Category Archives: Cell Therapy

Full TitleA Phase 1 Study to Evaluate the Safety, Proliferation and Persistence of GEN-011, an Autologous Adoptive Cell Therapy Targeting Neoantigens in Solid Tumors (TITAN)Purpose

The purpose of this study is to assess the safety of an investigational cellular immunotherapy called GEN-011 in people with advanced cancers of the bladder and kidney. Researchers will also see how the cancer responds to this treatment. GEN-011 is made in a laboratory using a patients own white blood cells (lymphocytes). The treatment is designed to attack cancer cells without harming healthy cells. It is given intravenously (by vein).

To be eligible for this study, patients must meet several requirements, including:

For more information about this study and to ask about eligibility, please contact the office of Dr. David Aggen at 646-422-4679.

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A Phase I Study of GEN-011 Cellular Therapy in People with Advanced Cancers of the Bladder and Kidney - On Cancer - Memorial Sloan Kettering

REGULATED INFORMATION

Article 14 of the Law of 2 May 2007 on disclosure of major holdings

Gosselies, Belgium, 10 December 2021, 7am CET BONE THERAPEUTICS (Euronext Brussels and Paris: BOTHE), the cell therapy company addressing unmet medical needs in orthopedics and other diseases, today announces that it has received a transparency notification dated 8 December 2021 indicating that the shareholdings held by Nyenburgh Holding NV have crossed above the threshold of 5% following the issuance of new shares of Bone Therapeutics via a private placement on 2 December 2021. The new shares were delivered to the participating investors on 7 December 2021.

The notification dated 8 December 2021 contains the following information:

The notification can be consulted on the website of Bone Therapeutics, under the heading Shareholder Information.

About Bone Therapeutics

Bone Therapeutics is a leading biotech company focused on the development of innovative products to address high unmet needs in orthopedics and other diseases. The Company has a diversified portfolio of cell therapies at different stages ranging from pre-clinical programs in immunomodulation to mid stage clinical development for orthopedic conditions, targeting markets with large unmet medical needs and limited innovation.

Bone Therapeutics core technology is based on its cutting-edge allogeneic cell and gene therapy platform with differentiated bone marrow sourced Mesenchymal Stromal Cells (MSCs) which can be stored at the point of use in the hospital. Currently in pre-clinical development, BT-20, the most recent product candidate from this technology, targets inflammatory conditions, while the leading investigational medicinal product, ALLOB, represents a unique, proprietary approach to bone regeneration, which turns undifferentiated stromal cells from healthy donors into bone-forming cells. These cells are produced via the Bone Therapeutics scalable manufacturing process. Following the CTA approval by regulatory authorities in Europe, the Company has initiated patient recruitment for the Phase IIb clinical trial with ALLOB in patients with difficult tibial fractures, using its optimized production process. ALLOB continues to be evaluated for other orthopedic indications including spinal fusion, osteotomy, maxillofacial and dental.

Bone Therapeutics cell therapy products are manufactured to the highest GMP (Good Manufacturing Practices) standards and are protected by a broad IP (Intellectual Property) portfolio covering ten patent families as well as knowhow. The Company is based in the BioPark in Gosselies, Belgium. Further information is available at http://www.bonetherapeutics.com.

For further information, please contact:

Bone Therapeutics SAMiguel Forte, MD, PhD, Chief Executive OfficerLieve Creten, Chief Financial Officer ad interimTel: +32 (0)71 12 10 00investorrelations@bonetherapeutics.com

For Belgian Media and Investor Enquiries:BepublicCatherine HaquenneTel: +32 (0)497 75 63 56catherine@bepublic.be

International Media Enquiries:Image Box CommunicationsNeil Hunter / Michelle BoxallTel: +44 (0)20 8943 4685neil.hunter@ibcomms.agency / michelle@ibcomms.agency

For French Media and Investor Enquiries:NewCap Investor Relations & Financial CommunicationsPierre Laurent, Louis-Victor Delouvrier and Arthur RouillTel: +33 (0)1 44 71 94 94bone@newcap.eu

Certain statements, beliefs and opinions in this press release are forward-looking, which reflect the Company or, as appropriate, the Company directors current expectations and projections about future events. By their nature, forward-looking statements involve a number of risks, uncertainties and assumptions that could cause actual results or events to differ materially from those expressed or implied by the forward-looking statements. These risks, uncertainties and assumptions could adversely affect the outcome and financial effects of the plans and events described herein. A multitude of factors including, but not limited to, changes in demand, competition and technology, can cause actual events, performance or results to differ significantly from any anticipated development. Forward looking statements contained in this press release regarding past trends or activities should not be taken as a representation that such trends or activities will continue in the future. As a result, the Company expressly disclaims any obligation or undertaking to release any update or revisions to any forward-looking statements in this press release as a result of any change in expectations or any change in events, conditions, assumptions or circumstances on which these forward-looking statements are based. Neither the Company nor its advisers or representatives nor any of its subsidiary undertakings or any such persons officers or employees guarantees that the assumptions underlying such forward-looking statements are free from errors nor does either accept any responsibility for the future accuracy of the forward-looking statements contained in this press release or the actual occurrence of the forecasted developments. You should not place undue reliance on forward-looking statements, which speak only as of the date of this press release.

