NCAPG Promotes The Proliferation Of Hepatocellular Carcinoma Through P | OTT – Dove Medical Press

Chengwu Gong,1,* Jiyuan Ai,1,* Yun Fan,2 Jun Gao,1 Weiwei Liu,1 Qian Feng,3 Wenjun Liao,1 Linquan Wu1

1Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, Peoples Republic of China; 2Department of Neurology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan 430000, Peoples Republic of China; 3Department of Emergency Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, Peoples Republic of China

*These authors contributed equally to this work

Correspondence: Linquan Wu; Wenjun LiaoDepartment of General Surgery, The Second Affiliated Hospital of Nanchang University, No. 1, Minde Road, Nanchang 330006, Peoples Republic of ChinaTel +86 791 86311529Fax +86 791 86262262Email wulqnc@163.com; liaowenjun120@163.com

Purpose: Studies show that high expression of non-SMC condensin I complex subunit G (NCAPG) is associated with many tumors. In this study, we explore the mechanism by which NCAPG promotes proliferation in hepatocellular carcinoma (HCC).Patients and methods: Liver cancer and paracancerous tissue specimens of 90 HCC patients were collected, and expression levels of NCAPG in these tissues and cell lines were evaluated by Western blotting and immunohistochemistry. HCC cells were transfected with siRNAs and plasmids, and pathway activators or inhibitors were added. The 5-ethynyl-2-deoxyuridine (EdU) proliferation assay was used to measure cell proliferation. Flow cytometry was used to evaluate cell apoptosis. Western blot assays were performed as a standard procedure to detect total protein expression. Treated HCC cells were subcutaneously injected into nude mice.Results: Analysis using the Oncomine database showed that NCAPG was upregulated in HCC and immunohistochemistry and Western blot assays showed it was upregulated in both HCC tissues and HCC cell lines. The overexpression of NCAPG could promote HCC cell proliferation and reduce HCC cell apoptosis. More importantly, RNA-sequencing analysis predicted that NCAPG plays a role in the HCC via PI3K-AKT signaling pathway. The PI3K/AKT/FOXO4 pathway was aberrantly activated, and the expressions of apoptosis-related protein were altered when NCAPG was overexpressed or silenced both in vitro and in vivo. LY294002, a PI3K inhibitor, could eliminate the NCAPG role of promoting HCC cell proliferation and reducing HCC cell apoptosis, while 740Y-P, a PI3K activator, contributed to the opposite effect.Conclusion: NCAPG functions as an oncogene in HCC and plays a role in promoting cell proliferation and antiapoptosis through activating the PI3K/AKT/FOXO4 pathway.

Keywords: NCAPG, hepatocellular carcinoma, PI3K/AKT, FOXO4, proliferation

This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution - Non Commercial (unported, v3.0) License.By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms.

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Community Oncologist: A Key Player in CAR-T Cell Therapy – Cancer Therapy Advisor

Although administration of anti-CD19 chimeric antigen receptor (CAR)-T cell therapy takes place at authorized treatment centers, community oncologists still play an important role, particularly in the recognition of eligible patients and the management of adverse effects of the treatment.

Arecent piece in The Oncologist detailed this crucial element of CAR-Tadministration and highlighted key aspects of CAR-T cell indications andeligibility for community oncology providers.1

Tomaximize the chances of a patient receiving CAR-T cell therapy, communityoncologists should refer patients early and broadly, as the time of referralto CAR-T cell infusion can take 4 to 6 weeks.

Mostbroadly, patients with relapsed or refractory large B-cell lymphoma who havefailed on 2 or more prior therapies can be referred. Patients who have failedor relapsed after first-line immunochemotherapy may also be eligible.

Patientswho progress on first-line therapy should be referred directly to academiccenters whenever possible for management because high rates of relapse areobserved with second-line treatments, the authors wrote. Academic centers areequipped to facilitate a smooth and rapid transition to the next line oftherapy, especially CAR-T cell therapy, if patients are already receivingtreatment there, which may be particularly important for patients with rapidlyprogressing disease.

Aspart of this process, community oncologists should be aware of which centers intheir state offer CAR-T cell therapy.

Communityoncologists also play an important role in postinfusion care. Patients treatedwith CAR-T cell therapy are advised to carry a wallet card with them at alltimes that defines symptoms that could indicate a serious adverse event forwhich to seek medical attention. Any patient in response that does notexperience a serious adverse event after a 4- to 8-week stay returns home.

Thesepatients can experience prolonged hypogammaglobulinemia and B-cell aplasia, andsome patients may require supportive care with IVIG. Prolonged cytopenias canalso occur. Because the treatment causes immunosuppression, patients are atongoing risk for serious infections after discharge as well.

Coordinationand communication between the local oncologist and CAR-T cell treatment oncologistare important during the months after patients return home from their minimum4-week stay near the treatment center, the authors wrote. After this period,the authorized treatment center, in coordination with the local oncologist, mayhave patient follow-ups every 2 weeks until month 3, then decreasing infrequency to 6 months and 12 months after CAR T-cell infusion, then yearlyuntil 5 years after CAR T-cell infusion, the authors wrote.

Reference

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Cell therapy GammaDelta spins off Adaptive to direct body’s surveillance system – Endpoints News

If alpha beta T-cells the foundation of CAR-T cell therapy are killer cells, trained in the biologically ancient art of executing intruders, think of their gamma delta cousins as armed guards, capable of engaging an interloper but also of sounding an alarm to kick the rest of the bodys defenses into action.

The key role they play is to conduct immune surveillance, Natalie Mount told Endpoints News. And once they find an intruder they can stimulate a whole immune response as well as be cytotoxic [cell-killing].

Only discovered in 1985, these gamma delta T-cells () have already become a popular target in cancer immunotherapy. This morning, a top British biotech exploring potential applications founded a new company to help reach that goal as GammaDelta Therapeutics spun off Adaptate Biotherapeutics with Mount at its helm.

While GammaDelta will continue to focus on a CAR-T-like cell therapy approach, the new company will develop antibodies that guide the cells as they patrol a patient, Mount said.Both have the same aim: getting these cellular guards to notice and effectively strike cancers.

We are developing antibodies that are able to recognize the gamma delta cells and target those and modulate their activities, Mount said. Weve discovered a range of substrates and what we can do now is take that forward in non-clinical development.

Gamma delta cells have risen in popularity in oncology research largely because they show potential to bring cell therapys effectiveness in blood cancers to solid tumors, although they present other potential advantages, including broader targeting and faster response.

GammaDelta Therapeutics got in on the ground floor, opening its doors in 2016. Since then, new and bigger players have entered the game. Last week, Regeneron dropped $25 million as part of an $80 million funding round for Adicet Bio, another company looking to use antibodies to guide gamma delta T cells.

Just in the last 2 to 3 years theres been a real solid interest, Mount said.

The broad idea of targeting these cells for oncology is not new. Clinical trials have been conducted evaluating gamma delta T cell treatments on several cancers, including leukemia and sarcoma. They were safe but with highly limited efficacy, although some appeared for not-fully-understood reasons to actually fuel tumors.

But GammaDelta and Adaptate say they work on a different subset of cells than these earlier trials did, one called 2. 2 is found in the tissues, making it an intuitive weapon for attacking solid tumors.

The antibody concept behind Adaptate is an increasingly popular form of therapy. AbbVie, Eli Lilly, Regeneron, and Sanofi, among a long list of others, are developing a form of antibody therapy called bispecific. Theyre still in the early stage, but last year Bairds Brian Skorney argued that the class of drugs has huge potential.

