A Phase I Trial to Evaluate Allogeneic NKG2DL-targeting Chimeric Antigen Receptor-grafted γδ T Cells (CTM-N2D) in Subjects With Advanced Solid Tumours or Haematological Malignancies

CAR-T is a pioneering cancer treatment which has found success in some cancers. This treatment is made first by taking blood cells from the patient. Then in the lab, an artificial protein - a Chimeric Antigen Receptor (CAR), is grafted on the surface of immune cells. The modified cells, which are readministered to the patient, have enhanced abilities to target and destroy cancers than unmodified immune cells.
Currently approved CAR-T can only be used autologously. i.e. the patient will receive CAR-T treatment made from their own cells. This is because current CAR-T treatment uses αβ T cells - a type of immune cell which are largely non-transferable between individual human beings due to the high risk of Graft-versus-Host Disease. However, autologous CAR-T comes with many limitations. A lengthy, manufacturing process follows after the patient donates their own blood, accompanied by a high risk of manufacturing failure, which can be attributed to the cell quality from cancer patients undergoing stressful anti-cancer therapy.
CytoMed Therapeutics pioneers a new CAR-T treatment (CTM-N2D) which may confer some benefit over current CAR-T treatment. CTM-N2D uses a subtype of immune cell -- γδ T cell. Secondly, the CAR on CTM-N2D targets a surface antigen called NKG2DL which are commonly present in many cancer. These two features may confer a safer product profile, of better quality and may be efficacious in cancers where previous CAR-T treatments has not.
The phase I clinical trial of CTM-N2D will be conducted at the National University Hospital, Singapore. The objective of this clinical trial is to determine the optimal dose of CTM-N2D, and to investigate its safety and tolerability. The subjects of the clinical trial will also be investigated for their tumour response to CTM-N2D.
CTM-N2D has undergone preclinical studies. Relevant data from other clinical trials are also used to infer the expected outcome, and strategies of management of this clinical trial. The institution's ethical review board must give its approval before the study may begin. An independent Data Safety Monitoring Board monitors the safety aspect of this trial.

Start Date01 Apr 2022

Sponsor / Collaborator

CytoMed Therapeutics Ltd.

[+1]

NCT04107142 / Unknown statusPhase 1

A Phase I Dose-escalation Trial to Evaluate Haploidentical / Allogeneic Natural Killer Group 2D Ligand (NKG2DL)-Targeting Chimeric Antigen Receptor-grafted Gamma Delta (γδ) T Cells (CTM-N2D) in Subjects With Relapsed or Refractory Solid Tumour

This clinical trial is an open-label, single-centre, dose escalation, phase I study designed to investigate the safety and tolerability of Haploidentical / Allogeneic NKG2DL-targeting Chimeric Antigen Receptor-grafted Gamma Delta (γδ) T Cells (CTM-N2D) in Subjects with Relapsed or Refractory Solid Tumour. The study objectives of this phase I study are to determine the safety, activity and the safe dose of haploidentical or allogeneic NKG2DL-targeting chimeric antigen receptor-grafted γδ T cells given four times weekly in patients with relapsed or refractory solid tumors of different types.

Start Date01 Dec 2019

Sponsor / Collaborator

CytoMed Therapeutics Ltd.

100 Clinical Results associated with Anti-NKG2DL gamma delta CAR-T cell therapy (Cytomed Therapeutics)

100 Translational Medicine associated with Anti-NKG2DL gamma delta CAR-T cell therapy (Cytomed Therapeutics)

100 Patents (Medical) associated with Anti-NKG2DL gamma delta CAR-T cell therapy (Cytomed Therapeutics)

Literatures (Medical) associated with Anti-NKG2DL gamma delta CAR-T cell therapy (Cytomed Therapeutics)

01 May 2023·Immunology and cell biology

T cells engineered with full‐length NKG2D linked to signaling domains of 4‐1BB and CD3ζ show enhanced antitumor activity

Article

Author: Yang, Wenjun ; Teng, Xia ; Lu, Zheming ; Li, Shance ; Rong, Zhuona

Abstract:

Since NKG2D ligands (NKG2DLs) are primarily overexpressed on multiple types of solid tumors but absent on most normal tissues, NKG2DLs could be optimal antigens for CAR‐T cells. To date, there have been two types of NKG2DL CARs: (i) the extracellular domain of NKG2D fused to the CD8a transmembrane domain, signaling domains of 4‐1BB and CD3ζ (NKBz) and (ii) full‐length NKG2D fused to the CD3ζ signaling domain (chNKz). Although NKBz‐ and chNKz‐engineered T cells both showed antitumor activities, a comparison of their functions has not been reported. In addition, use of the 4‐1BB signaling domain into the CAR construct could prolong the persistence and resistance to antitumor activities of CAR‐T cells, we designed a new NKG2DL CAR, full‐length NKG2D fused to the signaling domains of 4‐1BB and CD3ζ (chNKBz). Among the two types of NKG2DL CAR‐T cells reported in previous studies, we found that chNKz T cells had stronger antitumor ability than NKBz T cells in vitro, but their antitumor activity in vivo is similar. The chNKBz T cells showed antitumor activity superior to that of chNKz T cells and NKBz T cells in vitro and in vivo, providing a new option for the immunotherapy of NKG2DL‐positive tumor patients.

