Monthly Archives: June 2020

Base editing, a new player in the gene editing arena, could have an important role in the development of immune-based cell therapies to treat solid tumors. Using cell therapies, such as CAR-T cells, in solid tumors remains challenging: the current word on the street is that such chimeric antigen receptors (CARs) will need multiple gene modifications to make them efficient and it is in this space that base editing could have a substantial advantage.Immune-cell-based therapy is an exciting cell therapy approach to treat cancer where the natural defenses of a patients immune system are used to target and kill cancer cells. Hopes were high following the initial FDA approvals of the first autologous CAR-T therapies for Novartis KYMRIAH (Aug 2017) and Gilead/Kite Pharmas YESCARTA (Oct 2017), both for blood-based cancers, but translating these successes into solid tumors remains a challenge. This is a consequence of the complexity and heterogeneity of solid tumors together with the immune inhibitory nature of the tumor microenvironment.For T cell-based therapies to work, the patient is treated with modified T cells that are rendered capable of identifying and killing tumor cells and, through this, generating a wider immune response against the tumor. Two key approaches used to modify T cells are through expressing a T cell receptor (TCR) known to target the tumor cell or a CAR. Other approaches include using and/or modifying natural killer cells, gamma delta cells or tumor infiltrating lymphocytes. It is not clear which approach will provide the most effective treatment option and in fact it might be that each tumor type responds better to one approach or to a combination of approaches. Irrespective of the approach, it is clear that the current therapies all face similar challenges; the risk of graft vs host disease (GvHD), a lack of durable remissions, on-target or off-target toxicity and cytokine release syndrome.Another layer of complexity for T cell-based therapies lies with the source of T cellsusing the patients own (autologous T cells), or a donor or iPSC-derived T cells (allogeneic). Each approach has advantages and challenges. Briefly, autologous treatments are attractive because they mitigate the risk of immune rejection and GvHD when infused back into the patient. However, they require a complex manufacturing process that necessitates specialist equipment local to the patient to enable the isolation of their T cells followed by rapid manufacture to transform them into engineered T cells ready to infuse back into the patient. At all points during this manufacturing pipeline, the product must be kept sterile and tracible to ensure the correct cells are transfused back into the correct patient. The allogeneic T cells approach is appealing because of the possibility that these could be engineered to be universal donor cells (suitable for all or most patients). Such cells can be manufactured in bulk and administered to multiple patients all over the world. This bulk manufacturing would attract cost-savings once a critical mass of therapy is reached. It could also allow for engineered T cells to be available on-tap to any patient, a game-changer for particular patients whose own T cell count is either too low for engineering, or that transduce poorly with the engineered construct during manufacture. The challenge for allogeneic T cell therapies is the ability to generate cloaked T cells that do not provoke an immune-response in the patient, as this could kill the engineered T cells after transplantation such that they have no efficacy or potentially lead to the death of the patient as a result of a disseminated cytokine storm. Despite these challenges, in April 2019 the US Food and Drug Administration (FDA) approved the first allogeneic CAR-T for investigational use in patients with multiple myeloma and more are expected to follow.To try and achieve a stealth allogeneic T cell that flies under the radar of the patients immune system, genetic engineering is key. Although T cells can be engineered to express a specific TCR or CAR, additional genetic changes are required to provide a cloak of invisibility, prolong the survival of the cells in the patient and enable them to function in an immune suppressive tumor microenvironment. From a simplistic point of view, one could view the modified CAR or TCR as a sat nav, with the T cell being the engine. You need both to get to your destination and, if youre able to improve your engine, its possible the outcome could be achieved faster and in a more reliable fashion. There are several gene knockouts or gene knockdowns that are seen as a natural first step to improving the properties of engineered allogeneic T cells and these are summarized in the table below:As there are multiple gene knockout options, a gene engineering technology capable of making multiple gene edits with as few off-target effects as possible is needed. Indeed, it is conceivable that an effective allogeneic T cell-based therapy might require ten or more gene edits.This prompts the question What is the best gene editing platform or technology to support multiple gene edits? On the surface of it, and owing to its phenomenal adoption in research labs worldwide over the past decade, most currently use the gene editing approach provided by CRISPR-Cas9. CRISPR was first commercialized in 2012 and quite staggeringly made its debut in a clinical trial