CYAD-01 / Celdara Medical, Celyad Oncology - LARVOL DELTA

Identification and Functional Exploration of the ALKBH Gene Family in Oriental Melon Fruit Ripening. (PubMed, Int J Mol Sci) - "The transient overexpression (OE) of CmALKBH8 in oriental melon led to the increased expression of the ethylene synthesis genes CmACS1, CmACS2, and CmACO1. In summary, the ethylene-regulated gene CmALKBH8 may participate in oriental melon fruit ripening regulation by modulating the methylation levels of ethylene synthesis-related genes. These findings help us better understand how m6A methylation regulates melon ripening."

Journal • ACO1 • ALKBH7

Common polygenic variation in the early medication change (EMC) cohort affects disorder risk, but not the antidepressant treatment response. (PubMed, J Affect Disord) - "The present study confirms a polygenic contribution to MDD burden in the EMC patients. Larger GWAS with homogeneity in antidepressant treatments are needed to explore the genetic variation associated with ADR and realize the potential of PGS to contribute to specific response subtypes."

Journal • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry • CYP2C19

Chitosan-Derived Nanocarrier Polymers for Drug Delivery and pH-Controlled Release in Type 2 Diabetes Treatment. (PubMed, J Fluoresc) - "We loaded drug 1 and chromium phthalocyanine (CrPc) into folic acid-conjugated carboxymethyl chitosan (FA-CMCS) nanocarriers, forming FA-CMCS@1-CrPc...Additionally, due to its strong fluorescence performance, the nanomaterial demonstrated higher detection sensitivity, especially for monitoring the release of 5% trace drugs. An in vitro model of insulin-resistant cells was established to evaluate the effects of the drug delivery system on glucose degradation and AGE-RAGE regulation, providing a foundation for the development of new T2DM drugs."

Journal • Diabetes • Metabolic Disorders • Oncology • Prostate Cancer • Type 2 Diabetes Mellitus

Harbinger transposon insertion in ethylene signaling gene leads to emergence of new sexual forms in cucurbits. (PubMed, Nat Commun) - "Upon expression of CmACS11, EIN2 is recruited to repress the expression of the carpel inhibitor, CmWIP1...Characterization of a large collection of melon germplasm points to active transpositions in the wild, compared to cultivated accessions. Our study underscores the association between chromatin dynamics and the temporal aspects of mobile genetic element insertions, providing valuable insights into plant adaptation and crop genome evolution."

Journal

Hepatic Transarterial Administrations of NKR-2 in Patients With Unresectable Liver Metastases From Colorectal Cancer (clinicaltrials.gov) - P1 | N=1 | Terminated | Sponsor: Celyad Oncology SA | Unknown status ➔ Terminated; Difficulties in patient recruitment and clinical strategy modification based on new clinical data generated in the NKR-2 early development.

Trial termination • Colon Cancer • Colorectal Adenocarcinoma • Colorectal Cancer • Gastrointestinal Cancer • Hepatology • Oncology • Solid Tumor

Association Between Polygenic Scores for Lithium Response and Lithium Augmentation Outcomes in Unipolar Depression (WCPG 2023) - "We observed a significant positive association between LIR-PS and ΔHAMD (beta=-1.04 , CI=[-1.86,-0.23], p=0.012, R2=2.24%) but not between LIR-PS and categorical response (OR=1.11, CI=[0.87,1.41], p=0.414, NKR2 =0.32%) at a p-value threshold of PT=0.05. After excluding a subgroup with suboptimal lithium levels, LIR-PS was even stronger associated with symptom improvement during LA (beta=-1.23, CI=[-2.14,-0.32], p=0.008 at PT=0.05) explaining up to 3.16 % of variance in ΔHAMD. Although the discovery GWAS of lithium response in BD still has a modest sample size, our preliminary results suggest that LI-PS may also be useful in the prediction of LA outcomes in unipolar depression."

Bipolar Disorder • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

Identification of novel sex determination loci in Japanese weedy melon. (PubMed, Theor Appl Genet) - "The Opbf3.1 included the known sex determination gene CmACS11...This study suggests that Opbf3.1 and tpbf8.1 may promote the development of pistil and stamen primordia by inhibiting CmWIP1 and CmACS-7 functions, respectively, making the UT1 plants hermaphrodite. The results of this study provide new insights into the molecular mechanisms of sex determination in melons and considerations for the application of femaleness in melon breeding."

