Leveraging Natural Killer Cells as CAR-T Therapies

Celyad is developing CAR-T therapies that have the potential to treat both hematological and solid tumors.

Differentiated CAR-T Receptor

Cancer cells have evolved the capability to elude many antibodies and small molecule drugs. Chimeric antigen receptor (CAR)-T cell therapies take a different approach by leveraging the immune system and its innate biochemical pathways. Successes to date with CD19 targets in lymphoma and leukemia demonstrate the potential for this modality.

Celyad is developing CAR-T cell therapies based on research conducted by Charles Sentman and his team at Dartmouth College focused on natural killer (NK) cells. NK cells constitute the first line of defense against external aggression and cancer, holding the line until T cells and other immune cells arrive.

Sentman inserted genes into T cells encoding NK-activating receptors (NKG2D) that, rather than bind to a specific antigen, bind to eight different stress ligands found on both hematological and solid tumors. These ligands are naturally expressed by cancer cells in approximately 80% of hematological and solid malignancies. The NKG2D-based T cells also express a co-stimulatory molecule that increases their potency.

Manufacturing Advantage

We have developed proprietary manufacturing processes that have undergone two amendments (LY to mAb to OptimAb). OptimAb employs a shortened 8-day cell culture and incorporates a selective PI3K inhibitor. The OptimAb process generates a product that is enriched for T cells with a memory-like phenotype while maintaining the high level of manufacturing reliability required to support clinical development. The rapid acceptance of our process amendments by U.S. and European regulatory authorities reflects the expertise Celyad has built around NKG2D CAR-T cell manufacturing.

Personalized Therapies CYAD-01 and CYAD-02

Celyad’s lead candidate CYAD-01, a CAR-T cell therapy incorporating the NKG2D receptor, has been shown in preclinical studies to bind to ligands expressed by blood vessels that feed tumors and inhibitory cells that help tumors evade the immune system. CYAD-01 targets and kills the tumor while impacting the micro-environment and potentially inducing an adaptive immune response owing to the creation of long-term cell memory against targeted tumors.

CYAD-02 is a next-generation NKG2D-based CAR-T candidate that incorporates short hairpin RNA (shRNA) technology to target the NKG2D ligands MICA and MICB, silencing their gene expression via RNA interference (RNAi) on the CAR-T candidate. With our technology, the single shRNA modulates the expression of both ligands, which translates to increases in in vitro proliferation, in vivo engraftment and antitumor activity in early testing. SMARTvector shRNA technology from Horizon Discovery is deployed to design target shRNA sequences with high specificity, ensuring optimal gene silencing. CYAD-02 also incorporates our OptimAb process to enrich for T cells with memory-like phenotype.

Early clinical studies are underway with CYAD-01 in relapsed/refractory acute myeloid leukemia (AML), myelodysplastic syndrome (MDS) and metastatic colorectal cancer (mCRC), and all have provided promising initial results. The focus is now on increasing the potency to potentially deepen the breadth, frequency and duration of clinical responses for next-generation candidates. A phase I dose-escalation trial evaluating the safety and clinical activity of CYAD-02 with the preconditioning chemotherapy cyclophosphamide and fludarabine (CyFlu) for the treatment of relapsed/refractory AML and MDS is scheduled to begin in early 2020.

Off-the-Shelf Treatment for Colorectal Cancer

In addition to autologous therapies, Celyad is committed to developing effective off-the-shelf NKG2D CAR-T cell therapies for the treatment of solid tumors. Multiple allogeneic technologies are under investigation, including the novel inhibitory peptide TIM (T cell receptor (TCR) inhibitory molecule) and our shRNA platform, which targets the CD3zeta component of the TCR. Both technologies leverage non-gene-edited approaches.

Our current lead allogeneic candidate CYAD-101 is a non-gene-edited, healthy donor–derived CAR-T therapy that co-expresses the NKG2D CAR of CYAD-01 and TIM. The expression of TIM reduces signaling of the TCR complex, which is responsible for graft versus host disease (GvHD), a response triggered by the recognition of non-self human leukocyte antigen molecules expressed on recipient cells by the TCRs of donor cells and a key concern with allogeneic cell therapies.

Potential for Large Product Pipeline

Celyad has established a suite of patents and is strategically positioned for further candidate development. Our approach, based on a differentiated receptor and unique platforms for creating allogeneic treatments for both hematologic and solid tumors, has resonated with investors enabling us to establish Celyad as a leading CAR-T company.

Filippo Petti

Filippo Petti, CEO of Celyad, has previously served as Celyad’s CFO bringing a wealth of experience from both the biotech and financial industries. Mr. Petti previously worked in healthcare investment banking and equity research. He began his career as a research scientist at OSI Pharmaceuticals, Inc. focused on drug discovery and translational research before transitioning into corporate development. Mr. Petti holds an MBA from Cornell University, a MSc from St. John’s University and a BS from Syracuse University.