nature.com

31 Katy Rezvani light green

Safety, efficacy and determinants ofresponse of allogeneic CD19-specific CAR-NKcells in CD19+ B cell tumors: a phase 1/2 trial

•	Phase 1/2 clinical study of NY-ESO-1 TCR/IL-15 NK for relapsed or refractory multiple myeloma commences on track

•	NY-ESO-1 TCR/IL-15 NK is the lead clinical program of Syena, a Replay and MD Anderson cell therapy company based on the scientific discoveries of Professor Katy Rezvani, M.D., Ph.D.

•	Syena is Replay’s first product company to enter clinical development

__San Diego, California, London, UK, and Houston, Texas, March 11, 2024__ – Replay, a genome writing company reprogramming biology by writing, designing, and delivering big DNA, today announced that the first patient has been dosed in the Phase 1/2 study of NY-ESO-1 TCR/IL-15 NK, an engineered T-Cell Receptor Natural Killer (TCR-NK) cell therapy for relapsed or refractory multiple myeloma. 

NY-ESO-1 TCR/IL-15 NK is being developed by Syena, an oncology-focused product company [launched](https://replay.bio/news/kkr-backed-replay-and-md-anderson-form-syena) by Replay and The University of Texas MD Anderson Cancer Center,, based on the scientific discoveries of [Katy Rezvani, MD, PhD](https://faculty.mdanderson.org/profiles/katy_rezvani.html), Professor of [Stem Cell Transplantation & Cellular Therapy](https://www.mdanderson.org/research/departments-labs-institutes/departments-divisions/stem-cell-transplantation.html) at MD Anderson. Syena has an exclusive licensing agreement for MD Anderson’s TCR-NK technology platform. This first-in-class engineered cell therapy comprises cord blood-derived natural killer cells that express an affinity-enhanced TCR targeted against the NY-ESO-1 antigen. NY-ESO-1 is highly immunogenic and expressed on numerous cancer cell types. The ability of NY-ESO-1 to elicit humoral and cellular immune responses along with its restricted tissue expression makes it a compelling target for cancer immunotherapy. 

The Phase 1/2 clinical study will assess the safety and efficacy of NY-ESO-1 TCR/IL-15 NK in patients with relapsed or refractory multiple myeloma. It will be administered following lymphodepletion with standard doses of fludarabine/cyclophosphamide (Flu/Cy). The study will enrol up to 44 patients in total.

__Adrian Woolfson, Executive Chairman, President, and Co-Founder of Replay, said:__ “The dosing of the first patient in Syena’s NY-ESO-1 TCR-NK clinical study represents a major step forward in addressing the significant unmet medical need for ‘off-the-shelf’ cell therapies. I am delighted with the rapid progress that we have made to date. NY-ESO-1 is highly expressed in poor-prognosis multiple myeloma, making this a suitable indication for demonstrating proof of concept for Syena’s TCR-NK technology platform. We believe that the use of optimally selected cord blood donors is likely to translate into improved patient outcomes. We are grateful to the patients, clinical sites, and development teams for their ongoing commitment and efforts to advance this new technology into the clinic.”

__Lachlan MacKinnon, CEO and Co-Founder of Replay, commented:__ “This Phase 1/2 clincial study will be key to further understanding the potential of our TCR-NK platform, with Syena making significant strides towards delivering its pioneering first-in-class TCR-NK cell therapy to patients with relapsed or refractory multiple myeloma. We look forward to enrolling further patients and evaluating the safety and efficacy outcomes as the study progresses.”

For more information please visit [ClinicalTrials.gov](https://clinicaltrials.gov/study/NCT06066359?term=NY-ESO-1%20TCR%2FIL-15%20NK&rank=1) and reference identifier NCT06066359.

__Ends__

__About Replay__
Replay is a genome writing company, which aims to define the future of genomic medicine through reprogramming biology by writing, designing, and delivering big DNA. The Company has assembled a toolkit of disruptive platform technologies — including a high payload capacity HSV delivery platform — to address the challenges currently limiting clinical progress and preventing genomic medicine from realizing its potential. 

The Company’s hub-and-spoke business model separates technology development within Replay from therapeutic development in a portfolio of product companies that leverage its technology platforms. The Company recently incorporated a first-in-class engineered TCR-NK cell therapy product company, Syena, using technology developed by Katy Rezvani, MD, PhD, at The University of Texas MD Anderson Cancer Center in Houston, Texas. Replay’s synHSV™ technology, a high payload capacity HSV vector capable of delivering up to 30 times the payload of AAV, is used by Replay’s gene therapy product companies, bringing big DNA treatments to monogenic diseases impacting the skin, and eye. Replay is led by a distinguished team of academics, entrepreneurs, and industry experts. 

The Company has raised $85 million to date and is supported by an international syndicate of investors including: KKR, OMX Ventures, ARTIS Ventures, Lansdowne Partners and the Bill and Melinda Gates Foundation. 