Journal

CYAD-01, an autologous NKG2D-based CAR T-cell therapy, in relapsed or refractory acute myeloid leukaemia and myelodysplastic syndromes or multiple myeloma (THINK): haematological cohorts of the dose escalation segment of a phase 1 trial. (PubMed, Lancet Haematol) - P1/2 | "Treatment with a multiple CYAD-01 infusion schedule without preconditioning is well tolerated and shows anti-leukaemic activity, although without durability outside of patients bridged to allogeneic HSCT. These phase 1 data support the proof-of-concept of targeting NKG2D ligands by CAR T-cell therapy. Further clinical studies with NKG2D-based CAR T-cells are warranted, potentially via combinatorial antigen targeted approaches, to improve anti-tumour activity."

CAR T-Cell Therapy • Journal • P1 data • P1 data • Acute Myelogenous Leukemia • Bone Marrow Transplantation • Hematological Disorders • Hematological Malignancies • Leukemia • Multiple Myeloma • Myelodysplastic Syndrome • Oncology • Transplantation • NKG2D

Overcoming target-driven fratricide for CAR-T cell therapy (SITC 2018) - P1/2; "The broad Phosphoinositol-3- Kinase inhibitor (LY294002) was added following the two-day transduction. CYAD-01 CAR T cells are currently part of the phase I THINK clinical trial (NCT03018405) where clinical objective responses have been observed. Conclusions These results indicate that target-driven fratricide can be overcome using clinically relevant approaches where technologies such as gene-editing may be more challenging."

CAR T-Cell Therapy • Oncology

Uncovering the phenotype, the functional and homing properties of NKG2D CAR T cells (SITC 2018) - P1/2; "Importantly, we are performing large scale investigation of patient material to investigate whether CYAD-01 cells can respond effectively to bone marrow chemokines and to understand if this feature is critical for the clinical responses seen to date in our THINK clinical trial. This will be presented during the conference."

CAR T-Cell Therapy • IO biomarker • Acute Myelogenous Leukemia • Oncology

Tackling fratricide to manufacture clinical grade NKG2D-CAR T cells for cancer therapy (ESMO 2018) - P1/2; "Background: T cells bearing a chimeric antigen receptor (CAR) T-cell consisting of the fusion of the NKG2D NK receptor with the intracellular domain of CD3zeta (CYAD-01) can recognize eight stress ligands expressed in a large variety of cancers... Inclusion of the PI-3K inhibitor LY294002 into the manufacturing process was the first strategy used as an initial effort focused upon blunting the activity of the CAR T cells... Together, these results indicate that when fratricide is an issue preventing clinical development, CAR T cells can be efficiently manufactured through PI-3K inhibition and antibody mediated receptor blockade."

CAR T-Cell Therapy • Clinical • Oncology

Phase 1 studies assessing the safety and clinical activity of multiple doses of a NKG2D-based CAR-T therapy, CYAD-01, in metastatic colorectal cancer (ESMO 2018) - P1, P1/2; "Finally, the boosting of the adaptive immune response by CYAD-01 might control distant lesions due to a possible abscopal effect. Both studies were initiated in 2018 and the first patients were successfully enrolled."

Clinical • IO biomarker • P1 data • Colorectal Cancer • Hepatocellular Cancer • Ovarian Cancer

MODELING NKG2D-BASED CAR-T CELL THERAPY IN ANIMALS WITH ACUTE MYELOID LEUKEMIA (EHA 2019) - P1/2; "...Celyad’s lead CAR-T product CYAD-01 is based on the full length human NKG2D fused to the intracellular domain of CD3ζ...This has been verified by the promising preliminary results from the Phase I THINK trial (NCT03018405). Importantly, the persistence of CAR-T cells in the peripheral blood differs between healthy mice and AML models which requires much further investigation."

CAR T-Cell Therapy • Preclinical

[VIRTUAL] First Results from the Dose Escalation Segment of the Phase I Clinical Study Evaluating Cyad-02, an Optimized Non Gene-Edited Engineered NKG2D CAR T-Cell Product, in Relapsed or Refractory Acute Myeloid Leukemia and Myelodysplastic Syndrome Patients (ASH 2020) - P1 | "Results As compared to CYAD-01, CYAD-02 cell expansion in vitro was 3-fold increased...The study evaluates three dose-levels of CYAD-02 (1x108, 3x108 and 1x109 cells/infusion), administered as a single infusion after non-myeloablative preconditioning chemotherapy (cyclophosphamide 300 mg/m²/day and fludarabine 30 mg/m²/day, daily for 3 days, CyFlu) according to a classical Fibonacci 3+3 design...This next generation NKG2D CAR T-cell product is currently investigated in the CYCLE-1 Phase I study in r/r AML/MDS patient population, a difficult to target disease due in part to the absence of truly AML-specific surface antigens, its rapid clinical progression and the absence of disease control by the CyFlu preconditioning. Both the anti-MICA and MICB shRNA hairpin and the OptimAb manufacturing process for CYAD-02 aim to improve CAR T-cell persistence and clinical responses."