Our bias is that bispecifics pose an existential risk to the cellular therapies, he wrote. If a regularly administered therapeutic can keep anti-tumor pressure on by consistently engaging and activating T-cells, we think the much more expensive CART would become an even harder sell than it already is.

The exhaustive CAR-T process is like a specialized masterclass in tumor-killing, with doctors withdrawing cells, equipping them with a specific antigen receptor to identify malignancies and re-injecting them. The antibody approach for Adaptate can be thought of more as directives from a command center guiding the surveilling immune cells.

GammaDelta will focus on a cell therapy process similar to CAR-T, while Adaptate focuses on antibodies. But Mount argued one of the big advantages for GammaDelta Therapeutics and gamma delta cells is that they can identify cancer cells based on patterns as opposed to the specific antigens that CAR-T (chimeric antigen receptor T-cells) therapies use, opening up the potential for a range of targets.

GammaDelta is much closer to the clinic than the Adaptate spinoff, although they have yet to reveal exactly when they will begin trials, and for what indications. Mount said they were at least 12 months from evaluating whether they were ready to enter the clinic.

Social image: Adaptive CEO Natalie Mount via GammaDelta

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Intellia Therapeutics Announces Presentations at the 2019 Annual Congress of the European Society of Gene and Cell Therapy (ESGCT) – BioSpace

CAMBRIDGE, Mass., Oct. 16, 2019 (GLOBE NEWSWIRE) -- Intellia Therapeutics, Inc. (NASDAQ: NTLA), a leading genome editing company focused on the development of curative therapeutics using CRISPR/Cas9 technology both in vivo and ex vivo, announced one oral presentation and four poster presentations were accepted for the 27th Annual Congress of the European Society of Gene and Cell Therapy (ESGCT) taking place October 22-25, 2019, in Barcelona, Spain.

Intellias data includes important updates about the companys programs and platform development activities:

Oral Presentation:

In Vivo Gene Knockout Followed by Targeted Gene Insertion Results in Simultaneous Reduced Mutant Protein Levels and Durable Transgene Expression

Intellia will present data on its alpha-1 antitrypsin deficiency (AATD) program, which uses a modular hybrid delivery system combining lipid nanoparticle (LNP) encapsulated CRISPR/Cas9 with an adeno-associated virus (AAV) donor DNA template. Intellias gene knockout approach eliminates the production of the faulty PiZ variant of the protein, while targeted insertion of a wild-type gene copy facilitates production of a functional circulating protein. This builds on Intellias similar approach for targeted gene insertion of Factor 9, which achieved increased levels of circulating human Factor IX protein through two months in non-human primates and sustained through 12 months in mice.

Presenter: Anthony Forget, Ph.D.Abstract number: OR48Session 5b: New delivery systems and technologiesPresentation date/time: Friday, October 25, 2019, 11:30 a.m. 1:30 p.m. CETLocation: Room 113-115

Poster Presentations:

In Silico, Biochemical and Cell-Based Integrative Genomics Identifies Precise CRISPR/Cas9 Targets for Human Therapeutics

This poster presentation will highlight Intellias approach to assess off-target activity to identify highly specific CRISPR/Cas9 guides. Researchers demonstrated that potential off-target editing profiles discovered through empirical data from biochemical approaches were the most sensitive and accurate.

Presenter: Daniel OConnell, Ph.D.Poster ID Number: P655Date: Wednesday, October 23, 2019

Generation of a Library of WT1-Specific T Cell Receptors (TCR) for TCR Gene Edited T Cell Therapy of Acute Leukemia

This poster presentation focuses on Intellias ongoing research collaboration with IRCCS Ospedale San Raffaele to develop CRISPR/Cas9-edited T cell therapies to address intractable cancers, such as acute myeloid leukemia (AML). Researchers have successfully established a protocol enabling consistent and efficient tumor-specific TCR isolation and characterization from healthy donors. Based on these results, Intellia has selected multiple lead TCRs, which are undergoing development candidate evaluation.

Presenter: Erica Carnevale, Ph.D., Ospedale San RaffaelePoster ID Number: P111Date: Wednesday, October 23, 2019

Engineering of Highly Functional and Specific Transgenic T Cell Receptor (TCR) T Cells Using CRISPR-Mediated In-Locus Insertion Combined with Endogenous TCR Knockout

This poster presentation focuses on the companys T cell engineering technology, which is being applied in its Wilms Tumor 1 (WT1) lead ex vivo program. Intellia has identified an efficient CRISPR/Cas9-mediated process that inserts tumor-specific TCRs with high yield into the TRAC locus. Simultaneous knockout of the TRBC1 and TRBC2 loci substantially eliminates production of the endogenous T cell receptors.

Presenter: Birgit Schultes, Ph.D.Poster ID Number: P162Date: Thursday, October 24, 2019

CRISPR/Cas9-Mediated Gene Knockout to Address Primary Hyperoxaluria

This poster presentation will demonstrate the effects of independent CRISPR/Cas9-mediated knockout of each of two target genes involved in oxalate formation, lactate dehydrogenase A (LDHA) and hydroxyacid oxidase 1 (HAO1), to address primary hyperoxaluria type 1 (PH1).

Presenter: Sean Burns, M.D.Poster ID Number: P552Date: Thursday, October 24, 2019

About Intellia Therapeutics

Intellia Therapeuticsis a leading genome editing company focused on developing curative therapeutics using the CRISPR/Cas9 system. Intellia believes the CRISPR/Cas9 technology has the potential to transform medicine by permanently editing disease-associated genes in the human body with a single treatment course, and through improved cell therapies that can treat cancer and immunological diseases, or can replace patients diseased cells. The combination of deep scientific, technical and clinical development experience, along with its leading intellectual property portfolio, puts Intellia in a unique position to unlock broad therapeutic applications of the CRISPR/Cas9 technology and create a new class of therapeutic products. Learn more aboutIntellia Therapeuticsand CRISPR/Cas9 atintelliatx.comand follow us on Twitter @intelliatweets.

Forward-Looking Statements

This press release contains forward-looking statements ofIntellia Therapeutics, Inc.(Intellia or the Company) within the meaning of the Private Securities Litigation Reform Act of 1995. These forward-looking statements include, but are not limited to, express or implied statements regarding Intellias beliefs and expectations regarding its planned submission of an IND application for NTLA-2001 in mid-2020; its plans to generate preclinical and other data necessary to nominate a first engineered cell therapy development candidate for its AML program by the end of 2019; its plans to advance and complete preclinical studies, including non-human primate studies for its ATTR program, AML program and otherin vivoandex vivoprograms; develop our proprietary LNP/AAV hybrid delivery system to advance our complex genome editing capabilities, such as gene insertion; its presentation of additional data at upcoming scientific conferences regarding CRISPR-mediated, targeted transgene insertion in the liver of NHPs, using F9 as a model gene, via the Companys proprietary LNP-AAV delivery technology, and other preclinical data by the end of 2019; the advancement and expansion of its CRISPR/Cas9 technology to develop human therapeutic products, as well as maintain and expand its related intellectual property portfolio; the ability to demonstrate its platforms modularity and replicate or apply results achieved in preclinical studies, including those in its ATTR and AML programs, in any future studies, including human clinical trials; its ability to develop otherin vivoorex vivocell therapeutics of all types, and those targeting WT1 in AML in particular, using CRISPR/Cas9 technology; the impact of its collaborations on its development programs, including but not limited to its collaboration withRegeneron Pharmaceuticals, Inc. or Ospedale San Raffaele; statements regarding the timing of regulatory filings regarding its development programs; and the ability to fund operations into the second half of 2021.

