Category Archives: Genetic Therapy

Could gene therapy provide a solution to HIV? A new research project aims to find out.

The National Institutes of Health(NIH) has backed researchers at the University of Southern California and the Fred Hutchison Cancer Center with a five-year, $14.6 million grant to develop a gene therapy that could potentially control HIV without the need for daily medications. Most HIV patients take a well-regimented cocktail of medications each day to control the virus. This therapy could change that. According to an announcement from the Keck School of Medicine at USC, the goal will be to develop a therapy that prepares patients for a stem cell transplantation using their own cells with little to no toxicity, engineers their own stem cells to fight HIV and stimulates those cells to quickly produce new and engineered immune cells once they're reintroduced into the patient. The hematopoietic stem cell transplants, also known as bone marrow transplants, have been used to treat some blood cancers. The idea is to infuse an HIV patient withhealthy donor blood stem cells that can grow into any type of blood or immune cell.

The gene therapy strategy has been inspired by three cases where leukemia patients who also had HIV received blood stem cell transplants from donors who also carried a mutation that confers immunity to HIV. The mutation was in the CCR5 gene, which encodes a receptor that HIV uses to infect immune cells and is present in about 1 percent of the population, USC said.

The program will engineer blood cells to remove CCR5 from a patient's own stem cells.That will be combined with other genetic changes so that the progeny of engineered stem cells will release antibodies and antibody-like molecules that block HIV.

In addition to the potential gene therapy treatment, researchers are also assessing whether or not CAR-T treatments will benefit HIV patients. Researchers from Harvard University developed a Dual CAR T-cell immunotherapy that can potentially help fight HIV infection. First reported by Drug Target Review, the HIV-specific CAR-T cell is being developed to not only target and eliminated HIV-infected cells, but also reproduce in vivo to enable the patients to fight off the infection. HIVs primary target it T cells, which are part of the bodys natural immune response.

Todd Allen, a professor of Medicine at Harvard Medical School, said the Dual CAR-T cell immunotherapy has so far provided a strong, long-lasting response against HIV-infection while being resistant to the virus itself.

According to the report, theDual CAR T cell was developed through the engineering of two CARs into a single T cell. Each of the CARs contained a CD4 protein that allowed it to target HIV-infected cells and a costimulatory domain, which signaled the CAR T cell to increase its immune functions. As DTR reported, the first CAR contained the 4-1BB co-stimulatory domain, which stimulates cell proliferation and persistence, while the second has the CD28 co-stimulatory domain, which increases its ability to kill infected cells.

To protect the CAR-T cells from HIV, the team added the protein C34-CXCR4, which prevents HIV from attaching to and infecting cells. When that was added, the researchers found in animal models that the treatment was long-lived, replicated in response to HIV infection, killed infected cells effectively and was partially resistant to HIV infection.

Still, other researchers are looking to those rare individuals who are infected with HIV but somehow on their own are able to suppress the virus without the need for any treatment. Researchers have sought to replicate what this small percentage of patients can naturally do in other patients who require those daily regimens of medications. Through the sequencing of the genetic material of those rare individuals, researchers made an interesting discovery.

The team discovered large numbers of intact viral sequences in the elite controllers chromosomes. But in this group, the genetic material was restricted to inactive regions, where DNA is not transcribed into RNA to make proteins, MedNewsToday reported.

Now the race is on to determine how this can be replicated and used to treat the nearly 38 million people across the globe who have been diagnosed with HIV.

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New HIV Gene Therapy, CAR-T Treatments Could be on the Horizon for Patients - BioSpace

Sept. 2, 2020 12:00 UTC

CAMBRIDGE, Mass.--(BUSINESS WIRE)-- Magenta Therapeutics (NASDAQ: MGTA), a clinical-stage biotechnology company developing novel medicines to bring the curative power of immune reset to more patients, today announced the appointment of two new executives, Lisa M. Olson, Ph.D., as Chief Scientific Officer and Kevin B. Johnson, Ph.D., as Senior Vice President, Head of Regulatory and Quality. The Company also announced that Jason Ryan will transition from Chief Operating and Financial Officer to a consulting role for personal reasons while a search for his replacement is conducted.