CAR T-Cell Therapy • Clinical • P1 data • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • NKG2D

Phase 1 Studies Assessing the Safety and Clinical Activity of Multiple Doses of a NKG2D-Based CAR-T Therapy, Cyad-01, in Acute Myeloid Leukemia (ASH 2018) - P1, P1/2; "...The DEPLETHINK study (NCT03466320) aims at evaluating the CYAD-01 treatment administered after a cyclophosphamide and fludarabine preconditioning regimen to r/r AML patients...The EPITHINK study (EudraCT 2018-000745-39) aims at assessing the safety of the CYAD-01 treatment administered concurrently with SoC 5-azacytidine treatment in treatment-naïve AML pts ineligible for intensive treatment...Conclusion s: We have demonstrated the feasibility and safety of multiple injections of CYAD-01 without preconditioning chemotherapy (THINK). Preliminary safety, activity and correlative science data will be presented according a prior preconditioning (DEPLETHINK) and concurrent administration with SoC epigenetic treatment (EPITHINK)."

Clinical • P1 data • Acute Myelogenous Leukemia • Biosimilar • Hematological Disorders • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology

A phase I study assessing the safety and clinical activity of multiple doses of a NKG2D-based CAR-T therapy, CYAD-01, administered concurrently with the neoadjuvant FOLFOX treatment in patients with potentially resectable liver metastases from colorectal cancer (AACR 2018) - P1,P1/2; "...To address the challenge related to the immunosuppressive TME, the SHRINK trial (Standard cHemotherapy Regimen and Immunotherapy with NKR-2) has been developed to assess the safety and clinical activity of multiple infusion CYAD-01 treatment (every 2 weeks x 3 infusions) in patients undergoing standard-of-care FOLFOX (Folinic acid, Fluorouracil (5-FU) and Oxaliplatin) chemotherapy, as neoadjuvant treatment, for the treatment of colorectal metastatic disease with potentially resectable metastases (NCT03310008)...The expansion segment will then enroll 21 additional patients to further evaluate the safety and potential signs of activity of the CYAD-01 therapy when administered concurrently with chemotherapy. Peripheral blood samples, as well as tumor biopsies from patients at baseline and at resection, will be collected to determine, among others, CYAD-01 persistence, NKG2D ligand expression and systemic cytokine levels in peripheral blood post-infusion.

Clinical • IO Biomarker • P1 data • Colorectal Cancer • Hepatocellular Cancer

A phase I study assessing the safety and clinical activity of multiple hepatic transarterial administrations of a NKG2D-based CAR-T therapy CYAD-01, in patients with unresectable liver metastases from colorectal cancer (AACR 2018) - P1,P1/2; "Peripheral blood samples, as well as tumor biopsies will be collected to determine systemic CYAD-01 kinetics and within the liver tumor tissues, NKG2D ligand expression and systemic cytokine levels in peripheral blood post-infusion. This study will enroll 12 patients in case of no DLT and is open for recruitment."

Clinical • IO Biomarker • P1 data • Colorectal Cancer • Hepatocellular Cancer

[VIRTUAL] Results from the Phase I Clinical Studies Evaluating Cyad-01, a First-Generation NKG2D CAR T-Cell Product in Relapsed or Refractory Acute Myeloid Leukemia and Myelodysplastic Syndrome Patients (ASH 2020) - P1/2 | "To enhance CAR T-cell persistence, we evaluated a weekly dose schedule without preconditioning (THINK study) or the addition of cyclophosphamide and fludarabine (CyFlu) as a preconditioning regimen prior to CAR T-cell infusion (phase I DEPLETHINK study, NCT03466320). CYAD-01 manufactured using an optimized process, OptimAb, aims to improve CAR T-cell persistence and clinical responses. The data analysis of the same CAR-T product with different manufacturing processes, with or without preconditioning chemotherapy, will provide the medical community with clinical and scientific insights to guide the future of this therapeutic modality."

CAR T-Cell Therapy • Clinical • P1 data • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • IFNG • NKG2D

Celyad Oncology announces the publication of data from its Phase 1 THINK study of CYAD-01 (GlobeNewswire) - P1/2 | N=146 | THINK (NCT03018405) | Sponsor: Celyad Oncology SA | "Celyad Oncology...announces the publication of the data from the haematological arm of the THINK study which evaluated CYAD-01 in relapsed or refractory (r/r) acute myeloid leukaemia (AML) and myelodysplastic syndromes (MDS) or multiple myeloma (MM) patients....Overall, CYAD-01 showed favourable safety data with signs of clinical activity with three of the 12 evaluable AML/MDS patients presenting an objective response."