Any forward-looking statements in this press release are based on managements current expectations and beliefs of future events, and are subject to a number of risks and uncertainties that could cause actual results to differ materially and adversely from those set forth in or implied by such forward-looking statements. These risks and uncertainties include, but are not limited to: risks related to Intellias ability to protect and maintain our intellectual property position, including through our arbitration proceedings against Caribou; risks related to Intellias relationship with third parties, including our licensors; risks related to the ability of our licensors to protect and maintain their intellectual property position; uncertainties related to the initiation and conduct of studies and other development requirements for our product candidates; the risk that any one or more of Intellias product candidates will not be successfully developed and commercialized; the risk that the results of preclinical studies will not be predictive of future results in connection with future studies; and the risk that Intellias collaborations withNovartisor Regeneron or its otherex vivocollaborations will not continue or will not be successful. For a discussion of these and other risks and uncertainties, and other important factors, any of which could cause Intellias actual results to differ from those contained in the forward-looking statements, see the section entitled Risk Factors in Intellias most recent annual report on Form 10-K as well as discussions of potential risks, uncertainties, and other important factors in Intellias other filings with theSecurities and Exchange Commission. All information in this press release is as of the date of the release, andIntellia undertakes no duty to update this information unless required by law.

Intellia Contacts:

Media:Jennifer Mound SmoterSenior Vice PresidentExternal Affairs & Communications+1 857-706-1071jenn.smoter@intelliatx.com

Investors:Lina LiAssociate DirectorInvestor Relations+1 857-706-1612lina.li@intelliatx.com

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Adaptate Biotherapeutics Formed To Develop T-cell Modulating Antibody-based Therapies – Technology Networks

Product News Oct 16, 2019

GammaDelta Therapeutics, a company focused on harnessing the unique properties of gamma delta (d) T-cells to develop transformational immunotherapies, has announced the formation of a spin-out company: Adaptate Biotherapeutics. While GammaDelta Therapeutics primary goal is to develop d T-cell based cell therapy products, the new spin-out will build on GammaDeltas knowledge to modulate d T-cell activity using therapeutic antibodies, with the potential to trigger an immune response against cancer.

d T-cells are a distinct T-cell sub-type that respond to molecular patterns of distress and have been shown to have tremendous potential in treating cancer and other immunological disorders. GammaDelta Therapeutics was formed in 2016 to harness these properties, and since then has gained knowledge of d T-cell biology developing a portfolio of investigational cell therapies poised to enter clinical development. In addition to gaining insight into cell growth and isolation, the companys scientists have also discovered a number of potential drug targets and antibodies that have potential to modulate the activity of d T-cells in situ.

Adaptate Biotherapeutics has been formed to further develop these targets and antibodies for therapeutic purposes and advance them into clinical studies. The two companies will continue sharing their insights into d T-cell biology as they work towards developing different therapeutic modalities.

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Mogrify Raises Additional $16M To Advance Its Mission To Transform The Development Of Life-Saving Cell Therapies – Clinical Leader

Mogrify Ltd (Mogrify), a UK company aiming to transform the development of life-saving cell therapies, recently announced the initial close of its Series A funding. The Company raised $16M USD in this round, bringing the total investment to over $20M USD to date. The funding will support internal cell therapy programs, and the development and out-license of novel IP relating to cell conversions of broad therapeutic interest. Mogrify is also actively recruiting, and will increase headcount to 60 scientific, operational and commercial staff located at its state-of-the-art facility on Cambridge Science Park.

The funding round was led by existing investor Ahren Innovation Capital (Ahren), an investment fund co-founded by leading UK scientific entrepreneurs, supporting transformational companies at the cutting edge of deep science and deep tech. Parkwalk, the largest EIS growth fund manager, backing businesses with IP-protected innovations creating solutions to real-world challenges, 24Haymarket, an early investor in Mogrify and a prolific early-stage investment syndicate in deep technology and the life sciences, and the University of Bristol Enterprise Fund III, also contributed to the fundraise.

Mogrify has developed a proprietary direct cellular conversion technology, which makes it possible to transform (transmogrify) any mature human cell type into any other without going through a pluripotent stem cell- or progenitor cell-state. The Company is deploying this platform to develop novel cell therapies addressing musculoskeletal, auto-immune, cancer immunotherapy, ocular and respiratory diseases as well as generating a broad IP position relating to cell conversions that exhibit safety, efficacy and scalable manufacturing profiles suitable for development as cell therapies.

Mogrify is commercializing its technology platform via a model that includes development and out-license of internally developed cell therapy assets, development and license of novel cell conversion IP, and the formation of joint-ventures to exploit the platform and/or novel cell conversion IP in non-core areas.

Mogrify launched in February 2019, announcing $3.7M USD seed funding from Ahren, 24Haymarket and Dr. Darrin M. Disley, OBE and went on to secure grants from Innovate UK and SBRI Healthcare.

Mogrify also strengthened its management and scientific teams and relocated a 20-strong workforce to its new headquarters at TusParks Cambridge Bio-Innovation Centre on Cambridge Science Park in May. It has now begun recruiting up to 40 additional commercial, operational and scientific roles to support its expanding pipeline of internal programs, as well as supporting numerous biotech and pharma collaborators in developing novel IP to underpin existing and new cell therapy programs.

Dr. Darrin M. Disley, OBE, CEO, Mogrify, said: Following the recent announcement of Dr. Jane Osbourn, OBE, as Chair of Mogrify, I am delighted we have been able to make an initial close of this fundraising round, with the backing of both existing and new investors. Due to the significant interest, we have been able to secure this growth-funding without engaging in a protracted and distracting fund-raising process. Having now raised over $20M, we can focus on delivery of our business strategy with the support of an aligned investor group. We will continue to engage with high-caliber investors with computational biology and cell therapy domain expertise as part of our on-going investor relations and capital markets strategy.

Alice Newcombe-Ellis, Founder and Managing Partner, Ahren Innovation Capital, said: Mogrifys technology is well positioned to disrupt the global cell therapy market. The Company has grown rapidly since February, appointing a world-class management team and delivering strongly against its business plans. We look forward to supporting Mogrify as it continues to go from strength to strength.

Alastair Kilgour, Chief Investment Officer, Parkwalk, said: We are delighted to be supporting the team at Mogrify, many of whom have been involved successfully with companies we have previously invested in, in this investment round. The science and technology base Mogrify are building is truly unique and disruptive. If successful, the positive effect on patient outcomes across a wide range of diseases will be staggering.

Alice Newcombe-Ellis, Founder and Managing Partner of Ahren, and Alastair Kilgour, Chief Investment Officer, Parkwalk, both join Mogrifys board of directors along with Dr. Karin Schmitt, the Companys Chief Business Officer.

For more information, visit https://mogrify.co.uk/investors/

About MogrifyMogrify has developed a proprietary direct cellular conversion technology, which makes it possible to transform (transmogrify) any mature human cell type into any other without going through a pluripotent stem cell- or progenitor cell-state.

The platform takes a systematic big-data approach to identify, from next-generation sequencing and gene-regulatory networks, the transcription factors (in vitro) or small molecules (in vivo), needed to convert a cell. By bypassing the stem cell-stage of cell transformation, Mogrify simultaneously addresses challenges associated with efficacy, safety and scalability.

