Science Sub-journal: Immunotoxin spD-1 therapy offers new hope for this refractory cancer.

Immunocheckpoint inhibitors, including blocking antibodies against CTLA-4, PD-1 and PD-L1, have shown antitumor activity in cancer patients and have been approved for the treatment of many solid tumors, including advanced melanoma, non-small cell lung cancer, renal cell carcinoma and bladder cancer.immunocheckpoint therapy has greatly changed the pattern of cancer treatment, but due to many factors, a large number of patients still do not respond to these therapies.the main focus of many laboratory and clinical studies is to improve the effectiveness of immunocheckpoint inhibitors in combination with drugs that make tumors more sensitive to these therapies.mesothelioma is a rare and difficult to treat cancer. The prognosis of mesothelioma is poor. After first-line chemotherapy, pemetrexed and cisplatin are often easy to relapse. At this time, the treatment options of patients are very limited.although immunocheckpoint inhibitors are not approved by FDA for the treatment of mesothelioma, a number of clinical trials have shown that the remission rate of immunocheckpoint inhibitors is 9% to 20%.mesothelin is a cell surface glycoprotein with a molecular weight of 40 kDa. It is highly expressed in many malignant tumors, such as mesothelioma, non-small cell lung cancer, pancreatic cancer and ovarian cancer. It only exists in the pleura and pericardium of normal adults in a very limited way. This expression mode makes mesothelin an attractive target antigen, and there are many targets for mesothelin Clinical trials.recently, researchers from the National Institutes of Health (NIH) published a research paper entitled "enhanced efficiency of mesothelin targeted immunotoxin lmb-100 and anti – PD-1 antibody in patients with mesothelioma and mouse tumor models in Science Translational Medicine.in this clinical trial, the team used immunotoxin targeted mesothelin, and observed that immunotoxin treated patients showed good response to immune checkpoint inhibitors, especially if the tumor expressed the relevant immune checkpoint.the team described the immune response in the treated patients and confirmed the same phenomenon in mouse models of mesothelioma and lung cancer, paving the way for larger clinical trials of combination therapy.lmb-100 is a new generation of recombinant immunotoxin, which is composed of humanized anti mesothelin Fab fused to a 24 kDa truncated Pseudomonas exotoxin A fragment, which has mutations that inhibit B cell and T cell epitopes to reduce immunity to immunotoxin.after binding with mesothelin, Pseudomonas exotoxin A is specifically delivered to the mesothelin positive cancer cells, where the toxin reaches the cytoplasm, where it blocks protein synthesis and induces immunogenic cell death.the antitumor effect of lmb-100 has been confirmed in a variety of mesothelin expressing tumor models. A phase 1 clinical trial has confirmed the safety of lmb-100 for patients（ ClinicalTrials.govNCT02798536）。during the lmb-100 clinical trial, the researchers noted that some mesothelioma patients who received immunotoxin therapy and subsequently received treatment with the PD-1 inhibitor pimmab had long-term and long-term tumor regression.here, the research team described these clinical reactions in detail and tried to understand their mechanism basis by evaluating the changes of tumor in patients after lmb-100 treatment. The research team also conducted preclinical studies to verify the clinical observation results.National Cancer Institute (NCI) phase 1 clinical trial of lmb-100 in the treatment of mesothelioma, lmb-100 as a single drug (n = 10) or in combination with nab paclitaxel (n = 11)（ ClinicalTrials.govNct02798536). nine of them continued to receive the treatment of PD-1 inhibitor pemzumab, and one patient continued to receive the treatment of PD-1 inhibitor navumab. these patients had previously received pemetrexed and cisplatin, but none of them had received immunocheckpoint therapy. of the 10 patients who continued to receive immunocheckpoint inhibitors, 7 patients could be evaluated. Among the 7 evaluable patients, 1 patient had complete response (CR), 3 patients had partial response (PR), 1 patient had no progression (SD), and 2 patients had disease progression (PD). the total remission rate of all patients was 40%. the median progression free survival (PFS) was 3.3 months for immunocheckpoint inhibitors and 11.9 months for lmb-100 therapy. among the 5 patients with PD-L1 positive expression, 4 patients had objective tumor response. Compared with PD-L1 negative patients, the median PFS of PD-L1 positive patients was significantly prolonged, which was 2.1 months. although limited by the small number of patients, these results suggest a higher expected response rate and a longer PFS and OS than the PD-1 inhibitor pemmab alone in PD-L1 positive patients. the combination of lmb1-100 and anti PD-1 mAb showed significant anti-cancer effect in mice model. in general, this work provides clinical evidence for the combination therapy of immunotoxin lmb-100 and anti PD-1 antibody for patients with malignant mesothelioma. and the combination of lmb-100 and anti-PD-1 antibody can enhance the anti-tumor response mediated by CD8 + T cells. these preclinical and clinical studies have shown that the combination of mesothelin targeted drugs with checkpoint inhibitor immunotherapy may be an option for patients with mesothelin positive cancer, and the results pave the way for larger clinical trials of combination therapy. paper link: Source: yaoyan.com