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Bone Therapeutics SA: Transparency notification received - GlobeNewswire

DISCUSSION QUESTION

What are the key factors that influence yourdecision making for third-line therapy?

PAOLO CAIMI, MD: What are the key factors that influence your decision in choice of regimen for patients who are in the third-line therapy? Any comments about the things that you use when youre thinking about how to salvage a patient with DLBCL who has relapsed after the first salvage treatment?

DEVA NATHAN, MD: The most important thing for third-linefor [patients around] 75 years old, I want to see what their performance status is going to be like.

CAIMI: I think the capacity to tolerate treatment [is an important factor], and particularly with the treatments weve had so far. If you want to give them a lot of chemotherapy, its a bit tough. I think my first consideration is: Is the patient going to tolerate what Im going to throw at them?

PRIYA KUMAR, MD: I think convenience and logistics are important, too.

CAIMI: At any age, but I think [especially] for older patients, I agree with you. I think thats becoming more and more important. A lot of our patients ask us to be close to home.

JULIE CHANG, MD: I really like tafasitamab [Monjuvi] and lenalidomide [Revlimid], but its not very convenient for patients, so thats been a big barrier for that as an option.

CAIMI: Because it has the weekly dosing, and then they go on to continue treatment for a long period of time, I think the other thing isat least in my experiencedoing 25 mg of lenalidomide makes it tough for patients who are over 70. I end up dose reducing for a significant number of patients.

LYLE GOLDMAN, MD: I think all therapy is very important, whether or not you are looking to do something aggressive, like CAR [chimeric antigen receptor] T-cell therapy, with a reasonably good chance of having complete response [CR], as opposed to just a palliative mode. So, I think that eligibility for CAR T-cell therapy is really important in this space.

CAIMI: Yes, I think thats a good point for discussion. Are you going to give them something that at least has more data indicating that you have long-term remissions, and potential for cure? The Kaplan-Meier curves in CAR T-cell therapy seem to flatten, although we see with some of the newer agents the durations of the responses are getting longer and longer. But, if you can be aggressive in a patient, almost regardless of age, depending on their functional status, that is something to bring up to the table. In a patient with poor functional status, which you worry about the adverse events [AEs], you worry about the logistics of CAR T cells; for them, the options and the discussion changes.

DIVIS KHAIRA, MD: I think that with the CAR T cells, the neurological AEs can be pretty significant. I think with the rest of the treatmentsfor example, lenalidomidethats a big wallet biopsy for some patients, not always covered. The intravenous therapies are always covered; the oral medications depend on the patients insurance, and with Medicare and secondary [insurance], it doesnt adequately cover a lot of the oral medications.

CAIMI: Its a great point, because we tend to be sold on oral therapies [as opposed to intravenous therapies] for patients. But, if its $10,000 a month, and they really dont have coverage, they dont want an oral therapy. They want something that they can come to the infusion center and get. The coverage is so much more beneficial to their side. So, even though the convenience of taking something at home is good, if you have to pay for it, its much harder. If it was cheaper, it would be easier.

KHAIRA: What we find is a lot of patients are too proud to say that they cant afford it, so they just decline the treatment.

CAIMI: Yes, its a good point. So, we talked about performance status, tolerability, cost, the convenience as well. I think that these regimens can be complex, in terms of how we administer them. I think tafasitamab/lenalidomide has that issue that it is so frequent, and actually never ends, at least with 1 of the components of it.

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Part 1: Choosing a Third-Line Treatment for Refractory DLBCL - Targeted Oncology

Despite advances in novel therapies, survival rates remain poor for patients with relapsed/refractory aggressive B-cell lymphoma who develop progressive disease following CD19-directed chimeric antigen receptor (CAR) T-cell therapy, according to a study conducted by Joanna C. Zurko, MD, and colleagues, and presented at the 2021 American Society of Hematology Annual Meeting.

This study consisted of 400 patients who received anti-CD19 CAR T-cell therapy between 2015 and 2020 across 12 U.S. academic medical centers. The investigators collated demographic and clinical characteristics of the study population along with CAR T-cell therapy toxicities and response. Univariate analyses were performed to determine the impact of demographic and clinical variables on survival outcomes, the researchers noted.

According to the results, in the entire cohort, median progression-free survival (PFS) and overall survival (OS) from time of CAR T-cell infusion were 11 months and 27 months, respectively. Analyses showed that patients who received three or more lines of therapy before CAR T-cell infusion and those with refractory disease pre-infusion had both markedly worse PFS (p = 0.004 and p = 0.001) and OS (both p < 0.001).

Results showed that at 22.4 months follow-up, almost half (48%) of patients had progressive disease following CAR T-cell therapy. The investigators noted that, of patients with progressive disease, median PFS and OS from time of disease progression was just 83 days in patients who received salvage therapy and 174 days for all patients, respectively.