With the additions of Lisa and Kevin to our team, Magenta continues to deepen our technical expertise, bolstering our strong discovery, research, development and regulatory leadership to further our goal of delivering curative immune reset to patients in need, said Jason Gardner, D.Phil., Chief Executive Officer and President, Magenta Therapeutics. We are delighted to welcome Lisa and Kevin on board and look forward to their many contributions to the Magenta mission.

As Chief Scientific Officer, Dr. Olson will provide strategic direction, oversight and execution for Magentas research and discovery efforts. This entails driving research strategy as Magenta continues to optimize its preclinical and clinical pipeline. She will join the executive team and will be a key member of the R&D leadership team.

Dr. Olson is an experienced senior-level pharmaceutical executive, with more than 20 years of experience in research and drug discovery. She comes to Magenta following 15 years in leadership positions at the AbbVie Bioresearch Center, most recently as Vice President, Immunology Discovery and Site Head, where she was responsible for all immunology discovery scientific and portfolio decisions, including new target approval, project advancement and licensing opportunities. Under her leadership, 15 molecules advanced into clinical development, including Upadacitinib that launched last year as Rinvoq. Prior to AbbVie, she served as a Research Fellow and Group Leader in Inflammation & Immunology at Pfizer, Inc. She began her career as an Assistant Professor at Washington University School of Medicine, following a post-doctoral cardiovascular fellowship at the University of Chicago.

Dr. Olson holds a Ph.D. from the University of Illinois at Urbana-Champaign and a Bachelor of Science from Iowa State University.

As Senior Vice President, Head of Regulatory and Quality, Dr. Johnson will lead Magentas global regulatory strategy for the Companys programs across multiple therapeutic areas. He will also be responsible for the oversight and accountability for all quality activities to enable Good Practice (GxP) functions across the portfolio. In this role, Dr. Johnson will provide strategic guidance and leadership to members of the R&D leadership team and the regulatory and quality teams for Magentas portfolio for all phases of product lifecycle.

Dr. Johnson bring years of regulatory, quality assurance and development leadership, coming to Magenta from Imara, Inc., where he served as Senior Vice President, Regulatory Affairs, Quality and Pharmacovigilance, leading successful requests for several regulatory designations with the U.S. Food and Drug Administration (FDA). Prior to his time at Imara, Dr. Johnson led global regulatory strategy and implementation for breakthrough therapy-designated rare disease development programs at Vtesse, later acquired by Sucampo. He also served as Director, Global Regulatory Affairs for Rare Diseases and Gene Therapies at GlaxoSmithKline, where he was part of on the international regulatory team for the European approval of the gene therapy Strimvelis for ADA-SCID, and subsequently secured Regenerative Medicine Advanced Therapy (RMAT) designation for a retinal gene therapy product.

Dr. Johnson holds a Ph.D. in Neurobiology from the University of North Carolina (UNC) School of Medicine; a Master of Business Administration from the Kenan-Flagler School of Business, UNC; and a Bachelor of Science in Chemistry from the University of South Florida.

Along with these leadership team additions, Magenta also announced today that Jason Ryan, Chief Operating and Financial Officer, will step down from that role at the end of September. He will continue to contribute to Magenta in a consulting capacity, and the Company has commenced a search for a replacement.

Jason has been a dynamic and reliable leader at Magenta since he joined us in 2019, leading finance and operations, contributing to our strategic planning efforts, and spearheading two financings during a period of significant growth, said Gardner. We are truly grateful for his contributions to the patients we seek to serve, our employees and business partners.

About Magenta Therapeutics

Magenta Therapeutics is a clinical-stage biotechnology company developing medicines to bring the curative power of immune system reset through stem cell transplant to more patients with autoimmune diseases, genetic diseases and blood cancers. Magenta is combining leadership in stem cell biology and biotherapeutics development with clinical and regulatory expertise, a unique business model and broad networks in the stem cell transplant world to revolutionize immune reset for more patients.