for cell therapy in June 2016. Although CRISPR is an efficient gene editing tool, its mode of action of generating double-strand breaks in the DNA could be a source of concern. DNA double-strand breaks, which tend to be repaired by the cells repair machinery in an error prone fashion, can cause unintended changes in the genome of engineered cells. Although there are methods for minimizing these off-target effects when single genes are targeted, targeting multiple genes in one cell all at the same time could lead to genome-altering insertions, deletions and/or chromosomal translocations. The impact of this on a patient could be that the cell therapy is effective but the off-target genetic changes lead to deleterious side-effects, impacting patient recovery and potentially survival. Well-known alternatives to CRISPR include transcription activator-like effector nucleases (TALENS) and zinc finger nucleases (ZFN). These approaches have slightly different safety profiles to CRISPR and while optimized for single gene edits or knockouts, multiple gene knockouts still present a challenge for these technologies. Freedom to operate using these technologies in the therapeutics space can also be challenging, particularly for start-up and biotech companies.The potential deleterious impact of off-target effects, particularly for multiple gene edits has opened the door to a newcomer on the gene engineering scene: base editing. This technology first gained prominence from peer-reviewed papers published by researchers from Harvard University.1 Others, such as Rutgers University, have also developed base editing platforms.2 In brief, base editing uses a deaminase enzyme to make a specific base pair change in the DNA. The base pair alteration can either be an A to G or a C to T depending on which deaminase is used. Importantly, the CRISPR-Cas system is used to guide the deaminase to the base pair that is going to be altered, but in this version of CRISPR-Cas, a DNA double-strand break is not made, meaning that the off-target effects with base editing in terms of insertions, deletions or translocations should be substantially reduced.On the surface, this crucial characteristic makes base editing an excellent choice of gene editor for cell therapyit can be used to specifically knock-out multiple genes through the introduction of stop codons or splice site disruptions with limited capacity to introduce substantial, large-scale chromosomal abnormalities. However, as base editing was first published in May 2016,1 substantial research is required to understand fully the utility of base editing in the therapeutic space and to appreciate its advantages and challenges compared with standard gene editing approaches, such as CRISPR-Cas, TALENs and ZFNs.As is somewhat expected of a fashionable area for scientific research, the gene editing space does not stand-still for very long: Prime editing has followed hot on the heels of base editing. Unlike base editing, which makes changes to specific base pairs in the DNA, prime editing allows changes to be made to a run of base pairs by forcing the cell to use a DNA copying system that exists naturally in cells as part of the DNA repair mechanism. Initial data suggest3 that prime editing has higher off-target effects compared with base editing, in terms of introducing insertions and deletions, and more work is needed to understand the comparison and utility of base editing vs. prime editing. It will be interesting to see how prime editing evolves over the months and years within the cell and gene therapy space.Although cell therapy has demonstrated its potential for driving complete remissions in some patients with hematological cancers, the next big step is to translate these early successes into patients with solid tumors. However, due to the complexity of solid tumors, this is not a simple or straight-forward process and multiple factors need to be considered. While the sat nav in the form of an engineered TCR or CAR is crucial, the T cell engine could be the natural starting point for improving efficacy in patients with solid tumors, as could the use of allogeneic rather than autologous approaches. The multiple edits that will be needed to deliver a stealth, engineered, allogeneic off-the-shelf T cell are only now being investigated in earnest and it could be that the new kid on the block, base editing, provides a compelling route forward.References1. Komor, A.C., Kim, Y.B., Packer, M.S., Zuris, J.A. and Liu, D.R. (2016). Programmable editing of a target base in genomic DNA without double-stranded DNA cleavage. Nature, 533(7603), 420424. Doi:10.1038/nature179462. Horizon Discovery to provide access to novel base editing technology, January 2020;https://horizondiscovery.com/en/news/2020/Horizon-Discovery-to-provide-access-to-novel-base-editing-technology (accessed May 2020)3. Anzalone, A.V., Randolph, P.B., Davis, J.R., et al. (2019). Search-and-replace genome editing without double-strand breaks or donor DNA. Nature, 576(7785), 149157. doi:10.1038/s41586-019-1711-4Dr. Jonathan Frampton is a business development professional who has been working for Horizon Discovery for the past 9 years and currently as their Corporate Development Partner. He is always scouting for exciting novel technology that could complement Horizons already extensive gene engineering toolkit. In addition to this he works closely with Horizons partners to manage out-licensing opportunities.