Mogrify is deploying this platform to develop novel cell therapies addressing musculoskeletal, auto-immune, cancer immunotherapy, ocular and respiratory diseases as well as generating a broad IP position relating to cell conversions that exhibit safety, efficacy and scalable manufacturing profiles suitable for development as cell therapies.

Uniquely positioned to address a cell therapy market estimated to be $35B USD by 2023, Mogrify is commercializing its technology via IP licensing, product development, and drug development. Based in Cambridge, UK, the Company has raised over $20M USD funding from Ahren Innovation Capital, Parkwalk, 24Haymarket, Dr. Darrin M. Disley, OBE and the University of Bristol Enterprise Fund III. For more information, visit http://www.mogrify.co.uk

About Ahren Innovation CapitalAhren LP is an investment fund that supports transformational companies at the cutting edge of deep science and deep tech. The technologies of its Founding Partners are today valued more than $100B combined.

A group of highly diverse, creative and original thinkers leading their domains, Ahren believes in taking considered risk that will deliver superior rewards capturing a generational opportunity to provide smart capital to deep technology pioneers.

With a philosophy espousing the importance of relationships and trust, Ahren provides long-term capital and support to exceptional founders and teams, empowering them to achieve the unimaginable.

Ahren Innovation Capital was founded by Alice Newcombe-Ellis, together with Science Partners Sir Shankar Balasubramanian, Professor John Daugman, Professor Zoubin Ghahramani, Professor Steve Jackson, Professor Andy Parker, Sir Venki Ramakrishnan, Lord Martin Rees and Sir Gregory Winter. For more information, visit http://www.ahreninnovationcapital.com

About ParkwalkParkwalk is the largest growth EIS fund manager, backing world-changing technologies emerging from the UKs leading universities and research institutions. With 250M of assets under management, it has invested in over 100 companies across its flagship Parkwalk Opportunities EIS Fund as well as the award-winning enterprise and innovation funds Parkwalk manages for the Universities of Cambridge, Oxford and Bristol.

Parkwalk invests in businesses creating solutions to real-world challenges, with IP-protected innovations, across a range of sectors including life sciences, AI, quantum computing, advanced materials, genomics, cleantech, future of mobility, MedTech and big data.

For more information, visit http://parkwalkadvisors.com

About 24Haymarket24Haymarket is a premium deal-by-deal investment platform focused on high-growth businesses, investing up to 5M in any company. 24Haymarkets Investor Network includes several highly experienced private equity and venture capital investors, seasoned entrepreneurs and senior operators. We invest our own capital in direct alignment with entrepreneurs and typically seek Board representation to actively support their growth agenda. Since its inception in 2011, 24Haymarket has invested in more than 50 high-growth businesses. For more information, visit http://www.24haymarket.com

The University of Bristol Enterprise Fund III (Managed By Parkwalk)The University of Bristol Enterprise Fund is an early stage investment fund backing scientific and technological companies spun out of the University of Bristol or being supported by the Universitys SETsquared incubator. For more information, visit http://parkwalkadvisors.com/fund/university-of-bristol-enterprise-fund.

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LogicBio Therapeutics to Present New Data on Next Generation Capsid Development Program and GeneRide Platform Program at the European Society of Gene…

CAMBRIDGE, Mass., Oct. 16, 2019 (GLOBE NEWSWIRE) -- LogicBio Therapeutics Inc. (Nasdaq:LOGC), a genome editing company focused on developing medicines to durably treat rare diseases in pediatric patients, today announced upcoming presentations at the European Society of Gene and Cell Therapy (ESGCT) 27th Annual Congress, held in Barcelona, Spain, October 22-25, 2019.

We are thrilled to be presenting positive data on our Next Generation Capsid Development Program on the anniversary of our collaboration with Childrens Medical Research Institute of Australia, a leader in gene therapy, childhood cancer, embryology and neurological diseases. The goal of the collaboration is to develop novel, synthetic adeno-associated virus (AAV) capsids which are highly tropic for human tissues and optimized for manufacturing. These data give us further confidence that we can improve the performance of current AAV vectors, expanding our pipeline and strengthening our GeneRide platform, said Fred Chereau, CEO of LogicBio. Further, we are pleased to present additional preclinical data further supporting the durability of expression, compared to canonical gene therapy, in one of our GeneRide platform programs and to have been invited to speak on AAV manufacturing.

Panel PresentationTitle: AAV manufacturing: critical parameters influencing vector quality attributesPresenter: Matthias Hebben, Ph.D., VP, Technology Development, LogicBio Therapeutics (INV36)Session: 1d ATMP manufacturingSession date/time: October 23, 2019, 8:30-10:30 a.m. CEST

Poster PresentationsTitle: AAV development program: towards next generation of livertropic AAV variants (P025)Session date/time: October 23rd, 2019, 1:00-3:00 p.m. CEST

Title: Durability of factor IX expression in mice treated neonatally with a nuclease-free, promoterless, AAV-based gene therapy, GeneRide (P423)Session date/time: October 23rd, 2019, 1:00-3:00 p.m. CEST

Additional information on the meeting can be found on the ESGCT website: https://www.esgct.eu/home.aspx

About LogicBio TherapeuticsLogicBio Therapeutics is a genome editing company focused on developing medicines to durably treat rare diseases in pediatric patients with significant unmet medical needs using GeneRide, its proprietary technology platform. GeneRide enables the site-specific integration of a therapeutic transgene in a nuclease-free and promoterless approach by relying on the native process of homologous recombination to drive potential lifelong expression. Headquartered in Cambridge, Mass., LogicBio is committed to developing medicines that will transform the lives of pediatric patients and their families.

For more information, please visit http://www.logicbio.com.

Forward-Looking Statements

This press release contains forward-looking statements within the meaning of the federal securities laws. These are not statements of historical facts and are based on managements beliefs and assumptions and on information currently available. They are subject to risks and uncertainties that could cause the actual results and the implementation of the Companys plans to vary materially, including the risks associated with the initiation, cost, timing, progress and results of the Companys current and future research and development activities and preclinical studies and potential future clinical trials. These risks are discussed in the Companys filings with the U.S. Securities and Exchange Commission (SEC), including, without limitation, the Companys Annual Report on Form 10-K filed on April 1, 2019 with the SEC, and the Companys subsequent Quarterly Reports on Form 10-Q and other filings with the SEC. Except as required by law, the Company assumes no obligation to update these forward-looking statements publicly, even if new information becomes available in the future.

Contacts

Brian LuqueAssociate Director, Investor Relationsbluque@logicbio.com951-206-1200

Stephanie SimonTen Bridge Communicationsstephanie@tenbridgecommunications.com617-581-9333

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Dunbar CAR T-Cell Program brings advanced immunotherapy to cancer patients – WHAS11.com

LOUISVILLE, Ky. Cancer patients in Louisville and throughout the region soon will have access to some of the most advanced immunotherapy treatments available.

Louisville resident Thomas E. Dunbar has pledged $1 million to the University of Louisville to create a specialized center to provide chimeric antigen receptor positive T (CAR T) cell therapies to patients at the U of L James Graham Brown Cancer Center and other centers in the Midwest.

The new program will be named the Dunbar CAR T-Cell Program.

This gift will allow both kids and adults to be treated right here in Kentucky with the most innovative cell-based immunotherapy being developed, said Jason Chesney, M.D., Ph.D., director of the U of L Brown Cancer Center.

