Celyad’s T-cell immunotherapy approach is unique and builds on work conducted by Professor Charles Sentman and his team at Dartmouth College. 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.
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.
Now, the announced early results from the Phase 1 study saw a patient with relapsed acute myeloid leukemia (AML) achieve Morphological Leukemia-Free Status (MLFS). The next challenge is to back this up in “as many clinical settings as possible”.
Christian Homsy, CEO of Celyad comments: “We are pleased to have demonstrated the first objective clinical response of CYAD-01 (a.k.a. CAR-T NKG2D) as this is the very first time a relapsed, refractory AML patient has reached a MLFS with gene-engineered T cells without pre-conditioning lymphodepletion nor additional other concurrent treatment to CYAD-01 administration. This success further reinforces our confidence in our approach and the validity of NKG2D ligands as a target. We will now use the collected data to move forward with the next stage of our product development: reinforcing responses in as many clinical settings as possible.”
“The results announced today regarding CYAD-01 provide the first clinical validity of CYAD-01 as a tumor-specific antigen-receptor and AML as a disease sensitive to gene-engineered cell therapies. As antigen targeting offers significant challenges in AML, this outcome brings hope for the further use of gene-engineered T cells for patients with AML that have run out of therapeutic options. Itâs all the more striking that this outcome was observed without any prior lymphodepletion highlighting the potential of using a physiologic antigen-receptor”, said Dr. David Sallman, Assistant Member in the Malignant Hematology Department of Moffitt Cancer Center.
“With this first objective and ongoing response, obtained without additional treatments such as lymphodepletion, CYAD-01 confirms the potential to treat relapsed refractory AML, one of the deadliest cancers with a median overall survival of less than 4 months. The concept of CAR-T cells with the NKG2D receptor is now progressing to further validation.” Dr. Frederic Lehmann, Vice President Clinical Development and Medical Affairs at Celyad adds.