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Cell Therapy For Solid Tumors - Contract Pharma

Tom Farrell didnt have much to do after Bellicum announced in January 2017 that they were bringing in a new CEO. He had led the CAR-T company for over a decade, since before Carl Junes New England Journal of Medicinepaper had made cell therapy the hottest thing in cancer research. Now he was facing an 18-month non-compete.

So he worked quickly when, not long after that clock expired in 2018, a banker who helped take Bellicum public told him about a South Korean company called Green Cross LabCell that had built a natural killer cell factory and was looking to develop therapies off it. Farrell hopped a plane to Seoul.

It was hugely impressive, Farrell told Endpoints News.There was nothing [else] I came across that was truly disruptive from a business model perspective.

A year and a half later, Farrell has his new company. Called Artiva, it launches with $78 million in Series A funding and an exclusive deal with Green Cross to push some of their natural killer cell technology into the clinic. Theyll start with a therapy that combines NKs with an approved antibody therapy like rituximab to improve the antibodys effectiveness. Behind that, theyre working on CAR-NK therapy and, longer term, gene-edited CAR-NK cells. RA Capital Management, venBio and 5AM Ventures led the round.

Artiva joins what, after many years, has recently become a booming field. In February, MD Anderson showed that a Takeda-licensed CAR-NK therapy cleared tumors completely in 7 of 11 non-Hodgkins lymphoma patients. Two months later, J&J gave Fate Therapeutics, one of the earliest biotechs in the field, an up-to $3.1 billion deal for their CAR-NK and CAR-T therapies. The Big Pharmas are joined by a slate of recent upstarts, including Celularity, Nkarta, NantKwest, and Cytovia.

Unlike the other newcomers, Artiva makes virtually no claim on having original science. In fact, Farrell said, biotechs emphasis on novel technologies is part of why cell therapy has advanced only incrementally since the approval of the first two CAR-T therapies. Industry hasnt focused enough on addressing the manufacturing issues that have made therapies so costly and difficult to scale, he said.

Lewis Lanier, an immunologist at the University of California, San Francisco and an early pioneer in NK cell research, said Artiva would still face the same questions other drug developers face will some patient reject the cells? Will the natural killer cells actually last a significant amount of time after infusion? but the collaboration could give them an edge.

The Korean Green Cross manufacturing facility is really first rate, thats where the advantage is, Lanier, who is not involved in Artiva, told Endpoints. The science is really routine, theyre not doing anything particularly innovative.

For years, NK cells have been viewed as one of the key potential ways of making off-the-shelf cell therapy. Part of the innate immune system, implanting these cells from donors doesnt lead to the same resistance that donor T cells can. One of the problems, though, is that NKs are finicky, as Lanier puts it, vastly more difficult to grow and manipulate in a lab. Only recently have a couple companies figured out ways to do it consistently. Fate, for instance, uses master lines of iPSC stem cells.

At the Green Cross facility Farrell toured two Novembers ago, the South Korean company had refined a process to derive NK cells from donated umbilical cord blood and cryo-preserve it. A week after his tour, Farrell flew to San Diego for the ASH conference, where he ran into Pete Flynn, another longtime biotech executive out of a job. Flynn had run early development for Fate in its early years before leaving to run R&D for the anti-obesity company Orexigen, which had just gone bankrupt.

Farrell explained what he saw in Seoul and the two debated different approaches to off-the-shelf therapy. They figured the manufacturing base could be a launching pad.

Even though were a Series A company, were looking to become the go-to NK cell, Flynn, now COO, told Endpoints. Basically all the pieces are in place already, whereas for some of those other companies, there might still be some work to do.

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Out of jobs, a pair of early cell therapy executives went to Seoul, came back with a new company, $70M and a plan to leapfrog natural killer...

