab [Gazvya] with bendamustine [Bendeka]. They wont give you this, that, and the other. Youre not going to get JAK2 inhibition unless the patient has more symptoms.

A lot of it is driven by the NCCN, and thats a nightmare now. They make things way too specific. And maybe thats good, because advanced practice providers and nurse practitioners can practice like that, but the rest of us oncologists who have experience can wade through some of this information and make our own decisions. But thats now being driven by the NCCN, and this needs to stop, in my opinion.

CAIMI: I think its still important to bring this up.

DISCUSSION QUESTION

CAIMI: Would you consider loncastuximab either while youre waiting for CAR T-cell therapy, or in a patient for whom youre deciding for CAR T cell since its been demonstrated that they can have a response to CAR T cell afterwards?

YAN JI, MD: I do think these data provided peace of mind. I can see that although the study is small, at least theres a signal that a patient still can respond to CAR T-cell therapy after receiving loncastuximab.

KHAIRA: The question is: Whats the response to CAR T cell after fourth-line therapy? While 46% responded [to CAR T-cell therapy after loncastuximab], if they receive loncastuximab in the fourth-line and they go for CAR T cell therapy afterward, whats the response?

CAIMI: True. I dont think we know that. We know the patients who have more advanced disease tend to have worse [outcomes], and I think thats why comparing loncastuximab to the other 2 drugs that included patients on just 1 line of therapy is not necessarily a fair comparison, because they were sicker patients. I think well learn more as we start treating patients with less advanced disease with these drugs.

NATHAN: To answer your question, how about if you see 24% complete response and 24% partial response? Thats 48% compared with 46% on CAR T-cell therapy, theyre basically equivalent response rates. Can I say it in that way?

CAIMI: Yes, thats true.

NATHAN: Either the patient is too sick to go through CAR T-cell therapy or they are waiting for CAR T cell, then maybe you can use it before. I can see this can be transposed before or after. It makes it a more reasonable drug option.

CAIMI: Yes. So it would potentially be a bridge to CAR T-cell therapy. Thats 1 of the things were looking for, drugs that can get us a patient that can be using CAR T cells afterwards.

[In regard to the] phenomenon where people lose their CD19 expression, how much does this concern youpeople who are getting repeated CD19 drugs?

KHAIRA: Im not so concerned if you have a 46% response. Youre looking at loncastuximab in patients who have been treated with multiple other drugs. The real question is going to be, does it make a difference if you use it earlier?

CAIMI: Youre using drugs that target the same surface markers, which is something to be concerned with.

LYLE GOLDMAN, MD: Were getting away from lymphoma biology, germinal center and non-germinal center. Where do those things factor in when youre thinking about second-, third-, and fourth-line therapies? In the [L-MIND] study of tafasitamab [Monjuvi] and lenalidomide [Revlimid], I noticed that two-thirds of the patients were not classified in terms of germinal center versus non-germinal center subtype.2 And we know that lenalidomide is principally active in the non-germinal center subtype. But how do these other therapies factor in, considering that?

CAIMI: Good question. First, I think that you can see that these studies are reporting it less and less. The second thing that youre seeing is that the drugs are working in both subtypes. And the third thing that you can see is from the large phase 3 studies, that when they tested for cell of origin, those studies were either inconclusive or they werent positive. For tafasitamab/lenalidomide, it seems that it works in a proportion of patients that have the germinal center subtype. It may work a little bit differently; it may not work as well.

Then, it seems that both loncastuximab and polatuzumab [Polivy] are agnostic to the subtype. Which, at least in my opinion, is a good thing, because I think the cell of origin is a square box that were trying to fit our round peg into. I dont think it explains the whole biology of the disease, and I think, sadly, were still stuck with the outside of the cell instead of the inside of the cell. I think that will probably change soon. But thankfully, I think targeting the surface antigens allows us to move away from that thinking, and it works in both scenarios. At least in terms of efficacy for loncastuximab, theres no real difference between non-germinal and germinal.1 The results were comparable.

References:

1. Caimi PF, Ai W, Alderuccio JP, et al. Loncastuximab tesirine in relapsed or refractory diffuse large B-cell lymphoma (LOTIS-2): a multicentre, open-label, single-arm, phase 2 trial.Lancet Oncol. 2021;22(6):790-800. doi:10.1016/S1470-2045(21)00139-X

2. Salles G, Duell J, Gonzlez Barca E, et al. Tafasitamab plus lenalidomide in relapsed or refractory diffuse large B-cell lymphoma (L-MIND): a multicentre, prospective, single-arm, phase 2 study.Lancet Oncol. 2020;21(7):978-988. doi:10.1016/S1470-2045(20)30225-4

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Part 3: Barriers to Loncastuximab Before CAR T-Cell Therapy in DLBCL - Targeted Oncology