Magenta is based in Cambridge, Mass. For more information, please visit http://www.magentatx.com.

Follow Magenta on Twitter: @magentatx.

Forward-Looking Statement

This press release may contain forward-looking statements and information within the meaning of The Private Securities Litigation Reform Act of 1995 and other federal securities laws. The use of words such as may, will, could, should, expects, intends, plans, anticipates, believes, estimates, predicts, projects, seeks, endeavor, potential, continue or the negative of such words or other similar expressions can be used to identify forward-looking statements. The express or implied forward-looking statements included in this press release are only predictions and are subject to a number of risks, uncertainties and assumptions, including, without limitation risks set forth under the caption Risk Factors in Magentas Annual Report on Form 10-K filed on March 3, 2020, as updated by Magentas most recent Quarterly Report on Form 10-Q and its other filings with the Securities and Exchange Commission. In light of these risks, uncertainties and assumptions, the forward-looking events and circumstances discussed in this press release may not occur and actual results could differ materially and adversely from those anticipated or implied in the forward-looking statements. You should not rely upon forward-looking statements as predictions of future events. Although Magenta believes that the expectations reflected in the forward-looking statements are reasonable, it cannot guarantee that the future results, levels of activity, performance or events and circumstances reflected in the forward-looking statements will be achieved or occur. Moreover, except as required by law, neither Magenta nor any other person assumes responsibility for the accuracy and completeness of the forward-looking statements included in this press release. Any forward-looking statement included in this press release speaks only as of the date on which it was made. We undertake no obligation to publicly update or revise any forward-looking statement, whether as a result of new information, future events or otherwise, except as required by law.

View source version on businesswire.com: https://www.businesswire.com/news/home/20200902005236/en/

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Magenta Therapeutics Appoints Lisa M. Olson as Chief Scientific Officer and Kevin B. Johnson as Senior Vice President, Head of Regulatory and Quality;...

REDWOOD CITY, Calif. and RESEARCH TRIANGLE PARK, N.C., Sept. 3, 2020 /PRNewswire/ --Kriya Therapeutics, a next generation gene therapy company focused on developing transformative treatments for highly prevalent diseases,announced today that its CEO, Shankar Ramaswamy, M.D., will present at multiple upcoming healthcare conferences in September and October. These include the following:

Citi's 15th Annual BioPharma Virtual ConferenceDate: Tuesday, September 8thTime: 3:30 PM ET / 12:30 PM PT

H.C. Wainwright & Co. 22nd Annual Global Investment ConferenceDate: Wednesday, September 16thTime: 9:30 AM ET / 6:30 AM PT

Cantor Fitzgerald Virtual Global Healthcare ConferenceDate: Thursday, September 17thTime: 3:20 PM ET / 12:20 PM PT

Chardan 4th Annual Genetic Medicines ConferenceDate: Tuesday, October 6thTime: 9:00 AM ET / 6:00 AM PT

About Kriya Therapeutics

Kriya Therapeutics is a next-generation gene therapy company focused on developing transformative treatments for highly prevalent serious diseases. With core operations in California and North Carolina, Kriya's technology-enabled platform is directed to the rational design and clinical translation of gene therapies for large patient populations. For more information, please visit http://www.kriyatx.com.

Cautionary Note on Forward-Looking Statements

This press release includes forward-looking statements pertaining to our development programs and our proprietary platform. Such forward-looking statements are subject to risks and uncertainties that could cause actual results to differ materially from those expressed or implied in such statements. The forward-looking statements contained in this press release reflect Kriya's current views with respect to future events, and Kriya does not undertake and specifically disclaims any obligation to update any forward-looking statements.