Frontiers in immunologyQ2 · MEDICINE

Gamma-Delta CAR-T Cells Show CAR-Directed and Independent Activity Against Leukemia

Q2 · MEDICINE

ArticleOA

Author: Besser, Michal J ; Aharony, Yarden ; Bank, Ilan ; Schachter, Jacob ; Itzhaki, Orit ; Jacoby, Elad ; Rozenbaum, Meir ; Meir, Amilia

Autologous T cells engineered to express a chimeric antigen receptor (CAR) against the CD19 antigen are in the frontline of contemporary hemato-oncology therapies, leading to high remission rates in B-cell malignancies. Although effective, major obstacles involve the complex and costly individualized manufacturing process, and CD19 target antigen loss or modulation leading to resistant and relapse following CAR therapy. A potential solution for these limitations is the use of donor-derived γδT cells as a CAR backbone. γδT cells lack allogenecity and are safely used in haploidentical transplants. Moreover, γδT cells are known to mediate natural anti-tumor responses. Here, we describe a 14-day production process initiated from peripheral-blood mononuclear cells, leading to a median 185-fold expansion of γδ T cells with high purity (>98% CD3+ and >99% γδTCR+). CAR transduction efficacy of γδ T cells was equally high when compared to standard CAR-T cells (60.5 ± 13.2 and 65.3 ± 18.3%, respectively). CD19-directed γδCAR-T cells were effective against CD19+ cell lines in vitro and in vivo, showing cytokine production, direct target killing, and clearance of bone marrow leukemic cells in an NSG model. Multiple injections of γδCAR-T cells and priming of mice with zoledronate lead to enhanced tumor reduction in vivo. Unlike standard CD19 CAR-T cells, γδCAR-T cells were able to target CD19 antigen negative leukemia cells, an effect that was enhanced after priming the cells with zoledronate. In conclusion, γδCAR-T cell production is feasible and leads to highly pure and efficient effector cells. γδCAR-T cell may provide a promising platform in the allogeneic setting, and may target leukemic cells also after antigen loss.

News (Medical) associated with Anti-NKG2DL gamma delta CAR-T cell therapy (Cytomed Therapeutics)

15 Aug 2023

·www.biospace.com

CytoMed Therapeutics Announces China Research Collaboration to Enhance its Allogeneic CAR γD T In Vivo Persistency