In CAR T-cell therapies, immune cells are extracted from the patients own blood and then are genetically modified to fight cancer. The modified cells are infused back into the patient where they fight the cancer and create long-term immunity to its recurrence.

In addition to dramatic treatment results, CAR T-cell immunotherapy leads to fewer toxic side effects than traditional chemotherapy.

Patients who have been treated with all the conventional therapies who then underwent treatment in clinical trials with CAR T cells had dramatic response rates. Eighty-three percent of kids in the original trial who had lethal, terminal B-cell acute lymphoblastic leukemia responded to this therapy, Chesney said.

The Dunbar CAR T-Cell Program will include laboratories for manufacturing the CAR T cells and will administer both FDA-approved and clinical-trial therapies to adult and pediatric cancer patients.

The goal is for the facilities to be fully functional and receiving patients by Sept. 30, 2020.

Tom Dunbars son, Evan, lost his battle to cancer with neuroblastoma in 2001 at the age of 6. In 2009, Wally Dunbar, Tom Dunbars father, lost his battle with melanoma.

Donor Tom Dunbar with his son, Evan

U of L Brown Cancer Center

This year, Toms physician wife, Stephanie Altobellis, M.D., helped identify his own cancer.

Kentucky is at ground zero, with the nations highest rates of cancer diagnosis and death, Tom Dunbar said. Its completely unacceptable. We have to lead the charge right here where the need is the greatest and we can do the most good. We need treatments that are not toxic. Watching our loved ones miserable with pain, often just from the treatments, and yet still die in front of us simply cant be the best that we can do.

To learn more about how CAR T-cell treatment works visit: uoflbrowncancercenter.org

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Dunbar CAR T-Cell Program brings advanced immunotherapy to cancer patients - WHAS11.com

GSK partners with Lyell on cell therapies development – BioPharma-Reporter.com

GlaxoSmithKline announced a five-year collaboration agreement with Lyell Immunopharma, a San Francisco, US-based company, working on methods to prevent inhibition of T cells by tumors and relapses due to loss of T cell functionality.

The agreement will see the two companies working on the advancement of GSKs cell therapy pipeline, specifically on GSK3377794, a potential treatment for multiple cancer types currently in Phase II clinical development, which targets the NY-ESO-1 antigen.

According to GSK, although the first two chimeric antigen receptor (CAR)-T cell therapies, Yescarta (axicabtagene ciloleucel) and Kymriah (tisagenlecleucel), have now reached the market, engineered T cells have not yet delivered strong clinical activity in common solid tumours.

Improving the fitness of T cells and delaying the onset of T cell exhaustion could help engineered T cell therapies become more effective, the company stated.

Further than GSKs cell therapy candidate, the research partnership will look to advance Lyells approach of enhancing initial T cell response against solid tumours into a platform technology for future cell and gene therapies development projects to treat rare types of cancer.

Lyells technology, according to Rick Klausner, the companys CEO, looks to tackle three barriers to T cell efficacy in solid tumours.

We are redefining the ways we prepare patient cells to be made into therapies, modulating cells functionality so that they maintain activity in the tumour microenvironment, and establishing methods of control to achieve specificity and safety for solid tumour-directed cell therapies, Klausner explained.

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GSK partners with Lyell on cell therapies development - BioPharma-Reporter.com

Ziopharm: 13 Failed Programs With 3 More On Deck – Seeking Alpha

In our most recent article, we focused on Iovance (IOVA), a cell therapy company that in our opinion has consistently generated positive data, has developed a commercializable product and is deploying a de-risked clinical strategy for a clear unmet need. As a result, we saw nearly 100% upside in Iovance's stock.

In this article, we highlight Ziopharm (ZIOP), a cell therapy company that we think represents the polar opposite to Iovance. Ziopharm's history is long and littered with suspended and abandoned programs. The company has not shown an ability to develop a commercial product. Looking at the company today, we believe its three main programs will be proven worthless in time. While we think Iovance can double from current levels, it is our view that Ziopharm represents a compelling short opportunity with 100% downside. Our price target is $0.

Below, we summarize our short thesis for Ziopharm:

Ziopharm's history is littered with programs that have failed clinical trials or failed to develop meaningfully

For context, Ziopharm was founded in 1998 and became public by entering into a reverse merger with an OTC-listed company in 2005. In September 2006, Ziopharm shares were up-lifted onto the NASDAQ. We think this should serve as a red flag. Companies that enter the market through reverse mergers often carry greater risk of fraud and tend to be lower quality. In fact, the SEC has issued a Bulletin cautioning investors against reverse mergers and later tightened the rules for reverse merger listings. While we have not uncovered any evidence of fraud, in our opinion Ziopharm is a classic example of a lower quality company.

It is also important to point out that since its founding, Ziopharm has not successfully brought a drug to market. When Ziopharm first came to the market, it aimed to advance its lead assets ZIO-101 and ZIO-201. ZIO-101 was an organic arsenic in development to treat hematologic cancer, and ZIO-201 was a formulation of isophosphoramide mustard in development to treat solid tumors. At the time of its reverse merger, Ziopharm claimed that peak sales for the two products "could approach $800 million."

Those peak sales numbers failed to materialize, and the company has spent the last 10 years developing these products with little to show in the end.

While these two products were the first programs to disappoint during Ziopharm's history, they were certainly not the last. A summary of the company's failed attempts at drug development is contained in the following chart.

Ziopharm has consistently burned cash and diluted shareholders

As none of its programs have generated meaningful cash through product sales, Ziopharm has repeatedly issued equity and diluted shareholders. In fact, since the company's up-listing to the NASDAQ in Sept. 2006, Ziopharm has burned nearly $500 mn of cash from operations (source: Bloomberg). Meanwhile, shares outstanding have increased by nearly ~12x (source: SEC filings). Not surprisingly, share performance has been weak. Since the up-listing, Ziopharm shares have lost 16% of their value as compared to the +417% return for the NASDAQ Biotech Index (NBI).

Our research indicates that Ziopharm's largest shareholder has ties to Brian Kaspar, the disgraced scientist who allegedly fabricated Avexis animal data and that the largest shareholder has a history of making statements about the company that we view as promotional

With Ziopharm's history of repeated failures and shareholder value destruction, it's not surprising that Ziopharm lacks significant institutional ownership from established healthcare funds. Nevertheless, we were surprised by its largest shareholder who is a vocal backer of the company. Ziopharm's largest shareholder is White Rock Capital, which is managed by Thomas ("Tom") Barton.

Tom Barton was an early-stage investor of Avexis and was involved when the company hired Brian Kaspar. Kaspar has been implicated, along with his brother, as one of the two scientists responsible for the data manipulation of Zolgensma, the Avexis gene therapy drug that Novartis (NYSE:NVS) acquired. The FDA has indicated that it is considering pursuing criminal penalties.

Tom Barton also has a history of making highly promotional statements about Ziopharm. For example, in June 2015, Barton told a reporter at the Boston Business Journal that "he [Barton] believes Ziopharm will be ripe for an acquisition for as much as $10 billion in the next year-and-a-half." At the time, Ziopharm had a market cap of $1.2 bn. A takeout at $10 bn would have represented an unprecedented 733% premium at the time of the article's publication. Instead, shareholders were "rewarded" with a 30% drop in share price and underperformance relative to the NASDAQ Biotech Index (NBI) over the next year and a half.

Source: Bloomberg

Tom Barton has mentioned Ziopharm in other interviews and was the source of an article from 2014 when he suggested that the article's author should take a look at Intrexon (XON) and "Intrexon cubs" such as Ziopharm, Synthetic Biologics (SYN) and Fibrocell Science Inc. (FCSC). Synthetic Biologics and Fibrocell Science both now have market capitalizations of under $30 mn.