ContactDan ChenChief Financial Officer[emailprotected]

SOURCE Kriya Therapeutics

https://www.kriyatx.com/

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Kriya Therapeutics To Present At Upcoming Healthcare Conferences - PRNewswire

Fouad Namouni, a storied research exec who went from project leader on Opdivo and Yervoy to the top of the oncology research group at Bristol Myers Squibb, is joining the migration to biotech, picking up a new hat as president of R&D at Blueprint Medicines.

Once again, hes headed into a toe-to-toe showdown with a rival pharma organization.

Namouni will likely be coming on board just one step ahead of an approval for pralsetinib, Blueprints RET rival to Eli Lillys Retevmo, which got out in front with a May approval. Ironically, Lillys deal to buy into RET with its acquisition of Loxo also brought Josh Bilenker and his crew to the pharma giant, marking a rare career trajectory from a biotech into pharma, which has been bleeding talent for years now.

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Game change: A frontrunner in the cell therapy 2.0 field offers a first look at their lead therapy. And it's a doozy - Endpoints News

NEW YORK--(BUSINESS WIRE)--Rocket Pharmaceuticals, Inc. (NASDAQ: RCKT) (Rocket), a clinical-stage company advancing an integrated and sustainable pipeline of genetic therapies for rare pediatric disorders, today announces it has treated the first patient in the higher dose cohort in its open-label, Phase 1 clinical trial of RP-A501, the Companys adeno-associated viral vector (AAV)-based gene therapy for the treatment of Danon Disease. Treatment of the higher dose cohort comes after successful completion of the low dose cohort and clearance from the U.S. Food and Drug Administration (FDA) and Independent Data Safety Monitoring Committee (IDSMC). The second cohort of the Phase 1 study evaluates RP-A501 at a higher dose level of 1.11014 genome copies/kilogram in male patients 15 years of age and older. The Phase 1 study will assess the safety, tolerability and preliminary efficacy of RP-A501.

Today marks an important milestone in the development of RP-A501 for Danon Disease, the first investigational gene therapy in development for the treatment of inherited heart failure, said Gaurav Shah, M.D., Chief Executive Officer and President of Rocket. RP-A501 represents a potentially holistic and transformative approach to Danon Disease, a devastating disease often resulting in end-stage heart failure and early mortality. The only definitive treatment option available for this multisystemic disorder is heart transplantation, which is associated with a 50% mortality rate during the decade following transplant and does not address the full spectrum of the disease course. Our gene therapy approach, utilizing RP-A501, aims to address all manifestations associated with Danon Disease including cardiomyopathy, skeletal myopathy and intellectual disability. We look forward to progressing this trial and enabling a potentially curative treatment option for this devastating disease that affects so many lives.

The non-randomized, open-label Phase 1 trial aims to enroll both pediatric and young adult male patients in escalating dose cohorts. Following the review of safety data from the first cohort, all subsequent cohorts will include 2-4 patients per cohort, adjusted down from 3-6 patients in the original protocol. The study is designed to assess the safety and tolerability of a single intravenous (IV) infusion of RP-A501. Additional outcome measures include cardiomyocyte and skeletal muscle transduction by gene expression, histologic correction via endomyocardial biopsy, and clinical stabilization via cardiac imaging and functional cardiopulmonary testing.

About Danon Disease

Danon disease is caused by mutations in the gene encoding lysosome-associated membrane protein 2 (LAMP-2), an important mediator of autophagy. It is estimated to have a prevalence of 15,000 to 30,000 patients in the U.S. and the European Union. The disease is often fatal in male patients in the second or third decade of life due to rapidly progressive heart failure. Available therapies for Danon disease include cardiac transplantation, which is associated with substantial complications and is not considered curative. There are no specific therapies available for the treatment of Danon disease.

About Rocket Pharmaceuticals, Inc.