Cell and gene therapy has evolved into one of the biopharma industry's hottest markets with a major splash of investment and a run of approvals likely in the coming years. To meet what's likely to be massive demand for manufacturing capacity, industry experts are calling for "forward-looking" investmentsbut as one pointed out, those checks aren't easy to write.

During a virtual roundtable Monday hosted by Fierce Pharma, manufacturing experts from Novartis, Gilead's Kite unit, BioMarin and Astellas' Audentes said building capacity and figuring out how to scale production would make the difference in whether the industry will be ready to handle a slate of expected approvals.

According to former FDA Commissioner Scott Gottlieb, the agency could approve between 10 and 20 cell and gene therapies a year through 2025 with as many as 800 such therapies moving through drugmakers' pipelines.

Chuck Calderaro, Kite's global head of technical operations, said Kite's primary concern was how to scale production of its cell therapy offerings, including Yescarta, the company's only approved therapy in the space.

VIRTUAL ROUNDTABLE: Up to the Challenge: Manufacturings Central Role in the Cell- and Gene-Therapy Revolution (reg. req'd)

Calderaro noted that Kite has a turnaround time of 16 days from patients having their blood drawn to infusionand the drugmaker is hoping to keep that figure stable as its manufacturing chain grows.

"Access to capacity is always a challenge in a growing area, and especially in cell therapy, which is personalized to order," Calderaro said. "The challenge for us is to be able to scale that excellence as we begin to globalize our cell therapy treatments."

The first challenge for Gilead will come from bringing its newest facility in Amsterdam online after the EU gave it the go-ahead earlier this month.

RELATED: Gilead sees better days ahead for CAR-T therapy Yescarta with Amsterdam manufacturing hub online

Gilead's 117,000-square-foot CAR-T facility at SEGRO Park Amsterdam Airport won a green light after the European Medicines Agency (EMA) approved the plant's end-to-end manufacturing process. The site will house European production fo Yescarta, which won an EMA approval back in August 2018 to treat relapsed or refractory diffuse large B-cell lymphoma and primary mediastinal large B-cell lymphoma.

Calderaro highlighted the Amsterdam facility as the "next step" in Gilead's global manufacturing ramp-up for Yescarta as the site will be able to churn out enough of the pricey therapy for 4,000 patients each year.

Gilead also plans to build a 67,000-square-foot facility at its Oceanside, California, biologics site just for developing viral vectors, the tools needed to deliver genetic material into cells. Calderaro said that facility would give Gilead "a little more control" of its supply chain as it looks to scale up.

RELATED: Pharma's gene and cell therapy ambitions will kick into high gear in 2020despite some major hurdles

Meanwhile, Steffan Lang, Novartis' head of technical operations, pointed out that building capacity for the future will go hand-in-hand with building an experienced team to lead into the future.

"Its about the people and capabilities," Lang said. "You have to have the right team in place to build capacity at the appropriate scale across the globe."

Novartis' gene therapy Kymriah was the first FDA-approved therapy of its kind back in August 2017. Since then, Novartis has expanded Kymriah's reach globally, including opening a new facility in Stein, Switzerland, that cleared up a transatlantic bottleneck for shipments to Novartis' facility in Morris Plains, New Jersey.

Meanwhile, BioMarin and Audentes are both pursuing first FDA approvals for their cell and gene therapy candidates and are looking to scale up manufacturing to make the leap into commercial.

RELATED: Audentes investing $109M in gene therapy manufacturing facility with 200 jobs

In February, Audentes announced it would invest $109 million into a 135,000-square-foot facility in Sanford, North Carolina to flesh out its cell and gene therapy manufacturing needs. The first phase is slated to take 18 months to build and will be operational by 2021. The rest of the investment will play out over two more years.

Donald Wuchterl, Audentes' SVP of technical operations, said building capacity would require a "forward-looking" approach to investingbut the lengthy timelines for these therapies make that foresight difficult.

"These are tough checks to write," Wuchterl said. "Were looking at potentially three years out in a field thats growing rapidlyit takes some constitution, I would say."

BioMarin, which is in the homestretch for an FDA approval for its hemophilia A gene therapy candidate valoctocogene roxaparvovec, or valrox, is in a similar boat looking to make the leap to commercial. For the Robert Baffi, special advisor to the company's CEO, scaling up manufacturing is a big taskbut he hopes that a "biology revolution" could provide a big breakthrough for production in the coming years.

