Immunotherapy is a key area of cancer research today. In addition to the PD-(L)1 inhibitors that everyone is already familiar with, there are constantly New immunotherapy drugs are available. Recently, Roy S. Herbst from the Yale Cancer Center and others found that two new immunotherapy drugsOleclumab and Monalizumab, in combination with PD-L1 inhibitor Durvalumab, respectively Both can significantly improve efficacy[1]. In patients with stage III non-small cell lung cancer, Durvalumab, < span>Oleclumab or Monalizumabrespectively reduced the risk of disease progression or death in patients by 56 % and 58%.
Dr. HerbstOleclumabtargets the CD73 molecule[2] . CD73 is present on the surface of cancer cells and immune cells and is an AMP enzyme that hydrolyzes AMP to adenosine. Under normal circumstances, extracellular ATP is a pro-inflammatory signal, but cancer cells use CD73, CD39 and other molecules to hydrolyze it into adenosine, which inhibits inflammation, thereby evading immune attack [3]. Not long ago, we introduced a CD39 inhibitor targeting this pathway (a new immune checkpoint inhibitor! The CD39-targeting immune drug TTX-030 is on the scene, achieving a 61% objective response rate for gastric cancer) . 
CD73 and CD39 together hydrolyze pro-inflammatory extracellular ATP into pro-inflammatory molecules such as adenosine< span>AndMonalizumabtargets the NKG2A molecule, preventing it from binding to HLA-E< span lang="EN-US">[4]. HLA-E molecules are overexpressed in many tumors, and when it binds to NKG2A on immune cells, it will trigger immunosuppressive signals, reduce the secretion of cytokines, and reduce the killing ability of T cells and NK cells to cancer cells.
span>[5]. 
HLA-E binds to NKG2A, inhibits T cell and NK cell function span>Can these two new immunotherapy drugs be used in combination with PD-(L)1 inhibitors to enhance the therapeutic effect? The researchers recruited 189 patients with stage III non-small cell lung cancer who received Durvalumabmonotherapy, < span>Durvalumab+Oleclumabcombination therapy or Durvalumab+Monalizumabcombination therapy. The median age of these patients was 65 years, 68.3% were male, 93.1% were smokers or former smokers, 42.9% had squamous cell histology, and 34.9% had received cisplatin chemotherapy. In the three groups of patients, 68.7%, 50%, and 51.6% of the patients had tumor PD-L assessments, respectively1 expression. The study found that both Oleclumab targeting CD73 or Monalizumab, both significantly improved treatment outcomes. The objective response rate of Durvalumab alone was only 17.9%, while the addition of Oleclumab or After monalizumab, the objective response rate increased to 30.0% and 35.5%, respectively. 
The addition of Oleclumab and Monalizumab significantly improved the objective response rate< >After a median follow-up of 11.5 months, Durvalumabmonotherapy group, Durvalumab+Oleclumabgroup 1-year progression-free survival rates in the Durvalumab+Monalizumab group were 33.9%, 62.6%, and 72.7%, respectively, the median progression-free survival was 6.3 months, not reached, and 15.1 months, respectively. Compared to Durvalumab alone, Oleclumab and Monalizumab reduced the risk of disease progression or death by 56% and 58%, respectively. 
Both combination therapy groups had better progression-free survival than pan> >In terms of safety, the addition of Oleclumab and Monalizumab did not bring about additional adverse reactions. The incidences of serious adverse reactions of grade 3 and above in the three groups of patients were 39.4%, 40.7% and 27.9%, respectively. Common serious adverse reactions include cough, dyspnea, pneumonia, weakness and itching. In the trial, 16.7%, 15.3%, and 14.8% of patients in the three groups discontinued treatment due to adverse Death within 90 days, possibly related to adverse reactions. “These new data have the potential to change the standard of care for patients with advanced non-small cell lung cancer, providing us with new treatment options that can significantly impact patients’ lives,” said Dr. Herbst, author of the paper. Make a significant impact. I look forward to seeing the initiation of Phase 3 trials to help gather more insights into these combination therapies and better identify which patients will benefit from each combination therapy to help personalize effective treatments .”
References:[1]. Herbst R S, Majem M, Barlesi F, et al. COAST: An Open-Label, Phase II, Multidrug PlatformStudy of Durvalumab Alone or in Combination With Oleclumab or Monalizumab inPatients With Unresectable, Stage III Non–Small-Cell Lung Cancer[J]. Journal of Clinical Oncology, 2022: JCO. 22.00227.[2]. Geoghegan J C, Diedrich G, Lu X, et al. Inhibition of CD73 AMP hydrolysis by a therapeuticantibody with a dual, non-competitive mechanism of action[C]//MAbs. Taylor& Francis, 2016, 8(3): 454-467.[3]. Vultaggio-PomaV, Sarti A C, Di Virgilio F. Extracellular ATP: A feasible target for cancertherapy[J]. Cells, 2020, 9(11): 2496.[4]. André P, DenisC, Soulas C, et al. Anti-NKG2A mAb is a checkpoint inhibitor that promotes anti-tumor immunity by un leashing both T and NK cells[J]. Cell, 2018, 175(7):1731-1743. e13.[5]. van Hall T,André P, Horowitz A, et al. Monalizumab : inhibiting the novel immune checkpointNKG2A[J]. Journal for immunotherapy of cancer, 2019, 7(1): 1-8.