Replay is headquartered in San Diego, California. For further information please visit www.replay.bio and follow us on LinkedIn and Twitter.  

__About NY-ESO-1 TCR/IL-15 NK__
NY-ESO-1 TCR/IL-15 NKs are adoptive Natural Killer (NK) cells expressing an affinity-enhanced T-cell receptor (TCR) directed against NY-ESO-1-specific cord blood-derived NK cells. The cells are engineered to express the CD3 and TCR signalling complex and IL-15, and use the same manufacturing method as engineered CAR-NKs, which have demonstrated safety and efficacy in lymphoma (Liu et al, NEJM 2020 and Marin et al Nature Medicine 2024). 

NY-ESO-1 (New York Esophageal Squamous cell carcinoma 1) is an cancer-testis antigen with re-expression in multiple cancer types, and restricted expression in healthy tissues. This expression pattern and its ability to elicit humoral and cellular immune responses makes it a compelling target for TCR-T cell therapy. TCR-engineered NK cells retain their capacity to target tumor cells through their native receptors. The ability of NK cells to target tumor cells that down-regulate or lack MHC through the ‘missing self’ mechanism, may make disease escape through the most common mechanism of acquired resistance, less likely. IND-enabling studies have confirmed that NY-ESO-1 TCR/IL-15 NK cells do not kill healthy human cell lines derived from organs including the heart, lungs, liver, and kidneys. 

__Contacts:__

__Replay__

Dr. Adrian Woolfson/Lachlan MacKinnon

info@replay.bio

__ICR Consilium – media relations__

Amber Fennell/Tracy Cheung/David Daley 

replay@consilium-comms.com 


Syena

Replay’s cell therapy product company Syena announces first patient dosed in Phase 1/2 study of TCR-NK cell therapy for multiple myeloma

GEN Biotechnology

Portrait Adrian Woolfson Bright green Background

Defining the Rules of Biology in the Age of Genome Writing

•	Syena secures exclusive license to Miltenyi Biotec’s PRAME TCR

•	Syena, co-founded by Replay and MD Anderson in 2023, will develop an off-the-shelf PRAME TCR-NK cell therapy, with IND anticipated Q1 2024

•	Miltenyi Biotec to supply scalable, GMP-compliant, PRAME-targeted TCR-NK cell therapy product using the CliniMACS Prodigy® system for clinical development and future commercial supply 

__San Diego, California; London, UK and Bergisch Gladbach, Germany, December 18, 2023__ – Replay, a genome writing company reprogramming biology by writing, designing and delivering big DNA, and Miltenyi Biotec, a global provider of products and services for biomedical research and cellular therapy, today announced a licensing and manufacturing agreement to support the development of a GMP-compliant T-cell receptor (TCR) natural killer (NK) cell therapy targeting the tumor-associated neoantigen, PRAME. 

Under the terms of the agreement, Syena, the oncology-focused engineered cell therapy product company launched jointly by Replay and The University of Texas MD Anderson Cancer Center in February 2023, has secured an exclusive license to Miltenyi Biotec’s PRAME (PReferentially expressed Antigen in MElanoma) TCR. Miltenyi Biotec will use its CliniMACS Prodigy® closed and automated cell processing platform to manufacture a scalable, GMP-compliant, PRAME-targeted, TCR-NK cell therapy product for clinical development and provision of future commercial supply. 

PRAME has been extensively investigated by researchers as a target for cancer immunotherapy. It is highly expressed across a broad range of tumor types and has minimal expression in healthy tissue. It is the second validated cancer neoantigen to be targeted by Syena, which is creating the next generation of off-the-shelf cell therapies combining the safety, tolerability, efficacy, and scalability of NK cells with the ability of TCRs to target intracellular tumor antigens. The Company’s first target, NY-ESO-1, is being investigated in relapsed or refractory multiple myeloma, synovial sarcoma, and myxoid/round cell liposarcoma. Following two recent IND clearances, the Phase I/II clinical studies are anticipated to commence in Q4 of this year. 

__Adrian Woolfson, Executive Chairman, President and Co-Founder of Replay, said:__ “PRAME is an extensively validated target for immunotherapy in both solid tumors and hematological malignancies. It comprises a compelling addition to our expanding portfolio of targets for our first-in-class engineered TCR-NK cord blood derived cell therapies. We are, additionally, delighted to have Syena partner with Miltenyi Biotec at this early stage to use their CliniMACS Prodigy® cell manufacturing system to lock down our GMP commercial supply.” 

__Lachlan MacKinnon, CEO and Co-Founder of Replay, said:__ “Miltenyi Biotec’s extensive expertise and manufacturing capabilities will enable us to swiftly advance the clinical development of our cell therapy programs by providing a GMP-grade, commercial-scale supply of cell therapy products. This agreement demonstrates our confidence in our off-the-shelf TCR-NK therapies against a target with significant medical and commercial potential.”