In summary, our research indicates that Ziopharm came to the market with an inauspicious beginning, has a history of product development failures and shareholder dilution, and is backed by an investor whom we believe has a checkered history.

Ziopharm investors may not be aware of the shortcomings and potential issues regarding TCR T that make it different from successful CART T therapies

Today, Ziopharm bulls appear to be most excited about their TCR T therapy program. As we detailed in our Iovance article, the success of CAR T therapy in blood cancers was not repeated in solid tumors. Along with TIL therapy, TCR T has emerged as a potential cell-based technology to treat solid tumors. We are strong believers in Iovance's streamlined TIL approach and our research indicates it will likely be the next major revolution in cell-based cancer therapy for solid tumors. While TCR T could emerge as a viable alternative someday, we think Ziopharm is unlikely to be a major player in this market due to its risky approach. Some of these risks are innate to TCR Ts, but we think the major ones are tied to Ziopharm's methods.

For background, TCR T and CAR T therapy follow a very similar approach. In both, patient T-cells are extracted and combined with a DNA sequence that encodes for a protein that is designed to bind with a protein expressed by cancer cells. These cells are then usually expanded (allowed to multiply in vitro) and re-infused back into the patient, where they continue to multiply, detect, and eliminate the cancer.

The primary difference between the CAR T and TCR T approach lies in whether the engineered T cell product recognizes cancer proteins expressed on the surface of the cell (CAR T) or inside the cells (TCR T). Proteins called major histocompatibility complex (NYSEARCA:MHC) class I molecules present internalized proteins to the cellular surface for recognition by T-cells. The TCR T cells then bind with the MHC class I receptor along with the cancer protein ligand that is presented. If the T-cell recognizes the ligand as a foreign cancer protein (i.e., non-self), this is supposed to initiate an immediate response from the immune system against the non-self-antigen-presenting cell. This results in the cell's destruction (hopefully the cancer cell) and a further escalation of the immune response.

While TCR T may be a promising therapy for solid tumors and is similar to CAR T, it's important to note the TCR T approach remains to be validated. Importantly, there are a number of major obstacles that exist today.

1) "On-target, off tumor" toxicity could be substantial:

TCR T therapy appears to have higher sensitivity to its directed antigen compared to a CAR. While this is good in terms of potential potency, we believe it comes with increased safety risks. If the TCR T target is expressed on healthy cells, the targeting of healthy cells could result in substantial tissue destruction and toxicity. One of the frontrunners for TCR T therapy in the clinic, Adaptimmune (ADAP), has already seen five treatment-related deaths across four early-stage clinical trials; Additional literature has pointed out the "extreme care" that needs to be taken to ensure cross-reactivity with similar peptides does not occur following the death of a number of animal models.

Ziopharm is attempting to mitigate this risk by targeting its therapy on neoantigens, but there are no guarantees that the neoantigens will not also be expressed by some healthy cells. In addition, as we will go through later, we believe the neoantigen approach carries a risk of being less efficacious, is likely impractical from a manufacturing and cost perspective, and faces regulatory uncertainties.

2) Human leukocyte antigen (HLA) haplotype matching may drastically shrink the commercial opportunity:

The potency of TCR T relies on an interaction between the MHC and the peptides bound to it. In order to work, an "off-the-shelf" engineered T-cell product must be matched to the HLA alleles (genetic variations of a particular gene) of the patients it is treating to induce efficacy. There are three main HLA classes associated with MHC class I proteins (HLA-A, HLA-B, and HLA-C) and six main HLA classes associated with MHC class II proteins (HLA-DPA1, HLA-DPB1, HLA-DQA1, HLA-DQB1, HLA-DRA, and HLA-DRB1). Additionally, each HLA class has different mutational combinations that are donated by each parent (for example, HLA-A can be further subdivided into HLA-A*0201, HLA-A*0301, HLA-A*2402, among many other combinations of mutational variations of the HLA-A gene).

This is very problematic for TCR T therapy as therapeutic TCR can only be used in patients who express the appropriate HLA alleles. In addition to limiting the population from an efficacy perspective, if HLA alleles are mispaired, we believe patients risk developing potentially fatal graft-versus-host disease (GVHD), which has already been seen in murine models. Based on discussion with industry experts, we believe the FDA is taking a cautious approach initially to TCR T regulation and treating each HLA-matched therapy for each cancer type as a separate drug. This means a full development program would be needed for each HLA subtype in each type of cancer (including full clinical trials).

The end result is that the addressable market for each TCR T therapy is actually quite small given the number of TAM cuts that are needed for each therapy. For example, the most common HLA allele in white populations, HLA-A*0201, still only accounts for roughly 45% of the total white population (importantly, the US is only ~60% white and is becoming more heterogeneous over time).

3) TCRs have difficulty eradicating metastatic tumors because of the immunosuppressive tumor microenvironment:

Tumor cells are known to inhibit the expression of T-cell trafficking signals. Additionally, competition for glucose within the tumor frequently induces a hypoxemic state, thereby leading to suppressed T-cell activation.

We believe Ziopharm's "solutions" to address the above TCR T problems are likely to come with efficacy, efficacy, manufacturing time, and possible safety trade-offs

To date, Ziopharm has disclosed two main strategies to advance TCR T. The first is a partnership with the NCI to use Ziopharm's non-viral Sleeping Beauty cell therapy platform in creating personalized, neoantigen-directed TCRs. The second is a neoantigen "hotspot" (KRAS, p52, EGFR) program that appears to be moving forward internally within Ziopharm. Our research into these programs leads us to believe that the strategies are likely to add incremental risk to an already unproven and highly risky approach. As a result, we think Ziopharm's TCR T program is unlikely to work and, therefore, is worthless. Below we describe the basis for our views on these two strategies.

1) A partnership with the NCI for neoantigen-directed TCR T:

An investigator-sponsored trial has been started that is investigating the use of TCRs directed against neoantigens in glioblastoma, non-small cell lung cancer, breast cancer, and gastrointestinal/GU cancer. A neoantigen is a protein that results from a random somatic mutation that occurs in individual tumors and varies both between patients and within patients from time to time. Since this protein is not an endogenous protein normally made under any other circumstance, the hope is that by targeting these neoantigens, the risk of "on-target, off-tumor" binding can be eliminated.

However, in our view, such an approach would risk trading off substantial efficacy, would be very expensive, and would result in commercially unfeasible manufacturing time with today's technology. In order to identify unique tumor antigens, solid human tumors would require sequencing of the whole genome of each individual tumor in order to identify mutated genes and choose a motif of proteins that are presented by the HLA alleles. Tumor heterogeneity can thus result in mixed results depending on how many mutations the therapy "captures" when produced, reducing the efficacy potential. Additionally, each therapy is technically unique to the patient, which is problematic as there is no framework within the FDA to evaluate such a drug. This substantially increases regulatory risk in our view. The end result is summarized in neoantigen TCR T review papers that describe a personalized neoantigen approach as representing " a massive undertaking for the care of a single patients, at a time when there is an increasing focus on value in cancer care."

