Pembrolizumab (Keytruda)

Abstract

The programmed cell death protein 1 (PD1) is one of the checkpoints that regulates the immune response. Ligation of PD1 with its ligands PDL1 and PDL2 results in transduction of negative signals to T-cells. PD1 expression is an important mechanism contributing to the exhausted effector T-cell phenotype. The expression of PD1 on effector T-cells and PDL1 on neoplastic cells enables tumor cells to evade anti-tumor immunity. Blockade of PD1 is an important immunotherapeutic strategy for cancers. Pembrolizumab (Keytruda) is a humanized monoclonal anti-PD1 antibody that has been extensively investigated in numerous malignancies. In melanoma refractory to targeted therapy, pembrolizumab induced overall response rates (ORRs) of 21-34%. It was superior to another immune checkpoint inhibitor ipilimumab (Yervoy) in stage III/IV unresectable melanoma. In refractory non-small cell lung cancer (NSCLC), pembrolizumab induced ORRs of 19-25%. Based on these results, pembrolizumab was approved by the USA FDA for the treatment of advanced melanoma and NSCLC. Tumor cell PDL1 expression may be a valid response predictor. Molecular analysis also showed that tumors with high gene mutation burdens, which might result in the formation of more tumor-related neo-antigens, had better responses to pembrolizumab. In malignancies including lymphomas and other solid tumors, preliminary data showed that ORRs of around 20-50 % could be achieved. Adverse events occurred in up to 60% of patients, but grade 3/4 toxicities were observed in <10% of cases. Immune-related adverse events including thyroid dysfunction, hepatitis and pneumonitis are more serious and may lead to cessation of treatment.

PD1 blockade with pembrolizumab is highly effective in relapsed or refractory NK/T-cell lymphoma failing l-asparaginase

“…Histologic evaluation might show residual EBER 1 cells among infiltrating With EBV DNA remaining undetectable, these lesions resolved after further treatment, consistent with pseudoprogression [12][13][14] observed in solid tumors treated with immune checkpoint inhibitors. Similarly, in the presence of continued clinical remission, detectable EBV DNA was not necessarily associated with disease progression.…”

PD-1 inhibitors increase the incidence and risk of pneumonitis in cancer patients in a dose-independent manner: a meta-analysis

“…Nevertheless, PD-1 inhibitors were also documented with severe pneumonitis, which could lead to cessation of treatment38. Until now, the incidence of pneumonitis with PD-1 inhibitors treatment has not been fully evaluated.…”

E pluribus unum: Combining Molecular Strategies to Defeat Head and Neck Cancer

“…3 The Baylor group has used an imaginative approach that involves a series of genetic modifications to combine oncoviral tumor lysis with immunotherapy. They first targeted the tumor with a construct of two adenoviruses, one oncolytic and one helper-dependent, loaded with genes for anti-PDL1 (to inhibit checkpoint blockade) 4 and interleukin-12 (IL-12) (to drive cytotoxic T cells). 4 This novel viral construct, together with inflammatory signals from the injured and dying tumor cells, facilitated killing of primary and metastatic tumor by subsequent infusions of T cells genetically modified with a chimeric antigen receptor targeting the HER-2 tumor antigen on the HNSCC cells (Her2.CAR T cells).…”

“…They first targeted the tumor with a construct of two adenoviruses, one oncolytic and one helper-dependent, loaded with genes for anti-PDL1 (to inhibit checkpoint blockade) 4 and interleukin-12 (IL-12) (to drive cytotoxic T cells). 4 This novel viral construct, together with inflammatory signals from the injured and dying tumor cells, facilitated killing of primary and metastatic tumor by subsequent infusions of T cells genetically modified with a chimeric antigen receptor targeting the HER-2 tumor antigen on the HNSCC cells (Her2.CAR T cells). This extensive series of experiments can be summarized in two themes-first, the gener-ation and enhancement of HER2.CAR T cells and, second, the use and modification of intratumorally injected adenovirus to promote persistence of HER2.CAR T cells at the tumor site.…”

“…Alberico Luigi Catapano, 1,2 Angela Pirillo, 2,3 and Giuseppe Danilo Norata 1,3,4 https://doi.org/10.1016/j.ymthe.2017.10.008…”