CYAD-01 (CAR-T NKG2D) product candidate
In contrast to the scFv antibody method used by "classical" CAR-T, the Celyad CAR-T approach uses the full human NKG2D receptor to recognize the tumor antigen. This NKG2D activating receptor plays an important role in protecting the host from infections and cancer.
CYAD-01 cells are autologous T cells transduced with a CAR based on the NKG2D receptor. This receptor is composed of the full-length native human NKG2D gene fused with the cytoplasmic signaling domain of native human CD3ζ to allow NKG2D to function as a primary receptor in T cells (Figure 6).
Upon ligand-recognition the signaling domain of CD3ζ activates the transduced T cell. Although the co-stimulatory molecule DAP10 is not part of the transgene, NKG2D is known to associate with this costimulatory molecule for membrane stabilization and function (ref 100). Together NKG2D-CAR and DAP10 create a new receptor complex which enables T cells to recognize and kill tumor cells.
NKG2D ligand expression
Generally, NKG2D ligands (ULBP & MICA/B proteins) are expressed at mRNA level in tissues of healthy individuals, but remain under normal conditions absent at the protein level. NKG2D ligand mRNAs are regulated by transcriptional, translational, and posttranslational mechanisms which therefore prevents translational expression as well as cell-surface expression in healthy cells (ref 53,54).
The surface expression of NKG2D ligands is highly regulated in order to avoid inappropriate immune responses (ref 55) but is induced by various stress situations, such as viral infection, oxidative stress, genotoxic drugs, tissue damage, heat shock, inflammatory cytokines, and malignant transformation (ref 54,56,57). Many tumors express NKG2D ligands, making them an excellent target for cancer therapy (ref 51,57,58). Human ULBP proteins are expressed by ovarian (ref 59-62) and lung carcinomas (ref 63), colorectal cancer, head and neck squamous cells (ref 64,65) and melanoma tumor cells (ref 66,67) and MICA/B was expressed by most cancer types. Importantly, NKG2D ligands on primary tumor isolates are heterogeneous with respect to the ligands found and amounts expressed, and ligand expression can also vary with tumor progression (ref 59,66,68). Hence high NKG2D ligand expression might generally be considered as an independent indicator of prognosis in both hematologic (ref 69-71) and solid cancers (ref 61,62,64,67,72,73).
Preclinical studies: CYAD-01 well-defined and multiple mechanisms of action
In vitro and in vivo preclinical data have proven the efficacy and safety of CYAD-01 in different murine cancer models (solid and liquid cancers). Results also demonstrate that, in contrast to standard CAR-T cell therapies, CYAD-01 cells harbor multiple mechanisms of action which go far beyond simple direct killing of tumor cells, and that would be critical to impact more specifically solid cancer indications.
To download the preclinical data summary, please click here.
CYAD-01 Phase Ia Trial: Safe and Feasible
CYAD-01 Phase Ia Trial conclusions: Next stage cleared
- Among AML/MDS and MM patients, a single dose of CYAD-01 cells without lymphodepletion was feasible and well tolerated without DLTs over a range of 1x10^6 to 3x10^7 T cells (per injection).
- Cases of unexpected survival and/or improvement in hematologic parameters were noted in both AML and MM patients, some with and some without subsequent therapy.
CYAD-01 Phase Ia Trial: First efficacy signals despite single injection and low doses.
- One MM (Multiple Myeloma) patient is demonstrating longevity on subsequent myeloma therapies, despite aggressiveness of disease prior to infusion
- One MM patient maintained stable disease (bordering on Partial Response) for 6 months on a subsequent IDH-1 inhibitor trial despite having a mutated allele frequency of <5% IDH and 54% p53 mutation at infusion.
- One AML patient, despite 50% blasts and p53 mutation at infusion, demonstrated relative peripheral blood hematologic stability for 3 months. Marrow results were not available.
- One AML patient at the highest dose demonstrates “stable disease” at 3+ months without subsequent therapy. He has improvement in all hematologic parameters.
- NKG2D CAR-T-specific activity against autologous tumor-containing cells was demonstrated in vitro in the 2 patients tested.
- This paves the way for studies of multiple infusions and higher doses of NKG2D-expressing CAR-T cells in numerous malignancies.
THerapeutic Immunotherapy with NKG2D: the THINK trial study design
THINK (THerapeutic Immunotherapy with NKG2D) is a multinational (EU/US) open-label Phase Ib study to assess the safety and clinical activity of multiple administrations of autologous CYAD-01 cells in seven refractory cancers, including five solid tumors (colorectal, ovarian, bladder, triple-negative breast and pancreatic cancers) and two hematological tumors (acute myeloid leukemia and multiple myeloma).
The trial will test three dose levels: up to 3x108, 1x109 and 3x109 CYAD-01 cells. At each dose, the patients will receive three successive administrations, two weeks apart, of CYAD-01 cells. The dose escalation part of the study will enrol up to 24 patients while the extension phase would enrol 86 additional patients.
An allogeneic platform would enable the production of “off-the-shelf” CAR-T cell products from healthy donors
The injection of T-cells into a receiver (patient), different from the donor, leads to a severe rejection response in which TCR, a molecule present at the surface of T-cells, is largely responsible. Our allogeneic platform is based on the engineering of T-cells from healthy donors that, in addition to CAR, also express TCR Inhibitory Molecules (TIMs). TIMs inhibit TCR function allowing T-cells to persist when injected into patient. Our allogeneic platform therefore could allow us to manufacture “off-the-shelf” products to treat thousands of cancer patients. Moreover, we believe this platform can be applied not only to Celyad CAR-T cell products, but also to any other CAR-T cell.
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