Page 71 - Helicobacter pylori and Gastric Cancer: From Tumor microenvironment to Immunotherapy
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 Apart from targeting PD-1 on immune cells, inhibiting its cognate ligand PD-L1 on the tumor proper constitutes a therapeutic possibility. Various studies have addressed this possibility by testing the efficacy and performance of Avelumab (NCT01772004 (JAVELIN), MSB0010718C) in chemotherapy-failing gastric cancer patients[6]. Twice every month, patients were given 10 mg/kg of avelumab until either progression, or intolerable toxicity occurred. Cancerous growth, OR, adverse events and PFS were evaluated once every six weeks, and results were related to PD-L1 expression as determined by immunohistochemistry. In total, 75 Gastric cancer patients were treated with avelumab. Of these patients, seven showed a response and of these seven three were positive for PD-L1 as determined by histochemistry. It thus appears that PD-1 is the more attractive target for therapy in gastric cancer as compared to PD-L1 and again attempts at precision medicine, employing PD-L1 immunoreactivity as triaging agent mostly fail. In this context, it is interesting to note that in such studies PD-L1 expression is usually determined on material collected before the onset of conventional treatment. One can well imagine that chemotherapy etc. influences the expression of checkpoints. We thus call for studies investigating the potential of PD-L1 immunohistochemistry for selecting potential responders on material obtained immediately before anti-checkpoint therapy is initiated.
Clinical trial studies of CTLA-4 blockade approach in gastric cancer.
Apart from targeting the PD1/PD-L1 signaling system, CTLA4 is also a prominent immuno-checkpoint. CTLA4 is an immune checkpoint receptor that downregulates immune responses. The molecule is constitutively expressed in regulatory T cells but only upregulated in conventional T cells after activation. Ipilimumab targeted CTLA4 and was the first checkpoint inhibitor to reach the clinic, meeting substantial clinical success in metastatic melanoma. Results in gastric cancer were somewhat less encouraging. A recent study employing ipilumimab in unresectable Locally Advanced/Metastatic Gastric or Gastroesophageal Junction Cancer did not provide evidence ipilimumab efficacy as monotherapy[20]. Another CTLA4-targeting antibody is tremelimumab. In this study, a partial response in one patient, and stable disease in four others (out of 18 participants) was seen, which does not compare well with results obtained with PD-1-directed strategies. Hence, the usefulness of CTLA4 immuno-checkpoint targeting is doubtful, although currently also combinations between anti-CTLA4 and anti-PD1 are being tested, which may still uncover potential synergism.
                                 Immunotherapy Checkpoint Inhibition
Immuno checkpoint inhibition
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