Nanjing KAEDI Medical Technology is a new drug research and development company in the clinical stage, committed to the development of the next generation CAR-T cell immunotherapy. KAEDI recently announced that, in collaboration with Wei Jia, head of the Oncology Department at the Nanjing University Drum Tower Hospital, published the results of a preclinical study in the journal Cancer Science titled “Combination therapy of DKK1 inhibition and NKG2D chimeric antigen receptor T cells for the treatment of gastric Cancer”.
Among all cancer types in the world, gastric cancer ranks sixth in incidence and third in mortality. It has long been recognized as a highly heterogeneous disease with a poor prognosis and poor response to immunotherapy because of the suppressive tumor immune microenvironment. Immunotherapy (anti-PD-1) has limited efficacy in chemotherapy-refractory gastric cancer, with an overall objective response rate (Orr) of 12% . Even on first-line chemotherapy plus anti-PD-1 therapy, patients with a PD-L1 antigen-positive score ≥5 had a low median overall survival of approximately 14.4 months. Therefore, it is imperative to find a new way of immunotherapy for patients with gastric cancer.
NKG2D-CAR-T cells have promising therapeutic and potential applications in preclinical models of hematological malignancies and various solid tumors, including Glioblastoma multiforme, liver and breast cancers. Dickkopf-1(DKK1) is an antagonist of the canonical Wnt pathway, and previous studies have reported that DKK1 is overexpressed in a variety of tumors, including gastric cancer, and is associated with poor prognosis. Recent studies have shown that DKK1 can promote tumor progression by inducing the aggregation of MDSCs and inhibiting CD8 + T cell activation, thereby creating an inhibitory tumor immune microenvironment in melanoma and colorectal cancer.
NKG2D-CAR-T cells have promising therapeutic and potential applications in preclinical models of hematological malignancies and various solid tumors, including Glioblastoma multiforme, liver and breast cancers. Dickkopf-1(DKK1) is an antagonist of the canonical Wnt pathway, and previous studies have reported that DKK1 is overexpressed in a variety of tumors, including gastric cancer, and is associated with poor prognosis. Recent studies have shown that DKK1 can promote tumor progression by inducing the aggregation of MDSCs and inhibiting CD8 + T cell activation, thereby creating an inhibitory tumor immune microenvironment in melanoma and colorectal cancer.
The present findings suggest that in xenograft animal models of gastric cancer (FIG1 and FIG2) , the DKK1 inhibitor WAY-262611 combined with NKG2D-CAR-T (KD-025) cells demonstrated a significantly superior antitumor therapeutic effect than each single agent.Inhibition of DKK1 can significantly remodel the suppressive tumor immune microenvironment TIME in gastric cancer and upregulate the expression of NKG2DL in gastric cancer tumor tissues and cell lines. Notably, the combination of DKK1 inhibition and NKG2D-CAR-T (KD-025) had superior antitumor effects compared with in vitro and in vivo monotherapy, which may bring new insights into immunotherapy of gastric cancer.