Rocket Pharmaceuticals, Inc. (NASDAQ: RCKT) (Rocket) is advancing an integrated and sustainable pipeline of genetic therapies that correct the root cause of complex and rare childhood disorders. The companys platform-agnostic approach enables it to design the best therapy for each indication, creating potentially transformative options for patients afflicted with rare genetic diseases. Rocket's clinical programs using lentiviral vector (LVV)-based gene therapy are for the treatment of Fanconi Anemia (FA), a difficult to treat genetic disease that leads to bone marrow failure and potentially cancer, Leukocyte Adhesion Deficiency-I (LAD-I), a severe pediatric genetic disorder that causes recurrent and life-threatening infections which are frequently fatal, Pyruvate Kinase Deficiency (PKD) a rare, monogenic red blood cell disorder resulting in increased red cell destruction and mild to life-threatening anemia and Infantile Malignant Osteopetrosis (IMO), a bone marrow-derived disorder. Rockets first clinical program using adeno-associated virus (AAV)-based gene therapy is for Danon disease, a devastating, pediatric heart failure condition. For more information about Rocket, please visit http://www.rocketpharma.com.

Rocket Cautionary Statement Regarding Forward-Looking Statements

Various statements in this release concerning Rocket's future expectations, plans and prospects, including without limitation, Rocket's expectations regarding its guidance for 2020 in light of COVID-19, the safety, effectiveness and timing of product candidates that Rocket may develop, to treat Fanconi Anemia (FA), Leukocyte Adhesion Deficiency-I (LAD-I), Pyruvate Kinase Deficiency (PKD), Infantile Malignant Osteopetrosis (IMO) and Danon Disease, and the safety, effectiveness and timing of related pre-clinical studies and clinical trials, may constitute forward-looking statements for the purposes of the safe harbor provisions under the Private Securities Litigation Reform Act of 1995 and other federal securities laws and are subject to substantial risks, uncertainties and assumptions. You should not place reliance on these forward-looking statements, which often include words such as "believe," "expect," "anticipate," "intend," "plan," "will give," "estimate," "seek," "will," "may," "suggest" or similar terms, variations of such terms or the negative of those terms. Although Rocket believes that the expectations reflected in the forward-looking statements are reasonable, Rocket cannot guarantee such outcomes. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including, without limitation, Rocket's ability to monitor the impact of COVID-19 on its business operations and take steps to ensure the safety of patients, families and employees, the interest from patients and families for participation in each of Rockets ongoing trials, our expectations regarding when clinical trial sites will resume normal business operations, our expectations regarding the delays and impact of COVID-19 on clinical sites, patient enrollment, trial timelines and data readouts, our expectations regarding our drug supply for our ongoing and anticipated trials, actions of regulatory agencies, which may affect the initiation, timing and progress of pre-clinical studies and clinical trials of its product candidates, Rocket's dependence on third parties for development, manufacture, marketing, sales and distribution of product candidates, the outcome of litigation, and unexpected expenditures, as well as those risks more fully discussed in the section entitled "Risk Factors" in Rocket's Quarterly Report on Form 10-Q for the quarter ended June 30, 2020, filed August 5, 2020 with the SEC. Accordingly, you should not place undue reliance on these forward-looking statements. All such statements speak only as of the date made, and Rocket undertakes no obligation to update or revise publicly any forward-looking statements, whether as a result of new information, future events or otherwise.

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Rocket Pharmaceuticals Announces First Patient Treated in Higher Dose Cohort in Phase 1 Clinical Trial of RP-A501 for Danon Disease - Business Wire

Just as heat-seeking missiles race toward the infrared signatures of their targets, chimeric antigen receptor (CAR) T cells home in on cancer-associated or -specific antigens. Once the antigens are engaged, CAR T cells let fly with cytotoxic flak, granules containing perforin and granzymes, while activating supplementary tumor-killing mechanisms such as stromal sensitization and macrophage polarization. It is to be hoped that by the time the cytotoxic smoke clears, the cancer will have been destroyed.

The development of CAR T cells has revolutionized adoptive cellular therapies against cancer. CARs are genetically engineered to combine antigen- or tumor-specific-binding with T-cell activating domains. T cells, obtained from the patient (autologous cells) or from a healthy donor (allogeneic cells), are typically transduced with an engineered vector, expanded, and infused back into the patient for tumor eradication.