Furthermore, the results showed that median PFS was highest for in patients treated with polatuzumab vedotin plus bendamustine-rituximab (4.5 months; n = 14), followed by bispecific antibodies (2.5 months; n = 8), lenalidomide with or without an anti-CD20 antibody (1.8 months; n = 13), checkpoint inhibitors (1.6 months; n = 10), BTK inhibitors (1.2 months; n = 8), radiation alone (1.2 months; n = 17), chemotherapy (1.1 months; n = 12), and tafasitamab plus lenalidomide (0.9 months; n = 5). The median PFS for all treated patients was 1.8 months.

Twelve patients in the study (6.3%) later received an allogeneic hematopoietic cell transplant (alloHCT), and 10 were evaluated for response. The results showed that seven achieved CR and five remain in CR.

AlloHCT remains a potential curative therapy for select patients with over half with durable remission; however, few ultimately received alloHCT, the researchers concluded. Despite increased use of novel therapies, survival in patients who progress after CAR T-cell therapy is still dismal warranting more effective therapies.

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Outcomes in Patients With Aggressive B-Cell Lymphoma With Progressive Disease Following CAR T-Cell Therapy - DocWire News

Despite the increase in relapse risk, 2-year survival for patients with graft-versus-host disease (GVHD) who received matched sibling donor (MSD) allogeneic hematopoietic cell transplant (allo-HCT) administered post-transplant cyclophosphamide remained similar compared with patients receiving cyclosporine A with methotrexate prophylactically.

The use of post-transplant cyclophosphamide appears to increase the risk of relapse without affecting graft-versus-host disease (GVHD) risk in patients with acute myeloid leukemia (AML) who undergo matched sibling donor (MSD) allogeneic hematopoietic cell transplantation (allo-HCT), according to a new study.

The report complicates the question of how best to prevent GVHD, since it raises questions about the impact of an increasingly common prophylaxis regimen. The report was published in the journal Transplantation and Cellular Therapy.

Allo-HCT from human leukocyte antigen (HLA)-matched siblings is the ideal choice for patients with AML, according to corresponding author Bhagirathbhai Dholaria, MBBS, of the Vanderbilt University Medical Center, and colleagues. Still, 30% to 40% of patients who receive MSD allo-HCT end up experiencing acute GVHD, which in turn is a major cause of mortality and morbidity, Dholaria and colleagues wrote.

The prophylactic combination of cyclosporine A with methotrexate (CSA/MTX) can reduce the risk of GVHD, compared with either drug alone. However, other prophylactic options are available, including the use of post-transplant cyclophosphamide (PTCy), which was first used in bone-marrow grafts and non-myeloablative allo-HCT from an HLA haploidentical (haplo) related donor.

PTCy promotes graft tolerance by facilitating selective proliferation of regulatory T cells (Treg) and reduces the risk of GVHD, Dholaria and colleagues wrote.

Previous reports have suggested PTCy can achieve similar GVHD-prevention results to other types of prophylaxis, but the investigators said it was not yet known whether such outcomes would be similar in other transplant settings.

Dholaria and colleagues used a data set from the European Society of Blood and Marrow Transplantation in order to compare the outcomes of 118 patients who were treated with PTCy and 1202 who were given CSA/MTX prior to transplantation. All of the patients received MSD allo-HCT for AML.

Investigators used a matched-pair analysis to evaluate outcomes between the 2 groups. They found 41.1% of patients in the PTCy cohort experienced relapse by 2 years, compared to just 21.3% in the CSA/MTX group.

On the other hand, 180-day grade II-IV acute GVHD rates were similar at 25.2% for the PTCy group and 25.4% in the CSA/MTX group. Two-year chronic GVHD rates were also similar, at 42.6% in both groups.

In this registry-based observational study of MSD allo-HCT in AML, the risk of acute and chronic GVHD after PTCy was comparable to that with CSA/MTX, the authors wrote. The results confirmed the significant impact of GVHD prevention strategy on allo-HCT outcomes.

The investigators noted that while PTCy appeared to be linked with a greater risk of relapse, that did not translate into a statistically significant gap in 2-year overall survival (70.6% in the PTCy group versus 79.7% in the CSA/MTX group). Two-year leukemia-free survival and GVHD-free relapse-free survival were similarly not significantly different.

Dholaria and colleagues said the question of why a higher relapse rate was observed requires more study to fully understand. They said their study is limited by its retrospective nature, and a prospective study with uniform conditioning and immunosuppressive regimens would be helpful to confirm findings.