"While I think there's improvements to be had on the manufacturing side today, I think there's a biology revolution still to come in terms of making the vectors more specific, more targeted, more preciseand that would be a big boon for the industry," he said.

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With cell and gene therapy boom coming, experts at Novartis, Kite trumpet need for capacity: panel - FiercePharma

DUBLIN--(BUSINESS WIRE)--The "CAR T Cell Therapy Market Global Forecast by Regions, Targeted Antigens, Clinical Trials/Study, Companies" report has been added to ResearchAndMarkets.com's offering.

This latest study report CAR T Cell Therapy Market Global Forecast by Regions (North America, Europe, Asia Pacific, Latin America, Middle East, Africa), Targeted Antigens (CD19, CD20, GD2, CD22, CD30, CD33, HER2, MESO, EGFRvII, Others), Clinical Trials/Study (CD19, CD20, GD2, CD22, CD30, CD33, HER1, HER2, MESO, EGFRvII), Companies (Novartis, Gilead Sciences (Kite Pharma), Celgene Corporation (Juno Therapeutics), Celyad) provides a detailed and comprehensive insight of the global CAR T cell therapy market.

For many years, the support of cancer therapy was chemotherapy, surgery and radiation therapy. However, in recent times, CAR-T cell therapy has been introduced as an incredibly supportive treatment for cancer patients. Since the introduction of chemotherapy, this treatment is one of the most significant breakthroughs. In this therapy, immune cells are collected from patients, and it is modified in the laboratory by doctors. After modification, these immune cells are infused back into the patient as they can easily recognize and kill cancer cells. These infused cells get multiplied and stay in the body as living drugs. According to analysis, CAR-T Cell Therapy Market is expected to be USD 7.4 Billion by the end of the year 2028.

Growth Factors for CAR-T Cell Therapy

Factors such as growing numbers of cancer in adults and children, and increasing policy initiatives to encourage cell therapy research in cancer, and increasing numbers of clinical trials worldwide are some of the main drivers for the global demand for CAR T cell therapy. The economic scenario in the CAR-T cell therapy industry is very dynamic, and key players compete with each other to gain access to major markets in the United States and Europe. Companies are seeking to secure treatment facilities to increase access for patients to their treatments.

Developments did by Companies in CAR T Cell Therapy

In 2017, a new milestone was set for oncology patients when the FDA approved the first two CD19-targeted known as (Chimeric Antigen Receptor) CAR T cell therapies produced by Novartis and Gilead Sciences known as Kite Pharma in the United States. Such two approvals have helped to improve the global demand for CAR T cell therapy because more companies are searching for this excellent opportunity to reach the marketplace. More than 200 CAR T clinical trials are ongoing or completed in various parts of the world. In 2018, Novartis announced its 33 approved centres in the U.S. and Gilead announced its 28 approved centres for the care of patients. Companies are also coming up with new developments in the field.

Key Topics Covered:

1. Executive Summary

2. Global Chimeric Antigen Receptor (CAR)-T cell Therapy Market

3. Market Share - CAR-T Cell Therapy

3.1 By Geographical Region

3.2 By Targeted Antigens

4. Targeted Antigen Market

4.1 CD19

4.1.1 Introduction

4.1.2 Market Size and Forecast

4.2 CD20

4.3 GD2

4.4 CD22

4.5 CD30

4.6 CD33

4.7 HER2

4.8 Mesothelin (MESO)

4.9 EGFRvIII

4.10 Others

5. Geographical CAR-T Cell Therapy Market (2016 -2026)

5.1 North America

5.2 Europe

5.3 Asia Pacific

5.4 Latin America

5.5 Middle East

5.6 Africa

6. Global - CAR-T Cell Clinical Trials/Study

6.1 CD19

6.2 CD20

6.3 CD22

6.4 CD30

6.5 CD33

6.6 EGFRvIII

6.7 GD2

6.8 HER1

6.9 HER2

6.10 MESO

7. China CAR-T Cells Clinical Trials Details

7.1 By Cities CAR-T Cells Clinical Trials

7.2 CD19 Directed CAR-T Cells Clinical Trials

7.3 Non-CD19 Directed CAR-T Cells Clinical Trials

7.4 Solid Tumors CAR-T Cells Clinical Trials

8. CAR-T Cell Therapy SWOT Analysis

8.1 Strength

8.2 Weakness

8.3 Opportunities

8.4 Threats

9. Regulation in CAR-T Cell Therapy

9.1 United States

9.2 European Union

9.3 China

10. IPO/Investment/Funding/Partnership in CAR-T Cell Therapy Market

10.1 Venture Capital Investment

10.2 Initial Public Offerings of CAR-T Companies

10.3 CAR-T Companies Strategic Partnerships/Deals

10.4 Key CAR-T Technology Deals

11. Growth Drivers

11.1 FDA Approvals of CAR-T Therapy

11.2 Dramatically Increasing Number of CAR-T Cell Trials Globally

12. Challenges

12.1 Regulatory Challenges

12.2 Very Expensive CAR-T Therapy Treatment

13. Novartis

13.1 Company Overview

13.2 Initiatives

13.2.1 Point 1

13.2.2 Point 2 Kymriah (tisagenlecleucel), First-in-class CAR-T Therapy from Novartis Received Second FDA Approval

13.2.3 Point 2

13.3 Financial Insight

14. Gilead Sciences (Kite Pharma)

14.1 Company Overview

14.2 Company Initiatives

14.2.1 Point 1

14.2.2 Point 2

14.3 Company Financial Insight

15. Celgene Corporation (Juno Therapeutics)

15.1 Company Overview

15.2 Company Initiatives

15.2.1 Point 1

15.2.2 Point 2

15.3 Company Financial Insight

16. Celyad

16.1 Company Overview

16.2 Company Initiatives

16.2.1 Point 1

16.2.2 Point 2

16.2.3 Point 3

16.3 Financial Insight

Companies Mentioned

For more information about this report visit https://www.researchandmarkets.com/r/lssoan

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Global CAR T Cell Therapy Market to 2026 - by Regions, Targeted Antigens, Clinical Trials/Study & Companies - ResearchAndMarkets.com - Business...

The study titled Global Stem Cell Therapy Market Research Report includes detailed research undertaken by analysts as well as an in-depth analysis of the global market. A detailed, highly extensive study of this market alongside pivotal aspects that may impact the commercialization graph of this industry has been given in the study.

As per the latest research report, the global Stem Cell Therapy Market is anticipated to depict a CAGR of 10.2% through 2025, having recorded a valuation of 7.8 billion in 2018.

Request for a sample copy of this report @ https://www.gminsights.com/request-sample/detail/3331

By 2025, the Stem Cell Therapy Market is expected to hit a remuneration of 15 billion. An extremely definite evaluation of the global market in terms of qualitative as well as quantitative analysis has been covered in this report. The myriad aspects of this industry, having considered its historical and forecast data have been enlisted in the study. Also, the research report is inclusive of substantial details with regards to an efficient SWOT analysis, PESTEL analysis, and Porters five force model of the market.

The Stem Cell Therapy Market report coverage includes numerous aspects like the market size, geographical growth opportunities, important vendors in the market, driving factors and constraints, segmental evaluation, and competitive landscape.

The report intends to enlist myriad updates and data with regards to the market alongside various growth opportunities which may help the global industry expand at an appreciable rate. An in-depth summary of the Stem Cell Therapy Marketcombined with a well-defined set of market definitions as well as outline of the industry have been given in the report.

In the report, the abstract section is inclusive of information on the market dynamics. This section is further categorized into driving factors propelling the market growth, industry hindrances, trends characterizing the market growth, as well as the business opportunities prevalent in the industry.

The Stem Cell Therapy Market report also contains information pertaining to the anticipated CAGR of the global business through the forecast period. In addition, many technological developments and innovations that may possibly boost the industry outlook over the anticipated period are also mentioned in the study.

Top Companies

Split by application, the market is divided into

This study is inclusive of in-depth information with respect to the consumption of the product as well as application segment market share, in tandem with the growth rate likely to be registered by every application segment.

Report Growth Drivers

What are the key highlights of this report?

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Stem Cell Therapy Market Share Research By Applications And Regions - News.MarketSizeForecasters.com