In the 10 years since its inception, the CAR T-cell field has progressed rapidly. Two CAR T-cell products have been approved for clinical use, and many more products are undergoing clinical trials or are in development. Although the field initially focused on B-cell malignancies, it is now advancing on solid tumors.

Despite its initial success, the CAR T-cell field must find ways to generate products that are potent, affordable, and available. To achieve enduring success, the CAR T-cell field is undertaking a range of initiatives. These include the engineering of bridging proteins for multiantigen targeting; the creation of nonviral allogeneic off-the-shelf products; the organization of vein-to-vein networks; and the development of precisely tuned therapies, that is, precisely timed and dosed therapies.

Cellular therapy is a living drug, declares Steve Shamah, PhD, senior vice president, Obsidian Therapeutics. As with any drug, damage can occur if the therapy is not carefully regulated. Our company focuses on creating controllable cell therapies by engineering CAR T cells or tumor-infiltrating lymphocytes to produce regulatable cytokines and proteins that can enhance functional activity, especially against solid tumors.

For example, the company is developing a platform that armors CAR T cells with immunomodulatory factors such as interleukin-15 (IL-15) or CD40 ligand. Shamah explains, These factors can enhance functional activity by driving T-cell expansion, conferring resistance to immunosuppression, improving antigen presentation, and inducing antigen spread. However, both factors can also produce systemic toxicity. Our technology modulates the level and timing of their activity in a fully controlled, dose-dependent manner using an FDA-approved small-molecule drug.

The Obsidian platform, cytoDRiVE, adds a drug-responsive domain (DRD) onto a therapeutic protein of interest. DRD tags are misfolded or inherently unstable in the cell. However, they can be reversibly stabilized by the binding of approved small-molecule drugs. When the drug is absent, the DRD-tagged protein is turned off. When the drug is present, the DRD-tagged protein is turned on. When DRD tags are in place, the concentration of the small-molecule drug serves as a biological rheostat for controlling the dosing of the therapeutic protein.

Preclinical in vivo mouse studies assessed anti-CD19 CAR T cells that were engineered to express an IL-15-DRD that responded to the FDA-approved drug acetazolamide. In these studies, tumor regression was demonstrated.

Controlling the precise timing and expression level of these immunomodulatory factors in CAR T cells could significantly enhance safety and therapeutic efficacy, concludes Shamah.

Obsidian is currently focusing on the oncology space, but the company is also exploring other areas such as autoimmunity and even the regulation of transcription factors to enable controllable in vivoCRISPR-Cas9 gene editing.

Despite the remarkable success of CAR T-cell therapies, relapses can occur within six months for up to 50% of patients treated with anti-CD19 CAR T-cell therapy.Failures can occur due to loss of CD19 expression or to continued tumor proliferation. Aleta Biotherapeutics has developed a novel technology to reactivate CAR T cells in relapsed patients.

Our approach utilizes antigen-bridging proteins to coat tumors with CD19, says Paul Rennert, PhD, Aletas president and CSO. [The tumors are then] recognized by the patients anti-CD19 CAR T cells, essentially creating a cytotoxic synapse that results in tumor cell death.

To thwart anti-CD19 CAR T-cell therapy relapses, the company developed a bridging protein using the extracellular domain of CD19 and an anti-CD20 antibody domain. CD20 is an antigen present on the majority of B-cell malignancies. Rennert explains that these injected bridging proteins will coat the patients tumor cells with CD19, creating a target to activate or reactivate a patients anti-CD19 CAR T cells.

To show proof-of-principle, the company performed in vivo studies using a half-life-extended form of the bridging protein injected into mice carrying CD20-positive tumor cells and anti-CD19 CAR T cells. Rennert emphasizes, Our studies demonstrated this strategy can be used to reactivate CD19 CAR T cells to prevent and reverse relapses.