Reference

Nagler A, Labopin M, Dholaria B, et al. Graft-versus-host disease prophylaxis with post-transplantation cyclophosphamide versus cyclosporine A and methotrexate in matched sibling donor transplantation. Transplant Cell Ther. Published online November 29, 2021. doi:10.1016/j.jtct.2021.11.013

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Study Examines Relapse Risk in GVHD After Allo-HCT Using 2 Therapy Options - AJMC.com Managed Markets Network

Abstract #

Type

Title

Authors

Presenting (PST)

2

Plenary Scientific Session

Primary Analysis of ZUMA-7: A Phase 3 Randomized Trial of Axicabtagene Ciloleucel (Axi-Cel) Versus Standard-of-Care Therapy in Patients with Relapsed/Refractory Large B-Cell Lymphoma

Lori A. Leslie

Sunday, December 12, 2021: 2:00 PM-4:00 PM

7

Oral

Sustained Improvements in Patient-Reported Quality of Life up to 24 Months Post-Treatment with LentiGlobin for Sickle Cell Disease (bb1111) Gene Therapy

Stacey Rifkin

Saturday, December 11, 2021: 9:30 AM-11:00 AM

50

Oral

A Large Multicenter Real-World Evidence (RWE) Analysis of Autoimmune (AI) Diseases and Lymphoma: Histologic Associations, Disease Characteristics, Survival, and Prognostication

Tatyana A. Feldman, Jason Lofters

Saturday, December 11, 2021: 9:45 AM

66

Oral

Oral Decitabine/Cedazuridine in Patients with Lower Risk Myelodysplastic Syndrome: A Longer-Term Follow-up of from the Ascertain Study

James K McCloskey

Saturday, December 11, 2021: 10:45 AM

93

Oral

Long-Term Follow-up Analysis of ZUMA-5: A Phase 2 Study of Axicabtagene Ciloleucel (Axi-Cel) in Patients with Relapsed/Refractory (R/R) Indolent Non-Hodgkin Lymphoma (iNHL)

Pashna N. Munshi, Lori A. Leslie,

Saturday, December 11, 2021: 10:00 AM

133

Oral

Brentuximab Vedotin Plus Cyclophosphamide, Doxorubicin, Etoposide, and Prednisone (CHEP-BV) Followed By BV Consolidation in Patients with CD30-Expressing Peripheral T-Cell Lymphomas

Tatyana A. Feldman, Lori A. Leslie

Saturday, December 11, 2021: 12:00 PM-1:30 PM

165

Oral

Impact of Molecular Features of Diffuse Large B-Cell Lymphoma on Treatment Outcomes with Anti-CD19 Chimeric Antigen Receptor (CAR) T-Cell Therapy

Andrew Ip, MD, Andre Goy

Saturday, December 11, 2021: 12:30 PM

184

Oral

A Multi-Center Retrospective Review of COVID-19 Outcomes in Patients with Lymphoid Malignancy

Lori A. Leslie

Saturday, December 11, 2021: 12:00 PM-1:30 PM

307

Oral

Post Hoc Analysis of Responses to Ponatinib in Patients with Chronic-Phase Chronic Myeloid Leukemia (CP-CML) By Baseline BCR-ABL1 Level and Baseline Mutation Status in the Optic Trial

James K McCloskey

Saturday, December 11, 2021: 4:00 PM-5:30 PM

395

Oral

A Phase 2 Study Evaluating the Addition of Ublituximab and Umbralisib (U2) to Ibrutinib in Patients with Chronic Lymphocytic Leukemia (CLL): A Minimal Residual Disease (MRD)-Driven, Time-Limited Approach

Lori A. Leslie

Sunday, December 12, 2021: 10:30 AM

548

Oral

Updated Clinical and Correlative Results from the Phase I CRB-402 Study of the BCMA-Targeted CAR T Cell Therapy bb21217 in Patients with Relapsed and Refractory Multiple Myeloma

David S. Siegel

Sunday, December 12, 2021: 4:30 PM-6:00 PM

561

Oral

Polyclonality Strongly Correlates with Biological Outcomes and Is Significantly Increased Following Improvements to the Phase 1/2 HGB-206 Protocol and Manufacturing of LentiGlobin for Sickle Cell Disease (SCD; bb1111) Gene Therapy (GT)

Stacey Rifkin-Zenenberg

Sunday, December 12, 2021: 4:30 PM-6:00 PM

622

Oral

Phase 2a Study of the Dual SYK/JAK Inhibitor Cerdulatinib (ALXN2075) As Monotherapy in Patients with Relapsed/Refractory Peripheral T-Cell Lymphoma

Feldman

Monday, December 13, 2021: 11:15 AM

623

Oral

Nanatinostat (Nstat) and Valganciclovir (VGCV) in Relapsed/Refractory (R/R) Epstein-Barr Virus-Positive (EBV+) Lymphomas: Final Results from the Phase 1b/2 VT3996-201 Study

Tatyana A. Feldman

Monday, December 13, 2021: 11:30 AM

651

Oral

Universal Updated Phase 1 Data Validates the Feasibility of Allogeneic Anti-BCMA ALLO-715 Therapy for Relapsed/Refractory Multiple Myeloma

David S. Siegel

Monday, December 13, 2021: 11:00 AM

691

Oral

Venetoclax in Combination with Gilteritinib Demonstrates Molecular Clearance of FLT3 mutation in Relapsed/Refractory FLT3-Mutated Acute Myeloid Leukemia

