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Celyad Oncology announces the publication of the preclinical and clinical data of CYAD-211 providing proof-of-concept of its miRNA-based shRNA platform

Mont-Saint-Guibert, Belgium; February 18, 2025, 7:00 am CET – Celyad Oncology (Euronext: CYAD) (the “Company”), today announces the publication of the preclinical data of the non-gene edited allogeneic CYAD-211 and clinical data from the Phase I IMMUNICY-1 clinical study which evaluated CYAD-211 in relapsed or refractory (r/r) multiple myeloma (MM) patients. The findings were published in the International Journal of Molecular Science (IJMS).

CYAD-211 is the Company’s first allogeneic chimeric antigen receptor (CAR) T-cell candidate, engineered to co-express a B-cell maturation antigen (BCMA)-specific CAR and a microRNA-based single shRNA which interferes with the expression of the CD3ζ component of the T-cell receptor (TCR) complex, evaluated clinically.

The IJMS publication includes preclinical data which showcases the knockdown of CD3ζ efficiently removed the TCR complex from the cell surface, and inhibited TCR mediated activation in vitro and in vivo. The publication also presents clinical data of the dose-escalation segment of the IMMUNICY-1 phase-I clinical trial (NCT04613557) in patients with r/r MM.  Importantly, data highlighted an overall good safety profile and some clinical responses, with no signs of graft-versus-host disease (GvHD), demonstrating the effectiveness and safeness of the technology to abrogate the risk of GvHD.

Overall, these data provides the proof-of-concept of the safe administration of CAR T-cells engineered using a miRNA-based shRNA technology. CYAD-211 is the first allogeneic CAR T-cell candidate using a non-gene edited approach to achieve allogenicity. This differentiated strategy provides key advantages by being easily implemented, safe, efficient, tunable, and with the possibility to modulate multiple target genes simultaneously.

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Celyad Oncology published a review in ‘Frontiers in Immunology’ – Engineering strategies to safely drive CAR T-cells into the future

Abstract: Chimeric antigen receptor (CAR) T-cell therapy has proven a breakthrough in cancer treatment in the last decade, giving unprecedented results against hematological malignancies. All approved CAR T-cell products, as well as many being assessed in clinical trials, are generated using viral vectors to deploy the exogenous genetic material into T-cells. Viral vectors have a long-standing clinical history in gene delivery, and thus underwent iterations of optimization to improve their efficiency and safety. Nonetheless, their capacity to integrate semi-randomly into the host genome makes them potentially oncogenic via insertional mutagenesis and dysregulation of key cellular genes. Secondary cancers following CAR T-cell administration appear to be a rare adverse event. However several cases documented in the last few years put the spotlight on this issue, which might have been underestimated so far, given the relatively recent deployment of CAR T-cell therapies. Furthermore, the initial successes obtained in hematological malignancies have not yet been replicated in solid tumors. It is now clear that further enhancements are needed to allow CAR T-cells to increase long-term persistence, overcome exhaustion and cope with the immunosuppressive tumor microenvironment. To this aim, a variety of genomic engineering strategies are under evaluation, most relying on CRISPR/Cas9 or other gene editing technologies. These approaches are liable to introduce unintended, irreversible genomic alterations in the product cells. In the first part of this review, we will discuss the viral and non-viral approaches used for the generation of CAR T-cells, whereas in the second part we will focus on gene editing and non-gene editing T-cell engineering, with particular regard to advantages, limitations, and safety. Finally, we will critically analyze the different gene deployment and genomic engineering combinations, delineating strategies with a superior safety profile for the production of next-generation CAR T-cell.

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Schematic illustration of different gene delivery methods. Methodologies are divided into in vivo, ex vivo viral and ex vivo non-viral methodologies. Lentiviruses, retroviruses and transposons all are incorporated into the genome, and lead to stable CAR expression (upper half). In contrast, AAV LNP/Nanocarriers and mRNA all lead to transient CAR expression (lower half).

Celyad Oncology published a review in ‘Cells’ – Allogeneic CAR-T Therapy Technologies: Has the Promise Been Met?