Other programs in development include a bridging protein for injection to improve outcomes in multiple myeloma patients treated with CAR T cells, and bridging protein programs for HER2-positive breast cancer patients with central nervous system metastases. The company is preparing investigational new drug applications for its technology and plans to start Phase I trials in 2021.

Assessing whether engineered CAR T-cell and T-cell receptor (TCR) therapies have successfully attacked and penetrated solid tumors (and not normal cells) can be like finding the proverbial needle in the haystack. Traditional methods using immunohistochemistry are useful for immune profiling, but they cannot differentiate engineered versus endogenous cells, points out Christopher Bunker, PhD, senior director of business development, Advanced Cell Diagnostics, a Bio-Techne brand. We developed a means to easily detect and track engineered therapeutic cells and delineate their pharmacokinetics within the tumor microenvironment of intact tumor biopsies, as well as their on-target/off-tumor activity.

Enter RNAscope, an RNA in situ hybridization technology that can enable single-cell spatial transcriptomics. RNAscope, Bunker asserts, is the only off-the-shelf method that can specifically detect engineered CAR T cells and TCR T cells in solid tumor patient biopsies.

Most cell therapies employ lentivirus transduction. Because CAR or TCR transgenes have unique sequences in the viral untranslated regions, these can be used as tags for identification of engineered cell therapies with RNAscope probes. The technology utilizes pools of paired oligos that can be thought of as a ZZ pair, where the paired 3 ends hybridize to ~50 bases of target mRNA, and where the paired 5 ends hybridize to a signal amplification module, which is built through sequential hybridization steps. The signal amplification of paired oligos results in an assay able to detect individual transcripts that appear as visible and quantifiable dots.

Its a little like planting and lighting Christmas trees, quips Bunker. The ZZ pairs plant trees along the mRNA with branches that are decorated either with fluorophores or chromogens. Although the primary technology currently features four colors, the company has developed a HiPlex (12-plex) assay and foresees even higher-plex assays with different detection methods.

We envision assays based on our core technologies that enable spatial analysis of perhaps a hundred transcripts in combination with tens of proteins, Bunker projects. In the context of cell therapy development, these will enable a more comprehensive understanding of tumor biology and immune cell profiles to determine the most effective treatment strategy for a patient, as well as for monitoring efficacy of solid tumor cellular therapies.

Companies developing CAR T-cell products are also eyeing a future involving GMP production. Thus, a critical early question is how to choose the best T-cell medium for manufacturing processes. To test the suitability of a CAR T-cell growing medium, companies must assess factors such as cell viability, cell expansion, cytokine profiles, and cell purity. A medium suitable for a CAR T-cell manufacturing process also needs to support rapid activation and CAR transduction. Additionally, the selected medium needs to be compatible with a variety of donors.

There are many available choices for T-cell culture media ranging from do-it-yourself recipes to commercially available one-size-fits-all complete formulations. CellGenix has developed a novel T-cell medium that avoids the use of human serum. Sebastian Warth, PhD, a senior scientist at CellGenix, explains, To achieve consistent results, human serum requires extensive testing prior to its use for production of cellular products due to lot-to-lot inconsistencies. Since human serum is a limited resource and might not be available in large quantities, it is unfavorable for commercial-scale manufacturing. Furthermore, the human origin of serum poses a certain risk of containing adventitious agents and is, therefore, a risk to the safety of the T-cell therapy product.

The companys TCM GMP-Prototype medium provides a serum-free and xeno-free product for early-onset T-cell expansion. According to Warth, key advantages include promotion of sustained viability, support for expansion of CD4+ and CD8+ T cells, promotion of a central memory and early differentiated memory T-cell phenotype, and maintenance of a high proportion of cytokine-producing cells including polyfunctional cells. Further, it was optimized for and verified with CAR T cells.

While autologous CAR T-cell therapies have proven highly successful, they also require a long and expensive manufacturing process. The dream of being able to utilize off-the-shelf allogeneic T cells is on the horizon.