James McCloskey

Monday, December 13, 2021: 2:45 PM

744

Oral

Brexucabtagene Autoleucel for Relapsed/Refractory Mantle Cell Lymphoma: Real World Experience from the US Lymphoma CAR T Consortium

Andre H. Goy

Monday, December 13, 2021: 2:45 PM-4:15 PM

755

Oral

Standardizing the Diagnostic and Therapeutic Approach to Newly Diagnosed Children with ITP: An ITP Consortium of North America (ICON) Quality Improvement Initiative

Stacey Rifkin

Monday, December 13, 2021: 3:45 PM

1202

Poster 1

PK and PD Assessment of BET Inhibitor Pelabresib (CPI-0610) in Patients with Relapsed or Refractory Lymphoma: Findings from a Phase 1 Study

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John Theurer Cancer Center Investigators Present Pioneering Research at the American Society of Hematology Annual Conference - PRNewswire

HOUSTON, Dec. 9, 2021 /PRNewswire/ -- Marker Therapeutics, Inc.(NASDAQ: MRKR), a clinical-stage immuno-oncology company specializing in the development of next-generation T cell-based immunotherapies for the treatment of hematological malignancies and solid tumor indications, today announced the appointment of Katharine Knobil, M.D., to the Company's Board of Directors.

"We are excited to announce the appointment of Dr. Knobil to the Board of Directors," said Peter L. Hoang, President & CEO of Marker. "Dr. Knobil's extensive leadership experience in clinical development of new therapies, including 20 years of leadership at GlaxoSmithKline plc, will serve Marker well as the Company advances its novel cell therapies in the clinic. We look forward to Dr. Knobil's valuable counsel and expertise."

Dr. Knobil currently serves as Chief Medical Officer at Agilent Technologies, Inc. Prior to Agilent, she served as Chief Medical Officer and Head of Research and Development at Kaleido Biosciences, Inc. Previously, Dr. Knobil served in various leadership positions during a 20-year career at GlaxoSmithKline plc, before becoming Chief Medical Officer. Dr. Knobil received a B.A. in Biological Sciences from Cornell University and an M.D. from the University of Texas Southwestern. She currently serves on the Board of Directors of Arena Pharmaceuticals, Inc.

About Marker Therapeutics, Inc.

Marker Therapeutics, Inc. is a clinical-stage immuno-oncology company specializing in the development of next-generation T cell-based immunotherapies for the treatment of hematological malignancies and solid tumor indications. Marker's cell therapy technology is based on the selective expansion of non-engineered, tumor-specific T cells that recognize tumor associated antigens (i.e. tumor targets) and kill tumor cells expressing those targets. This population of T cells is designed to attack multiple tumor targets following infusion into patients and to activate the patient's immune system to produce broad spectrum anti-tumor activity. Because Marker does not genetically engineer its T cell therapies, we believe that our product candidates will be easier and less expensive to manufacture, with reduced toxicities, compared to current engineered CAR-T and TCR-based approaches, and may provide patients with meaningful clinical benefit. As a result, Marker believes its portfolio of T cell therapies has a compelling product profile, as compared to current gene-modified CAR-T and TCR-based therapies.

To receive future press releases via email, please visit: https://www.markertherapeutics.com/email-alerts.

View original content to download multimedia:https://www.prnewswire.com/news-releases/marker-therapeutics-appoints-biotech-executive-katharine-knobil-md-to-board-of-directors-301440745.html

SOURCE Marker Therapeutics, Inc.

Recent Stories You Might Have Missed

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Marker Therapeutics Appoints Biotech Executive Katharine Knobil, M.D., to Board of Directors - Tyler Morning Telegraph

By Paul Nicolaus

December 9, 2021 | A group of cell engineers and synthetic biologists at Harvard University and Massachusetts Institute of Technology (MIT) has developed a tech tool called eToeholds that could help improve the safety and efficacy of RNA and cell therapies, in addition to enabling new forms of detection.

The eToeholds are RNA-based sense-and-respond devices that only allow the expression of a linked protein-coding sequence when a particular cell-specific or viral RNA is present.

The researchers believe their line of work could help enhance therapeutic and diagnostic approaches in humans, plants, and other types of organisms. They also see potential as a basic research and synthetic biology tool.

In a recently publishedNature Biotechnologystudy (DOI:10.1038/s41587-021-01068-2), the researchers pointed out that their approach moves beyond existing RNA-based sensor systems by expanding the length and specificity of trigger sequences and enabling dose responsiveness to triggers of varying quantity.

Were at a very exciting time around harnessing RNA as a therapeutic molecule, senior author James Collins, a core faculty member at Harvards Wyss Institute for Biologically Inspired Engineering and professor of medical engineering & science at MIT, toldBio-IT World.

A key feature of the work detailed in this paper is that it demonstrates the capability of introducing control to RNA therapeutics, Collins explained. More specifically, it involves introducing a level of control that will enable RNA therapeutics to be used in a cell or tissue-specific wayvia lipid nanoparticles or gene therapy.

The next generation of life-saving drugs will be complicated, Evan Zhao, a research fellow at Harvards Wyss Institute and co-first author of the study, toldBio-IT World. There will be a need for scientists to design them in a way in which they are smart and capable of responding to their environments.

