The TRAIL in the Treatment of Human Cancer: An Update on Clinical Trials

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• trigger extrinsic apoptotic pathway in malignant cells

• p53 independent manner

• agonistic properties due to their intracellular death domain (DD) which transmits the apoptotic signal.

• membrane-bound TRAIL (mTRAIL)

• soluble TRAIL (sTRAIL)

• caspase–8 which directly enables the activation of other effector caspases, including the executor caspases, caspase-3 and caspase-7 triggering the final steps of apoptosis

• engage the intrinsic (mitochondrial) apoptotic pathway

• chimeric antigen receptor (CAR) T cell cytotoxicity

• TRAIL to promote pro-tumorigenic activity against tumor cells regardless of their p53 status is thought to be the major advantage of TRAIL-based therapies

• KRAS-mutated cancers where TRAIL signaling was newly found to mediate migration, invasion, and metastasis.

• TRAILshort

• extracellular vesicles and serves as a dominant negative ligand for DR4 and DR5

• induce also the antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytolysis (CDC)

• ability to trigger apoptosis in the absence of TRAIL-R2 crosslinking

• advanced NSCLC patients, tigatuzumab did not improve the efficacy of carboplatin/paclitaxel

• rapid clearance from the serum

• phase II in patients with NSCLC and B-cell lymphomas

• improved PFS (6.4 months vs. 3.5 months in the placebo arm)

• circularly permuted TRAIL, also known as CPT

• CPT-mediated liver injury