Devon J. Shedlock, PhD, senior vice president, research and development,Poseida Therapeutics, reports, With our technology, we are able to genetically modify cells to create a fully allogenic, or off-the-shelf, product that does not require additional immunosuppression treatment like earlier generation approaches. We also have developed technology to allow us to make hundreds of doses from a single manufacturing run from healthy donors, thereby dropping the cost substantially.

According to Shedlock, the technology consists of three key aspects: 1) the piggyback DNA Modification System, 2) the Cas-CLOVER site-specific gene editing system, and 3) the Booster Molecule.

The PiggyBac DNA Modification System is a nonviral technology for stably integrating genes into DNA. One key feature is that piggyBac preferentially inserts into less mature T cells, enabling the production of therapies that have a high proportion of stem cell memory T cells, or Tscm cells.

Viral technologies are virtually excluded from Tscm cells, Shedlock states. However, Tscm cells are the ideal cell type for cell-based therapies because they have the ability to engraft and potentially last a lifetime, can produce wave after wave of more differentiated cells to attack the tumor, and are much more tolerable with low levels of adverse events compared to other CAR T-cell products.

The companys Cas-CLOVER gene editing technology is a hybrid gene editing technology used to edit the T cells to make allogeneic products. Cas-CLOVER works well in resting T cells, which is important in preserving Tscm cells in a fully allogeneic CAR T-cell product, Shedlock elaborates. It also is a very precise and clean system. This is a particularly important safety issue for allogeneic products that may be given to many patients.

The Booster Molecule is added during manufacture and is temporarily expressed on the cell surface to allow cell stimulation. Normally when allogeneic CAR T-cell products are created, the T-cell receptor must be eliminated to avoid the graft-versus-host reaction, which is a major safety issue. Importantly, this booster stimulation occurs while preserving the Tscm phenotype.

Poseida Therapeutics expects to launch a clinical trial for its multiple myeloma allogeneic product late this year or early next year. The company will also begin clinical trials later in 2021 on its pan-solid tumor allogeneic program.

Creation of partnerships can help drive development of CAR T-cell therapeutics from concept through clinical trials. Advanced therapies require advanced supply chain and data management, advises Minh Hong, PhD, head of autologous cell therapy, Lonza Pharma & Biotech. Prior biopharmaceutical models of mass production and distributionand the systems that support themare not effective for personalized therapeutics. As manufacturing demand increases for autologous cell therapies, there is an overarching need to both industrialize and simplify the entire supply chain ecosystem.

Hong says the overall project needs to be considered from a more comprehensive perspective: Due to the criticality of the starting material, everything from cell sourcing, patient coordination and scheduling for collection/infusion, transportation logistics, and manufacturing logistics needs to be coordinated, ensuring the highest standards, regulatory compliance, and safety throughout the process.

To meet these needs, Lonza is building a network of partners to develop a fully integrated vein-to-vein solution, that is, a system that includes all touch points involved in patient scheduling and sample collection, through material shipping logistics, manufacturing, and eventually the infusion of the cell therapy back into the patient. The partner network, Hong indicates, will help participants define smart workflows and execute an integration strategy. Hong sums up the networks therapeutic implications as follows: We believe these partnerships will decrease time to clinical program setup.

Lonza has more than a 20-year history of providing clinical and commercial manufacturing. Hong asserts, Our company brings to the table our process development and manufacturing experience along with proprietary solutions including a manufacturing execution system solution, MODA-ESTM, for electronic batch records and manufacturing traceability. In addition, we have announced partnerships with Vineti for a supply chain orchestration system and Cryoport to aid in shipping and logistics.

Lonza is also looking beyond CAR T-cell therapies. We would not limit our solutions and partnerships to autologous cell therapies, Hong declares. We can envision solutions for our in vivo viral vector manufacturing clients as well as our traditional allogeneic cell therapy clients.

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CAR T-Cell Optimization Starts in Production, Extends to Therapy - Genetic Engineering & Biotechnology News