In this paper, Zhao said, he and colleagues put forth technology behind themessenger RNA (mRNA) vaccines that have emerged in response to the coronavirus pandemic.We give those technologies the capability to sense their surroundings and try to adapt their therapeutic capability after sensing their surroundings, he added.

Targeted Approach Looks to Reduce Unwanted Side Effects

Scientists have considered RNA as a biomaterial that could be used to come up with new forms of biomarkers, therapies, and (as the pandemic has shown) vaccinations.

A synthetic RNA molecule delivered into a cell essentially tells it to produce a particular protein for diagnostic, therapeutic, or other purposes. To steer clear of side effects, though, researchers have traditionally faced the tricky task of allowing only the cells that cause a diseaseor only the cells affected by itto express that protein.

In their study, the group noted that their capacity to initiate translation of a desired protein in response to the presence of cell-type-specific or cell-state-specific RNA transcripts has therapeutic potential considering many therapies are hindered by unwanted and potentially harmful side effects.

The ability of an eToehold module to translate a protein or protein-based precursor in response to an mRNA signature will help address this challenge by restricting activation of a desired therapy to specific target cells, they added.

A lot of therapy involving drug delivery runs the risk of off-target side effects, explained co-first author Angelo Mao, a technology development fellow at Harvards Wyss Institute.There is often a desire to deliver a drug to specific tissues or cells within the body without impacting other tissues or cells. But if the drug is active in different types of cells, it can cause ill health and sickness in patients.

One of the capabilities of the eToehold is that it prevents the creation of a therapeutic protein in non-target cells by reading the RNA thats present inside cells, he toldBio-IT World.

An aspect that makes the technology especially attractive is that it is so readily programmable, said Mao, while highlighting its flexibility and versatility. We can very easily design the eToehold to detect theoretically any RNA molecule that were interested in detecting, and also design it to produce any protein of interest that we want to produce, he added.

Wyss Founding Director Donald Ingber, a professor of vascular biology at Harvard Medical School and Boston Childrens Hospital and a Harvard professor of bioengineering, highlighted how this research could wind up positively impacting the lives of patients down the road.

The study shows how this research group is coming up with innovative tools that can advance the development of more specific, safe, and effective RNA and cellular therapies, hesaidin a press release announcing the research advance.

eToehold Potential Could Go Beyond Human Applications

The recently published study also highlighted the potential to extend the eToehold technology to organisms other than humans.

The researchers took internal ribosome entry site (IRES) elements and engineered them into devices that can be programmed to sense trigger RNAs in yeast and plant cells, in addition to human cells.

The proven functionality of eToeholds in multiple domains of eukaryotic life, including fungal, plant, and mammalian systems, suggests its potential for broad utility in biotechnology, the researchers pointed out.

In a plant, for example, the idea is that you could potentially program it to report on a pathogen infection, Collins said, or to both report and respond to it.

He explained that the first scenario would involve programming the plant to produce a detectable molecule that would indicate the plant had been infected. The latter scenario, on the other hand, would mean making a molecule that could be detected and producing molecules that could kill the infection or stop its growth.

Earlier Toehold Work Led Up to Latest Design

Years ago, Collins and colleagues came up with toeholds of a different sort. Detailed in a 2014 paper (DOI:10.1016/j.cell.2014.10.002), these bacterial toeholdsa different design with different applicationswere meant to function in bacterial cells and were extended to cell-free systems.

This earlier work garnered interest from academic groups and investors who were intrigued about applications in the diagnostic space and potentially the therapeutic space as well, Collins said.The interest in therapeutic applications was almost exclusively geared toward developing toeholds that could function in human cells.

Because the bacterial toehold design could not be tweaked or modified for use with more complex cells, however, it helped motivate and lead to eToeholdsan entirely new design.

In spirit, he said, the earlier toehold technology and the newer eToehold iteration are similar in that the researchers are pursuing synthetic biology designs for translational control. But a notable distinction is that eToeholds are geared toward eukaryotic cells.

The new design makes it possible to produce RNA elements that could function in human cells and turn on in the presence of RNA sequences of interest.

eToeholds Capable of Detecting Zika, SARS-CoV-2, and More

According to Zhao, he and colleagues forward-engineered IRES sequences by introducing complementary sequences that bind to one another and prevent the ribosome from binding the IRES.The hairpin loop-encoding sequence built into eToeholds is meant to overlap with specific sensor sequences that are complementary to trigger RNAs.

When present, the trigger RNA binds to its complement, the loop breaks open, and the ribosome can then switch on to produce the desired protein.

In their study, the group reached up to 16-fold induction of reporter genes linked to eToeholds in the presence of their trigger RNAs compared to control RNAs.

In other words, they can get a very large output in response to the detection or the trigger event to flip on the switch, Collins said.In response to an RNA produced by a specific cell type or associated with a pathogen infecting a particular cell type, they can get a substantial expression on the output of their RNA control element.