Perhaps not surprisingly, Ziopharm has never discussed how such a therapy is even close to being commercially viable. Recall that TIL therapy had remained an interesting academic experiment (but not a commercial drug) for nearly 20 years largely because the "vein-to-vein" manufacturing process took up to eight weeks before Iovance's innovations reduced this process to approximately three weeks. Based on our conversation with Ziopharm, it is our understanding that the neoantigen screening phase will take 4-6 months (17-26 weeks) per patient enrolled. In other words, this screening process is 5-9 times longer than what is viewed as commercially viable as a "vein-to-vein" time with both TIL and CAR T therapy. We believe that after factoring in patients who have progressed during the screening process and are no longer eligible or alive to receive therapy, this approach will result in a very low ORR rate on an ITT-basis.

Per clinicaltrials.gov, the trial is expected to enroll 200 evaluable patients across the four tumor types (50 per tumor) in 2-4 years. Since this trial is open-label, we would not be surprised if Ziopharm pushes the NCI to look opportunistically to report early-stage data in order to try and convince investors of the platform's activity. However, unless Ziopharm pre-specifies when the trial readouts will occur, such an approach would confound the unblinded nature of the trial (this happens by continuously "looking" at the evolving data results until they happen to look interesting and then publishing on that) vs. a true drug effect signal. We believe the institutional biotech investing community will be unconvinced by such an outcome.

To sum it up, Ziopharm's neoantigen-directed approach that is currently in clinic through the NCI may be so specialized and patient-specific that it may not be economic for broad use and may also not be approvable by the FDA. Furthermore, when accounting for patients who progress during the very lengthy screening process, it may not be an effective treatment for aggressive cancer. The first phase 1 trial is expected to take 2-4 years to enroll, which we feel means commercialization is likely a decade away even if Ziopharm's approach is viable.

2) A neoantigen "hotspot" trial that we understand will be developed internally by Ziopharm:

Few details are known about how this trial will be designed, but we believe the theory is relatively straightforward. There are certain mutations that are associated with a number of different cancer types that produce a neoantigen, such as KRAS, p53, and EGFR. Ziopharm appears to be attempting to develop a TCR product directed against these neoantigens hotspots. We believe Ziopharm will face the same substantial challenges that we detailed above regarding neoantigens generally. Solid tumors are highly heterogeneous, so the expressed neoantigen may actually only be a percentage of the total tumor burden of the patient and thus TCR T may have limited efficacy in such a patient.

Furthermore, HLA alleles, as described earlier, would significantly reduce the total addressable market for each individual therapy if the company proceeds with developing these drugs using an "off-the-shelf" approach. A TCR T expert that we spoke with believes that the largest HLA haplotype (group of alleles inherited from a single parent) for KRAS (HLA-CW8) represented only ~10% of all U.S. patients with a KRAS mutation. Ziopharm bulls may not realize that this approach will likely result in a small market opportunity.

Another obstacle for Ziopharm arises because the development of a drug to target neoantigens such as KRAS has been notoriously difficult. Initially hyped expectations are now being tempered by more mature data with the risk that follow-up confirmation scans may further reduce ORR. Therefore, there is a high risk that Ziopharm will not be able to successfully design a product that reproducibly engages the KRAS binding pocket, or that the efficacy of targeting KRAS may disappoint relative to what we see as current lofty expectations.

Lastly, while the neoantigen approach to TCR T is designed to improve the safety profile of the product, the safety profile of this general approach is still an unknown, as is Ziopharm's specific product. In summary, we view this program as very unlikely to succeed and do not believe a program that has publicly disclosed so few details at such an early-stage of development should warrant any value being ascribed to it.

Ziopharm investors may not be aware of what we believe is Kite Pharma/Gilead's superior approach to TCR T

We believe Ziopharm will face stiff competition from competitor programs if the general TCR T approach is eventually validated. In particular, we would note that Kite Pharma/Gilead (GILD), the manufacturer that developed Yescarta, has an exclusive license with the NCI for the use of TCR-based product candidates directed against MAGE A3 and A3/A6 as well as an exclusive license from Steve Rosenberg's lab for TCR Ts targeting neoantigens. We believe many investors in Ziopharm are completely unaware of the viral-based neoantigen program that is currently in development at Gilead and that directly competes with Ziopharm's TCR T program. We believe Kite/Gilead's viral approach is well-established and could easily leverage the entire validated Kite/Gilead cell therapy development platform.

While Ziopharm loves to highlight its relationship with the Rosenberg lab, we believe the relationship between Rosenberg and Kite/Gilead must be much closer given Kite helped brandish Rosenberg's legacy by commercializing his CAR T approach, and since their formal partnership has lasted since 2012. This is in comparison to Ziopharm's relationship with TCR T that began in 2017 and is still in very early stages of development.

In terms of execution, we believe it's no contest on whether investors should bet on Ziopharm (who has not been able to get a product to market) vs. Kite/Gilead (who successfully developed and marketed Yescarta, along with many other blockbuster drugs) if they desire TCR T exposure.

Source: Zhang et al. 2019

In the end, a combination of very high clinical and execution risk, direct competition from validated cell therapy platforms, and manufacturing/commercial uncertainty leads us to ascribe $0 of value to the Ziopharm TCR T program.

Ziopharm investors may be placing too much emphasis on the company's hiring of Drew Deniger

Ziopharm bulls have pointed to the company's hiring of Drew Deniger as a significant positive, but we think bulls may have gotten over their skis. Before market open on July 3rd, 2019, Ziopharm announced the hiring of Dr. Drew Deniger to direct Ziopharm's TCR-T program. The announcement added $100 mn of market cap to Ziopharm's stock that day, and bulls have pointed to Deniger as a key hire and compared him as an "heir" to the Rosenberg lab and even claimed that he could win a Nobel prize:

While we recognize that Drew has research experience in cell therapy and worked with Steve Rosenberg, we believe bulls place far too much value on the hiring of him than they should. Deniger was still very early in his academic career when he was hired as head of Ziopharm's TCR T program. As far as we can tell, he has never held an academic professorship position of any kind. A search on Pubmed yields 15 total publications of which he's been an author, and 8 first author publications after spending 13 years in academic research (seven as a graduate student at MD Anderson and six as a post-doc fellow at the NCI). This is compared to a search of Steve Rosenberg which yields 654 publications.

Our research leads us to believe Ziopharm's non-viral approach may carry significant safety risks

While investors are most excited about Ziopharm's TCR T program, some seem to still cling to hopes that Ziopharm's earlier CAR T program will bear fruit. Despite an FDA clinical hold that has been ongoing for over a year, investors hope that the Clinical Hold for the 3rd generation, point-of-care CAR T program will be resolved and that the new Investigational New Drug (NYSE:IND) application in later stage cancers will save the program.

We think these hopes are misplaced. Instead, we anticipate Ziopharm's CAR T program is likely to fail to materialize into a meaningful, active program and will be discontinued.

First, we believe there are efficacy and safety issues inherent to Ziopharm's non-viral CAR T approach. Investors may not realize that Ziopharm's Sleeping Beauty "point-of-care" approach to CAR T has never been clinically validated.

In contrast, the CAR T viral vector approach as a treatment for blood cancers has been validated through the clinical success and approval of both Yescarta and Kymriah. It's important to understand the differences in the approaches. We believe a good starting point to understanding the risks to the Ziopharm CAR T program comes from knowing the six main manufacturing steps to the FDA-approved CAR T therapies, as seen in the chart below.

While approved CAR T therapies offer a highly efficacious option for patients with blood cancer, the logistical complexities of manufacturing and administering CAR T therapy (i.e., steps 2-4 in the above chart) have been a headwind to broad use. Manufacturing time (also known as "vein-to-vein" time) of Yescarta is ~17 days, and Kymriah is ~22 days. Many people believe that shorter vein-to-vein times would improve efficacy and commercial success as long as CAR activity is not sacrificed.