__Dr Boris Stoffel, Managing Director and Member of the Executive Board of Miltenyi Biotec, said:__ “At Miltenyi Biotec, we bring over 30 years of expertise in developing innovative products and solutions for cell and gene therapy and biomedical research. In line with our mission to advance cell therapies to treat patients with cancer and other serious diseases, we’re excited to collaborate with Replay and the Syena team on their GMP-compliant PRAME TCR-NK cell therapy product.”

__Ends__

__About Replay__

Replay is a genome writing company, which aims to define the future of genomic medicine through reprogramming biology by writing and delivering big DNA. The Company has assembled a toolkit of disruptive platform technologies — including a high payload capacity HSV platform, a hypoimmunogenic cell therapy platform, and a genome writing platform — to address the challenges currently limiting clinical progress and preventing genomic medicine from realizing its potential. 

The Company’s hub-and-spoke business model separates technology development within Replay from therapeutic development in a portfolio of product companies that leverage its technology platforms. For example, the Company recently incorporated a first-in-class engineered TCR-NK cell therapy product company using technology developed by Katy Rezvani, MD, PhD, at The University of Texas MD Anderson Cancer Center in Houston, Texas. Replay’s synHSV™ technology, a high payload capacity HSV vector capable of delivering up to 30 times the payload of AAV, is utilized by Replay’s four gene therapy product companies, bringing big DNA treatments to diseases affecting the skin, eye, brain, and muscle. Replay is led by a distinguished team of academics, entrepreneurs, and industry experts. 

The Company raised $55 million in seed financing in July 2022 and is supported by an international syndicate of investors including: KKR, OMX Ventures, ARTIS Ventures, and Lansdowne Partners. 

Replay is headquartered in San Diego, California. For further information please visit www.replay.bio and follow us on LinkedIn and X/Twitter.  

__About Miltenyi Biotec__

Miltenyi Biotec is a global leader innovating products and services that empower biomedical research and advance cellular therapy. The company's solutions support all stages of cell and gene therapy product development from process and analytical development to commercial-scale manufacturing. Its platform technologies have set industry standards in automated, integrated manufacturing and analysis of complex cellular products such as CAR-T cells, TCR-T cells, gene-modified NK and stem cells. Miltenyi Biotec’s comprehensive product portfolio is complemented by CDMO services for lentiviral vectors and cell manufacturing. The company has more than 4,700 employees in 23 countries and its products have been used in more than 100,000 cell therapy procedures.

Miltenyi Bioindustry, as a division of Miltenyi Biotec, uses its end-to-end expertise towards developing and manufacturing lentiviral vectors and cell and gene therapy products based on the CliniMACS Prodigy® fully automated cell manufacturing platform – from pre-clinical to commercial scale.

Miltenyi Biotec is headquartered in Bergisch Gladbach, Germany. For further information please visit www.miltenyibiotec.com and follow us on LinkedIn and X/Twitter.

__Contacts:__

__Replay__
Dr Adrian Woolfson/Lachlan MacKinnon
info@replay.bio

__Miltenyi Biotec B.V. & Co. KG – Corporate Communications__
Kim Münster
corpcom@miltenyi.com

__ICR Consilium – Media relations__
Amber Fennell/Tracy Cheung/David Daley
replay@consilium-comms.com 


Replay’s oncology-focused product company Syena and Miltenyi Biotec enter into exclusive licensing and GMP manufacturing agreement for PRAME TCR-NK cell therapy based on CliniMACS Prodigy®

Home Page Hero

Home Page Applications 1-150kb

Replay Bio Construct Illustration

- Write and deliver big genes, genomic genes, or multiple genes 
- Complex regulatory elements 
- Address polygenic medicine

Home Page Applications In Vivo

- Deliver DNA to autologous, allogeneic, and iPSC-derived cell therapies
- Write and install large constructs to replace multiplex editing 
- Potential to multiplex CARs and TCRs

Home Page Applications Ex Vivo

Engineering T-Cell Receptors into Natural Killer cells 

Home Page Applications 150kb-10Mb

- Off-the-shelf
- Cord-blood derived
- Developed by NK pioneer Professor Katy Rezvani 

Home Page Applications 150kb-10MB

Authoring the next generation of genomic medicines, leveraging high payload delivery & cord-blood derived NK cells.

Replay’s cell therapy product company Syena announces first patient dosed in Phase 1/2 study of TCR-NK cell therapy for multiple myeloma

Latest news

Safety, efficacy and determinants ofresponse of allogeneic CD19-specific CAR-NKcells in CD19+ B cell tumors: a phase 1/2 trial

Replay’s cell therapy product company Syena announces first patient dosed in Phase 1/2 study of TCR-NK cell therapy for multiple myeloma

Defining the Rules of Biology in the Age of Genome Writing

Replay’s oncology-focused product company Syena and Miltenyi Biotec enter into exclusive licensing and GMP manufacturing agreement for PRAME TCR-NK cell therapy based on CliniMACS Prodigy®