This is useful, he continued, because it means they can produce plenty of a reporter signal that could be read out in a diagnostic application or a lot of protein for use in a therapeutic application.

The eToeholds detected the presence of SARS-CoV-2 viral RNA in human cells as well as Zika virus infection. And other eToeholds are triggered by cell-specific RNAs, such as an RNA expressed only within skin cells that produce melanin.

Importantly, eToeholds and the sequences encoding desired proteins linked to them can be encoded in more stable DNA molecules, Mao explained.When introduced into cells, they are converted into RNA molecules geared toward the intended protein expression. This broadens the possibilities of delivering eToeholds to target cells, he added.

Envisioning the Next Generation of eToeholds

While the researchers foresee plenty of potential, they also acknowledged that their work isnt finished just yet. Currently, their technology does have limitations, and they intend to pursue improvements moving forward.

For instance, they are now looking to make it easier to program their eToeholds, and there are two primary components involved with this endeavor. The first involves developing as small of a module as possible that behaves as robustly as possible, said Zhao.

As the group continues to build their system, they are attempting to turn this initial iteration into a tool that a therapeutic designer could take and turn into something that significantly improves their therapy.

The other major component is geared toward moving beyond the current ability to sense just one transcript. Theres only really one knob that we can turn for each of these designs, he explained.

Zhao used the analogy of a vehicle to help illustrate. Its kind of like the ability to turn a car left or right. Although that ability is beneficial, theres still a desire to do more, such as accelerate or decelerate, when designing therapies. So they now have their sights set on adding other types of knobs.

Say you have a therapy that you want to turn on only in the presence of a small molecule or something that activates therapy, Zhao said. We are designing those things into the next generation of eToeholds.

The group plans to continue to build upon this line of work by seeing how they might alter and expand the control in terms of handling multiple RNA inputs and different ligands that can trigger RNA switches, Collins added. And moving forward, they are looking to extend their technology toward clinical implementation.

Paul Nicolaus is a freelance writer specializing in science, nature, and health. Learn more at http://www.nicolauswriting.com.

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Harvard and MIT Researchers Pursue Improved RNA and Cellular Therapies with eToehold Technology - Bio-IT World

Data on small, hypo-immune CRISPR systems show efficient edits in vivo in pre-clinical study

Novel gene editing systems are shown to enable efficient and specific edits in T cells, NK cells, and B cells

EMERYVILLE, Calif., December 08, 2021--(BUSINESS WIRE)--Metagenomi, a genetic medicines company with a versatile portfolio of next-generation gene editing tools, today announced that the company will share data related to their novel, compact, and hypo-immune gene editing systems at the 63rd Annual Meeting and Exposition of the American Society of Hematology (ASH), which is taking place in Atlanta, GA and virtually, December 1114.

"The development of CAR T therapies and other genetically engineered cell therapies in recent years has resulted in significant benefits for patients, yet there remains a large unmet need for gene editing systems that can be used to develop novel immunotherapy approaches to treat blood cancers," said Brian C. Thomas, PhD, CEO and Co-Founder of Metagenomi. "At ASH, we are presenting data on our novel nucleases that display highly efficient and specific gene editing both in vivo and ex vivo and hold significant potential to drive the development of new and efficacious therapies for patients."

In a poster titled "A Novel Type V CRISPR System with Potential for Genome Editing in the Liver," it is shown that Metagenomis novel Type V CRISPR-associated nuclease was highly active in the liver of mice when systemically administered via lipid nanoparticles (LNP). The nuclease was derived from a unique natural environment and is phylogenetically distinct from previously identified Type V systems. Moreover, no antibodies to the nuclease were detected in serum from 50 healthy human donors, while between one third and half of the same serum samples contained antibodies that bind to spCas9, which is derived from a Streptococcus bacteria that commonly infects humans. In summary, this novel Type V CRISPR-associated nuclease is a promising new gene editing system for in vivo editing of the liver.

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In a separate poster titled "Novel CRISPR-Associated Gene Editing Systems Discovered in Metagenomic Samples Enable Efficient and Specific Genomic Engineering for Cell Therapy Development," three novel gene editing systems were used to make reproducible and efficient edits to human immune cells, demonstrating utility for the next generation of cell therapy development for blood cancers. Metagenomis novel gene editing systems were used to disrupt the T cell receptor alpha-chain constant region and the T cell receptor beta-chain constant region in approximately 90 percent of cells. Beta-2 microglobulin was edited in 95 percent of T cells. A chimeric antigen receptor (CAR) construct was also shown to be integrated in up to 60 percent of T cells. Novel gene editing systems were deployed in NK cells to disrupt CD38 a cell surface immune modulator that can be targeted in the development of cancer immunotherapy and to integrate a CAR construct that led to robust CAR-directed cellular cytotoxicity. B cell editing occurred in approximately 80% of target cells with successful transgene integration. Whats more, as these gene editing systems are taken from environmental samples as opposed to human pathogens, pre-existing immunity is expected to be rare. In summary, these novel systems were shown to result in highly efficient and specific gene edits in human immune cells and display the potential for use in cell therapy development.