The MOU signed by CytoMed and Hangzhou CNK Therapeutics Co., Ltd is the first of several collaborative efforts in North Asia. SINGAPORE, Aug. 15, 2023 /PRNewswire/ -- CytoMed Therapeutics Limited (NASDAQ: GDTC) ("CytoMed" or "Company"), a Singapore-based biopharmaceutical company focused on harnessing its proprietary technologies to develop novel donor-derived cell-based immunotherapies for the treatment of various cancers, announces today that it signed a Memorandum of Understanding (MOU) with Hangzhou CNK Therapeutics Co., Ltd (CNK). With this agreement, CytoMed can utilize CNK's PiggyBac technology to permanently graft the Chimeric Antigen Receptor (CAR) gene into its gamma delta (γδ) T cells via a non-viral gene editing method. "We are currently using mRNA technology whereby the CAR gene is transient, and hence, the CAR expression would cease after a period of time, leaving non-CAR γδ T cells in the patient's body," said Dr. Tan Wee Kiat, Chief Operating Officer of CytoMed. "The γδ T cells that remain continue to be cytotoxic with the ability to kill cancer cells. Leveraging CNK's technology, the CAR gene now would be expressed for as long as the γδ T cells are present in the body. This means that the CAR-γδ T cells can now exert a targeted attack for as long as it is present in the patient's body, potentially increasing the efficacy of our CAR γδ T cells in the patient." CytoMed was initially introduced to this opportunity by Professor Wang Shu, an advisor on the CytoMed Scientific Advisory Committee and co-inventor of the Company's CAR γδ T cell technology. Professor Wang Shu's deep understanding of cell therapy research, specifically CytoMed's technology, made it possible to discern the potential matching synergy between CytoMed and CNK's PiggyBac technologies. The MOU has a duration of one year, with the option to renew, and is subject to a definitive agreement and customary closing conditions. There remains a potential opportunity for a joint venture to conduct clinical trials in China. The signing ceremony took place on Tuesday, August 15 at the 17th Singapore-Zhejiang Economic and Trade Council Meeting. In attendance was Senior Minister of State for National Development and Foreign Affairs Sim Ann and Zhejiang Vice Governor Lu Shan. "Such strategic partnerships augment CytoMed's technology and bring us one step closer to our goal of advancing affordable, "off-the-shelf" allogeneic cellular immunotherapies for a broad spectrum of cancers," said Peter Choo, Chairman of CytoMed. "We look forward to continuing our growth with new and innovative partnerships." About CytoMed Therapeutics Limited (CytoMed) Incorporated in 2018, CytoMed was spun off from the Agency for Science, Technology and Research (A*STAR), Singapore's leading research and development agency in the public sector. It is a biopharmaceutical company focused on harnessing its licensed proprietary technologies to create novel cell-based immunotherapies for the treatment of human cancers. The development of novel technologies has been inspired by the clinical success of existing CAR-T therapies in treating hematological malignancies, as well as the current clinical limitations and commercial challenges in extrapolating the CAR-T principle into the treatment of solid tumors. For more information, please visit and follow us on Twitter @CytomedSG,on LinkedIn, and Facebook Forward Look Statements This press release contains forward-looking statements as defined by the Private Securities Litigation Reform Act of 1995. Forward-looking statements include statements concerning plans, objectives, goals, strategies, future events or performance, and underlying assumptions and other statements that are other than statements of historical facts. When the Company uses words such as "may, "will, "intend," "should," "believe," "expect," "anticipate," "project," "estimate" or similar expressions that do not relate solely to historical matters, it is making forward-looking statements. Forward-looking statements are not guarantees of future performance and involve risks and uncertainties that may cause the actual results to differ materially from the Company's expectations discussed in the forward-looking statements. These statements are subject to uncertainties and risks including, but not limited to, the following: the Company's plans to develop and commercialize its product candidates; the initiation, timing, progress and results of the Company's current and future pre-clinical studies and clinical trials and the Company's R&D programs; the Company's expectations regarding the impact of the ongoing COVID-19 pandemic on its business, the Company's industry and the economy; the Company's estimates regarding expenses, future revenue, capital requirements and needs for additional financing; the Company's ability to successfully acquire or obtain licenses for additional product candidates on reasonable terms; the Company's ability to establish and maintain collaborations and/or obtain additional funding and assumptions underlying or related to any of the foregoing and other risks contained in reports filed by the Company with the SEC. For these reasons, among others, investors are cautioned not to place undue reliance upon any forward-looking statements in this press release. Additional factors are discussed in the Company's filings with the SEC, which are available for review at . The Company undertakes no obligation to publicly revise these forward–looking statements to reflect events or circumstances that arise after the date hereof. Company Codes: NASDAQ-NMS:GDTC

ImmunotherapyCell Therapy

01 Aug 2023

·www.prnewswire.com

Chinese Patent Granted for A*STAR Spinoff, CytoMed Therapeutics' Licensed Allogeneic CAR-Gamma Delta T Cell Technology