Abstract: This last decade, chimeric antigen receptor (CAR) T-cell therapy has become a real treatment option for patients with B-cell malignancies, while multiple efforts are being made to extend this therapy to other malignancies and broader patient populations. However, several limitations remain, including those associated with the time-consuming and highly personalized manufacturing of autologous CAR-Ts. Technologies to establish “off-the-shelf” allogeneic CAR-Ts with low alloreactivity are currently being developed, with a strong focus on gene-editing technologies. Although these technologies have many advantages, they have also strong limitations, including double-strand breaks in the DNA with multiple associated safety risks as well as the lack of modulation. As an alternative, non-gene-editing technologies provide an interesting approach to support the development of allogeneic CAR-Ts in the future, with possibilities of fine-tuning gene expression and easy development. Here, we will review the different ways allogeneic CAR-Ts can be manufactured and discuss which technologies are currently used. The biggest hurdles for successful therapy of allogeneic CAR-Ts will be summarized, and finally, an overview of the current clinical evidence for allogeneic CAR-Ts in comparison to its autologous counterpart will be given.

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Celyad Oncology published in Molecular Therapy – Nucleic Acids a manuscript detailing our proprietary microRNA (miRNA)-based multiplex shRNA platform

Genome engineering technologies are powerful tools in cell-based immunotherapy to optimize or fine-tune cell functionalities. However, their use for multiple gene edits poses relevant biological and technical challenges. Short hairpin RNA (shRNA)-based cell engineering bypasses these criticalities and represents a valid alternative to CRISPR-based gene editing. Here, we describe a microRNA (miRNA)-based multiplex shRNA platform obtained by combining highly efficient miRNA scaffolds into a chimeric cluster, to deliver up to four shRNA-like sequences. Thanks to its limited size, our cassette could be deployed in a one-step process along with all the CAR components, streamlining the generation of engineered CAR T cells. The plug-and-play design of the shRNA platform allowed us to swap each shRNA-derived guide sequence without affecting the system performance. Appropriately choosing the target sequences, we were able to either achieve a functional KO, or fine-tune the expression levels of the target genes, all without the need for gene editing. Through our strategy we achieved easy, safe, efficient, and tunable modulation of multiple target genes simultaneously. This approach allows for the effective introduction of multiple functionally relevant tweaks in the transcriptome of the engineered cells, which may lead to increased performance in challenging environments, e.g., solid tumors.

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Celyad Oncology announces the publication of data from its Phase 1 THINK study of CYAD-01

Mont-Saint-Guibert, Belgium – Celyad Oncology (Euronext & Nasdaq: CYAD) (the “Company”), a biotechnology company focused on the discovery and development of innovative technologies for chimeric antigen receptor (CAR) T-cell therapies, today 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. The findings were published in the journal The Lancet Haematology.

CYAD-01 is the Company’s first autologous CAR T-cell candidate, based on the natural killer receptor NKG2D, assessed clinically. The completed THINK study was an open-label, dose-escalation Phase 1 study for patients with r/r AML, MDS, or MM, after at least one previous line of therapy. Patients were recruited from five hospitals in the USA and Belgium.

The Lancet Haematology publication includes data from the 16 patients treated with CYAD-01 in the dose escalation segment of the study, which evaluated three dose levels of CYAD-01 using a schedule of three infusions at two-week intervals in the absence of any preconditioning chemotherapy. 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.

Importantly, the THINK study is one of the first completed dose-escalation CAR T-cell studies in r/r AML/MDS. Unlike the majority of the studies evaluating CAR T-cell therapy candidates, the THINK study evaluated multiple infusions of CYAD-01 as a stand-alone product candidate (i.e., without prior bridging or preconditioning chemotherapy). This feature is of particular interest considering the median older age and the poorer general condition of patients with r/r AML or MDS at diagnosis.

Although the need to improve the anti-tumour activity is warranted, these data in a difficult-to-treat patient population potentially provide the proof-of-concept of targeting NKG2D ligands by a CAR T-cell product candidate, and support the further development of NKG2D-based CAR T-cell therapies.

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