Details of the presentations are below:

Presentation Title: A Novel Type V CRISPR System with Potential for Genome Editing in the LiverSession Title: 801. Gene Therapies: Poster IPresenting Author: Morayma Temoche-Diaz, PhDPublication Number: 1862 Session Time: Saturday, December 11, 5:30 p.m. ET

Presentation Title: Novel CRISPR-Associated Gene-Editing Systems Discovered in Metagenomic Samples Enable Efficient and Specific Genome Engineering for Cell Therapy DevelopmentSession Title: 801. Gene Therapies: Poster IIIPresenting Author: Gregory Cost, PhD, Vice President of Biology, MetagenomiPublication Number: 3984 Session Time: Monday, December 13, 6:00 8:00 p.m. ET

About Metagenomi

Metagenomi is a gene editing company committed to developing potentially curative therapeutics by leveraging a proprietary toolbox of next-generation gene editing systems to accurately edit DNA where current technologies cannot. Our metagenomics-powered discovery platform and analytical expertise reveal novel cellular machinery sourced from otherwise unknown organisms. We adapt and forge these naturally evolved systems into powerful gene editing systems that are ultra-small, extremely efficient, highly specific and have a decreased risk of immune response. These systems fuel our pipeline of novel medicines and can be leveraged by partners. Our goal is to revolutionize gene editing for the benefit of patients around the world. For more information, please visit https://metagenomi.co/.

View source version on businesswire.com: https://www.businesswire.com/news/home/20211208005131/en/

Contacts

Metagenomi

Investor:Simon HarnestCIO, SVP Strategysimon@metagenomi.co (917) 403-1051

Media:Ashlye HodgeSr. Marketing and Communications Specialistashlye@metagenomi.co (510) 734-4409

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Metagenomi to Present Preclinical In Vivo and Ex Vivo Gene-Editing Data at the 63rd American Society of Hematology (ASH) Annual Meeting - Yahoo...

Sanford Health is continuing to explore the potential of orthobiologics and regenerative medicine with a study that may advance treatment for those living with osteoarthritis.

This trial known as ENDURE, which is run in full compliance with the FDA, will examine the safety and effectiveness of adult, adipose (fat)-derived stem cells.

Im really excited to get the trial started, said Donella Herman, M.D., a specialist in sports medicine at Sanford Health. Im even more excited about a year from now because I feel like were just going to learn so much about how effective this treatment is and what it is effective for.

Learn more: Orthopedics regenerative medicine at Sanford Health

Essentially, orthobiologics and regenerative medicine tap into the bodys natural healing ability.

Orthobiologics, a part of regenerative medicine, refers to the use of biological substances found in the body to help treat muscle and bone issues.

This may include injuries to muscles, tendons, and ligaments and as the focus of this trial more chronic conditions such as osteoarthritis.

When used properly by qualified providers, cell therapies are proving to be effective treatment options.

Our goals are to collect data for the different branches of orthobiologics, Dr. Herman said. Do people with knee osteoarthritis respond better with PRP (platelet rich plasma) or bone-marrow derived cells or fat-derived stem cells? Which works best? Which works for the longest time? Thats the kind of information were looking for. Its that kind of ratio that we just dont have right now.

One of the obstacles in regenerative medicine at this point, Dr. Herman said, is that its often being marketed by people with dubious clinical qualifications. They use underdeveloped research and make unfounded claims.

Its become a little bit of a wild, wild west with stem cells and PRP, Dr. Herman said. There are pop-up shops all over the place. Its one thing to have access to these things and allow access to people, but if youre not doing that in a responsible way and using that opportunity to build on a knowledge base, its kind of smoke and mirrors.

In sharp contrast to that scenario, this trial aims to add to the bank of knowledge in regenerative medicine.

We know we can tell people what were putting in their knee or their hip or their shoulder because were testing, Dr. Herman said. A lot of other places theyre just injecting it. They dont know if the stem cells are viable or not.

A typical candidate for the study, as described by Dr. Herman, might have osteoarthritis in their wrist and would not want to sacrifice a loss of motion that could come with surgery. They also would likely have exhausted the steroid injections treatment options that offer temporary relief.

We think of regenerative medicine as a possible alternative therapy that may help people put off surgery, Dr. Herman said. I dont ever tell people it means you will never need surgery but what it does is hopefully buy a little time until youre ready for that. There are lots of times where well do steroid injections until those fail and then they have to get a new joint. Were hoping for this to give us a bridge.

Once a patient is approved to be part of the ENDURE study, the procedure includes:

Follow-ups are then completed in person and over the phone.

Qualified candidates must be 18 or older and:

The cost associated with the study is not currently covered by insurance. By enrolling in the ENDURE study, however, participants may be playing a role in advancing regenerative cell research that could have the potential to improve care for future generations.

Those interested in hearing more about possible eligibility in the study can call (605) 328-3700.

Posted In Innovations, Orthopedics, Research, Specialty Care, Sports Medicine

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Sanford Health opens study of cell injections for arthritis - Sanford Health News