The Company now has exclusive rights to a US and Chinese patent. SINGAPORE, Aug. 1, 2023 /PRNewswire/ -- CytoMed Therapeutics Limited (NASDAQ: GDTC) ("CytoMed" or "Company"), a Singapore-based biopharmaceutical company focused on harnessing its proprietary technologies to develop novel donor-derived cell-based immunotherapies for the treatment of various cancers, announced that the chimeric antigen receptor gamma delta T cell (CAR-γδ T cell) technology, which is exclusively licensed from the Agency for Science, Technology and Research (A*STAR), has been granted a patent by the China National Intellectual Property Administration (CNIPA). "With our first-in-human trial for CAR-γδ T cells set to begin in Singapore in the second half of 2023, and the recent successful recruitment of our first blood donor for the trial, we are especially thrilled to learn that our technology has received a Chinese patent," said Peter Choo, Chairman of CytoMed. "We have also started to seek partnerships in the vast China market." The patent titled "Gamma Delta T Cells and a Method of Augmenting the Tumoricidal Activity of the Same" covers technologies for the clinical-scale expansion of γδ T cells from a small amount of donor peripheral blood cells, as well as the modification of the expanded γδ T cells to incorporate a CAR that enables the modified cells to recognize a wide range of cancers, including both solid and hematologic cancers. Patent No. ZL201880023646.8, published as CN 110494558 B, is owned by A*STAR and exclusively licensed to the Company. The Company holds an exclusive, worldwide license, for use in immunotherapy, including stem cell therapy, until the expiration of the patent covering technology. The Company received approval in January 2023 from the Health Sciences Authority (HSA) in Singapore to conduct a Phase I clinical trial. The clinical trial, in partnership with the National University Hospital (NUH), Singapore has recruited its first blood donor. The donor blood will be used to manufacture allogeneic CAR-γδ T cells for the study. The cells will be processed in CytoMed's current PIC/S Good Manufacturing Practice (GMP) facility in Malaysia. The Phase I trial is expected to initiate in the second half of 2023. CytoMed's CAR-γδ T cell technology has been developed as an investigational cancer therapy to target NKG2D ligands, a type of stress-induced cancer antigens. The risk of "on-target-off-cancer" side effects may be reduced by targeting stress-induced antigens that are mainly expressed on cancer cells such as NKG2D ligands. The Company's other licensed technology from A*STAR is an induced pluripotent stem cell (iPSC)-based technology to derive a novel synthetic γδ NKT cells for the treatment of various types of cancers. A patent for this proprietary technology has already been granted in Japan, and this asset is under preclinical development. About CytoMed Therapeutics Limited (CytoMed) Incorporated in 2018, CytoMed was spun off from the Agency for Science, Technology and Research (A*STAR), Singapore's leading research and development agency in the public sector. It is a biopharmaceutical company focused on harnessing its licensed proprietary technologies to create novel cell-based immunotherapies for the treatment of human cancers. The development of novel technologies has been inspired by the clinical success of existing CAR-T therapies in treating hematological malignancies, as well as the current clinical limitations and commercial challenges in extrapolating the CAR-T principle into treatment of solid tumors. For more information, please visit and follow us on Twitter @CytomedSG,on LinkedIn, and Facebook About the Agency for Science, Technology, and Research (A*STAR) The Agency for Science, Technology and Research (A*STAR) is Singapore's lead public sector Research and Development (R&D) agency. Through open innovation, we collaborate with our partners in both the public and private sectors to benefit the economy and society. As a Science and Technology Organization, A*STAR bridges the gap between academia and industry. Our research creates economic growth and jobs for Singapore, and enhances lives by improving societal outcomes in healthcare, urban living, and sustainability. A*STAR plays a key role in nurturing scientific talent and leaders for the wider research community and industry. A*STAR's R&D activities span biomedical sciences to physical sciences and engineering, with research entities primarily located in Biopolis, Singapore, and Fusionopolis, Singapore. Forward Look Statements This press release contains forward-looking statements as defined by the Private Securities Litigation Reform Act of 1995. Forward-looking statements include statements concerning plans, objectives, goals, strategies, future events or performance, and underlying assumptions and other statements that are other than statements of historical facts. When the Company uses words such as "may, "will, "intend," "should," "believe," "expect," "anticipate," "project," "estimate" or similar expressions that do not relate solely to historical matters, it is making forward-looking statements. Forward-looking statements are not guarantees of future performance and involve risks and uncertainties that may cause the actual results to differ materially from the Company's expectations discussed in the forward-looking statements. These statements are subject to uncertainties and risks including, but not limited to, the following: the Company's plans to develop and commercialize its product candidates; the initiation, timing, progress and results of the Company's current and future pre-clinical studies and clinical trials and the Company's R&D programs; the Company's expectations regarding the impact of the ongoing COVID-19 pandemic on its business, the Company's industry and the economy; the Company's estimates regarding expenses, future revenue, capital requirements and needs for additional financing; the Company's ability to successfully acquire or obtain licenses for additional product candidates on reasonable terms; the Company's ability to establish and maintain collaborations and/or obtain additional funding and assumptions underlying or related to any of the foregoing and other risks contained in reports filed by the Company with the SEC. For these reasons, among others, investors are cautioned not to place undue reliance upon any forward-looking statements in this press release. Additional factors are discussed in the Company's filings with the SEC, which are available for review at . The Company undertakes no obligation to publicly revise these forward–looking statements to reflect events or circumstances that arise after the date hereof. Investor and Media Contacts Investors: Matt Hughes Allele Capital Partners [email protected] Media: Toni McLaughlin Allele Communications [email protected] SOURCE CytoMed Therapeutics

ImmunotherapyCell TherapyLicense out/inPhase 1

100 Deals associated with Anti-NKG2DL gamma delta CAR-T cell therapy (Cytomed Therapeutics)

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Indication	Highest Phase	Country/Location	Organization	Date
Advanced cancer	Phase 1	SG	CytoMed Therapeutics Ltd.	01 Apr 2022
Advanced Malignant Solid Neoplasm	Phase 1	SG	CytoMed Therapeutics Ltd.	01 Apr 2022
Hematologic Neoplasms	Phase 1	SG	CytoMed Therapeutics Ltd.	01 Apr 2022
Refractory Cancer	Phase 1	SG	CytoMed Therapeutics Ltd.	01 Apr 2022

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Anti-NKG2DL gamma delta CAR-T cell therapy (Cytomed Therapeutics)

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