Ziopharm claims its non-viral approach can reduce the manufacturing time to less than two days and offer a "point-of-care" offering. This is also sometimes referred to as the "third-generation CAR T" program or "Rapid Personalized Manufacturing (RPM)" process by the company.

While this may seem impressive on the surface, the details of how Ziopharm reduces the traditional CAR T manufacturing method to a two-day process are highly concerning to us. It appears that Ziopharm shortcuts at least two of the six steps in the viral CAR T process that is currently used:

Additionally, we believe Ziopharm may also be attempting to eliminate the lymphodepletion portion of the CAR T process, which we think also poses risks by reducing the ability for the CAR T cells to propagate appropriately in vivo:

We believe this is a very risky approach to CAR T. As the cell transformation process is never 100% efficient, cell expansion allows for the enrichment of CAR+ cells and therapeutic dosing of T-cells. This also enables a rapid in vivo (in person) expansion that peaks at roughly 14 days post-infusion.

While Ziopharm may save up-front time by electing not to expand the T-cells ex vivo (outside the body), we think this will almost certainly be offset by a longer in vivo expansion period. This also may not allow the drug to reach the peak CAR T concentration levels that are achievable with the on-market CAR T therapies. Efficacy may be further hindered if the lymphodepletion step is removed from the process as lymphodepletion is through to support T-cell engraftment by depleting populations of suppressive T regulatory (Treg) cells and eliminating competition for IL-7, IL-15, and IL-21. While Ziopharm attempts to circumvent the lymphodepletion step by tethering IL-15 onto the T cell's membranes, we see this as an unvalidated approach that may not be as effective as suppression of Tregs via administration of lymphodepleting agents such as cyclophosphamide and fludarabine (cy/flu). Due to these issues, we do not believe the patient will achieve CAR T activity that is equivalent to Yescarta and Kymriah.

Ziopharm's 3rd generation CAR T program remains on FDA Clinical Hold, perhaps due to the issues we highlighted above

We view FDA's decision to place the CAR T program on clinical hold on June 18th, 2018 due to poor cell viability as validation of our views. While Ziopharm has referred to this as a hold relating to the "chemistry, manufacturing and controls" (CMC), we think it is likely related to patient safety. We believe a product below the 70% viability threshold would not only trigger ethical concerns about injecting a product that may not have enough live cells to result in meaningful activity, but also that cellular debris caused by the dead cells could pose as a risk for potentially life-threatening occlusion and thrombosis (blood clots) especially in cancer patients who already have an extremely elevated risk of thrombosis.

In fact, we believe FDA makes it crystal clear in a regulatory consideration slide deck that "unreasonable or significant risk of illness or injury" is the driver for IND holds in cell therapy. Based on our discussions with industry experts, we understand that these two on-market competitors are well above 70% cell viability. In fact, we know that Yescarta production is 97% on-specification. Therefore, even if Ziopharm is able to consistently reach the 70% cell viability threshold, it certainly does not ensure that it will have a product with competitive safety and efficacy relative to existing on-market options. In fact, we believe the company's decision to pursue this CAR T strategy will result in an inferior product if it is ever able to obtain approval.

Based on Ziopharm's 2Q19 conference call, Ziopharm now claims it "understands" how to produce T-cells to reach the 70% viability threshold. Note that the company states only that it believes it knows how to do it and not that it has consistently achieved this important milestone.

Furthermore, Ziopharm's recent actions to move the CAR-T program into what we view as sicker patients suggest problems remain. The company is now highlighting a new IND for donor-derived CAR T therapy in transplant failure patients, specifically in patients who have relapsed with CD19+ leukemias and lymphomas.

Ziopharm bulls claim this is a signal that the company has improved the manufacturing process to meet the FDA's threshold for releasing the clinical hold. We disagree. We think the company is attempting to move its CAR-T program into a sicker patient population where the FDA is more lenient with regards to safety risk and that the company has not addressed the potential underlying safety issues behind the clinical hold. Additionally, this patient population represents a significantly smaller market opportunity than the 3rd generation CAR T trial that is on clinical hold. Therefore, while we're aware some investors may view this IND clearance as a positive signal for the 3rd generation program coming off hold soon, we believe they are entirely independent events.

Finally, the new IND is for donor-derived CAR T therapy, which we believe is very risky and poses its own unique safety concerns. By pursuing an allogenic approach with patient-derived cells, we think Ziopharm will now be faced with risks of inducing graft vs. host disease (GVHD), CAR T rejection, and off-target cleavage with gene editing that could result in oncogenic mutations of the T-cells.

Ziopharm tried the IL-12 program in melanoma and breast but stopped due to what we believe were efficacy and safety concerns

Our final section addresses Ziopharm's IL-12 program. Ziopharm has been working on the IL-12 program since at least 2014. To date, the program consists of all phase 1/2 programs and the data has been underwhelming in our view. Still, some investors believe the IL-12 program holds much promise. Below, we will describe the history of the program and reasons we do not place any value on IL-12.

The Ziopharm IL-12 program is an adenoviral vector for IL-12 expression that is controlled via an oral activator. While originally designed to treat melanoma and breast cancer, these programs were discontinued in these indications following what we believe to be unacceptable efficacy/safety profile in phase 2 studies. When the company announced plans to discontinue melanoma and pause the breast cancer program at a banking conference in early 2017, the company cited that the primary driver of its decision was "introduction and approval of highly promising new single and combination agents."

In effect, the company admitted that it didn't believe the IL-12 program in melanoma and breast cancer was competitive enough to pursue development in light of emerging competition and the new standard of care. However, we believe a safety issue also played into the decision, since 6 of the 9 breast cancer patients developed dangerous cytokine release syndrome. We believe the combination of a lack of efficacy versus standard of care and safety issues "deep sixed" the melanoma and breast cancer programs.

We believe the IL-12 program's focus on recurrent glioblastoma multiforme is likely to fail

Ziopharm then pivoted toward the backup indication of recurrent glioblastoma multiforme (rGBM) as the lead IL-12 program. We believe the reasons why GBM was reserved as a backup indication is clear. First, Ziopharm saw GBM as by far the smallest market for IL-12, as seen in investor presentations from 2014.

Second, GBM is an exceptionally difficult-to-treat cancer that has resulted in a large number of phase 3 failures even when earlier data has been positive. In fact, a recent study found that between January 2005 and December 2016, of eight completed phase 3 trials, only a single trial reported a positive outcome and implied a high degree of risk when trusting early-stage open-label data in GBM.

As a base case, we believe investors' risk adjustment to any GBM trial should be exceptionally high. Moreover, Ziopharm's IL-12 program should be viewed as even riskier since it previously failed to show a favorable risk/reward in easier-to-treat cancer.

In fact, the difficulties in GBM have already been seen in the IL-12 program. Despite originally licensing the IL-12 technology in 2011 and starting preclinical development in June 2013, the monotherapy GBM program has only managed to advance into phase 1. In fact, the monotherapy program was in phase 3 at one point; however, a CMC issue forced the program to be placed on an indefinite hold. As a result, Ziopharm reverted back to testing the drug in phase 1. We think this is yet another example of how Ziopharm hyped up a potential opportunity only to miss on execution.

We do not believe the IL-12 combination program holds much promise and may be unsafe

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Ziopharm: 13 Failed Programs With 3 More On Deck - Seeking Alpha