Abstract
CBP501, a calmodulin-binding peptide, is an anti-cancer drug candidate and functions as an enhancer of platinum uptake into cancer cells. Here we show that CBP501 promotes immunogenic cell death (ICD) in combination with platinum agents. CBP501 enhanced a clinically relevant low dose of cisplatin (CDDP) in vitro as evidenced by upregulation of ICD markers, including cell surface calreticulin exposure and release of high-mobility group protein box-1. Synergistic induction of ICD by CDDP plus CBP501 as compared to CDDP alone was confirmed in the well-established vaccination assay. Furthermore, cotreatment of CDDP plus CBP501 significantly reduced the tumor growth and upregulated the percentage of tumor infiltrating CD8+ T cell in vivo. Importantly, the antitumor effect of CDDP plus CBP501 was significantly reduced by anti-CD8 antibody treatment. Based on this novel effect of CBP501, we analyzed the combination treatment with immune checkpoint inhibitors in vivo. Mice treated with CBP501 in combination with CDDP and anti-PD-1 or anti-PD-L1 showed an additive antitumor effect. These results support the conclusion that CBP501 enhances CDDP-induced ICD in vitro and in vivo. The findings also support the further clinical development of the CBP501 for enhancing the antitumor activity of immune checkpoint inhibitors in combination with CDDP.
Highlights
A calmodulin-binding peptide, CBP501, was previously described as a unique G2 checkpoint-directed agent [1] and as an enhancer of platinum uptake into cancer cells [2]
We measured several known immunogenic cell death (ICD) markers such as upregulation of phosphorylation of eIF2α (p-eIF2α), cell surface expression of CRT and release of high-mobility group protein box-1 (HMGB1) to determine if clinically relevant low doses of CDDP or CDDP plus CBP501 induces ICD to CT26WT cells in vitro
MTX was used as a potent inducer of ICD for the vaccination assay; MTX-treated cells did not enhance the tumor rejection compared to vehicle-treated cells (Figure 1E), suggesting that the sensitivity of this assay was not high enough to show the effect of MTX-induced ICD on CT26WT cells to the tumor rejection
Summary
A calmodulin-binding peptide, CBP501, was previously described as a unique G2 checkpoint-directed agent [1] and as an enhancer of platinum uptake into cancer cells [2]. Platinum agents are used to treat almost 50% of cancer patients [4] and, cisplatin (CDDP) is effective for the treatment of diverse solid tumors, including bladder, head and neck, lung, ovarian, and testicular cancers [5]. Cytotoxic drugs, including platinum agents, are thought to be immunosuppressive; recent studies show that some cytotoxic agents enhance antitumor effects by modulation of the immune system [8]. One of these effects is the induction of immunogenic cell death (ICD)
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