P1 data • Acute Myelogenous Leukemia • Hematological Malignancies • Multiple Myeloma • Myelodysplastic Syndrome • Oncology

CYAD-01, an autologous NKG2D-based CAR T-cell therapy, in relapsed or refractory acute myeloid leukaemia and myelodysplastic syndromes or multiple myeloma (THINK): haematological cohorts of the dose escalation segment of a phase 1 trial (Lancet Haematol) - P1/2 | N=146 | THINK (NCT03018405) | Sponsor: Celyad Oncology SA | "Between Feb 6, 2017, and Oct 9, 2018, 25 patients were registered in the haematological dose-escalation segment. Seven patients had manufacturing failure for insufficient yield and two had screening failure. 16 patients were treated with CYAD-01....No treatment-related deaths occurred, and the maximum tolerated dose was not reached. Three (25%) of 12 evaluable patients with relapsed or refractory acute myeloid leukaemia or myelodysplastic syndromes had an objective response. Among responders, two patients with acute myeloid leukaemia proceeded to allogeneic haematopoietic stem-cell transplantation (HSCT) after CYAD-01 treatment, with durable ongoing remissions (5 and 61 months)."

P1 data • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology

Co-Expression of an shRNA Targeting MICA/Micb Improves the Clinical Activity of a NKG2D-Based CAR T in Patients with Relapsed / Refractory AML/MDS (ASH 2021) - P1, P1/2 | "In clinical trials, CYAD-01 showed a good tolerability profile but with a disappointing level of clinical activity when combined with cyclophosphamide / fludarabine preconditioning (DEPLETHINK trial, NCT03466320)...The knockdown of MICA/MICB appears to have a positive contribution to the initial clinical activity of CYAD-02 as compared to that achieved with the first generation CYAD-01 CAR T, together with good safety and tolerability...One approach to further drive the potency of NKG2D-based CAR T cells would likely be armoring the CAR T through using the T cell as a vehicle to secrete cytokines alongside the CAR. Overall, shRNA knockdown technology provides a means to modify CAR T function and here shows that single shRNA can target two independent genes to enhance the phenotype of the CAR Ts."

Clinical • Acute Myelogenous Leukemia • Febrile Neutropenia • Hematological Disorders • Hematological Malignancies • Inflammation • Leukemia • Myelodysplastic Syndrome • Neutropenia • Oncology • IL15 • IL7 • NKG2D

A NKG2D-based CAR-T therapy in a multinational phase I dose escalation and expansion study targeting multiple solid and hematologic tumor types. (ASCO 2017) - P1; "The expansion segment will then enroll 96 additional patients in 7 separate cohorts for each indication with 3 steps of statistical analysis (overall futility, cohort futility and final evaluation). The study is open for recruitment in both EU and US."

P1 data • Acute Myelogenous Leukemia • Biosimilar • Bladder Cancer • Colorectal Cancer • Gynecologic Cancers • Inflammation • Myelodysplastic Syndrome • Pancreatic Cancer • Triple Negative Breast Cancer

Regulation of ethylene biosynthesis and signal transduction by nitric oxide leading to resistance against Alternaria alternata in Hami melon. (PubMed, J Sci Food Agric) - "The NO treatment enhanced postharvest disease resistance of Hami melon attacked by A.alternata possibly by postponing ethylene biosynthesis and signal transduction."

Journal

Characterization of Paeniclostridium sordellii Metalloproteinase-1 in vitro and in an experimental model of infection. (PubMed, Anaerobe) - "Similar to proteolytic virulence factors from other pathogens, Mcs1 is a promiscuous protease that cleaves multiple human-host factors. Despite minimal impact of Mcs1 on the murine model of P. sordellii infection, it is worth considering its role in humans and other animal models."

Journal • Preclinical • Infectious Disease • ICAM1 • VCAM1

The THINK clinical trial: Preliminary evidence of clinical activity of NKG2D chimeric antigen receptor T cell therapy (CYAD-01) in acute myeloid leukemia (AACR 2018) - P1/2; "Interestingly, even at this early stage of the evaluation, there is variation in the phenotype of the CYAD-01 cells (e.g. CD4/CD8 ratio) and an early observation of a relative increase in the systemic levels of SDF-1 and RANTES in the patient who achieved MLFS. In summary, we report the first objective response to CAR-T in r/r AML using CYAD-01 without preconditioning chemotherapy and with no significant toxicities, highlighting the potential of targeting NKG2D ligands in AML."

CAR T-Cell Therapy • Clinical • IO biomarker • Acute Myelogenous Leukemia • Multiple Myeloma • Myelodysplastic Syndrome • Pancreatic Cancer