Chongfan Technology
News
04
2024
-
09
Sun Yat-sen University Xu Ruihua Team's Latest STTT
Author:
Patients carrying polymerase epsilon/polymerase delta mutations exhibit positive responses to immune checkpoint inhibitors. However, prospective trials of efficacy in patients with polymerase epsilon/polymerase delta mutations are still lacking.
On September 2, 2024,Sun Yat-sen UniversityXu Ruihua, Wang Feng andYanxia ShiCommon CommunicationInSignal Transduction and Targeted Therapy Published online entitled“A phase II clinical trial of toripalimab in advanced solid tumors with polymerase epsilon/polymerase delta (POLE/POLD1) mutation”The research paper,The studyIt is shown that neither exonuclease domain mutations nor non-exonuclease domain mutations can fully predict the efficacy of immunotherapy. Therefore, more research is needed to clarify the potential immune sensitization between polymerase ε/polymerase delta mutant variants. difference.
A phase II clinical trial was initiated to evaluate the efficacy of toripalimab (a human-derived IgG4K monoclonal antibody for human PD-1) in patients with advanced solid tumors that have unselected polymerase epsilon/polymerase delta mutations but are not as high as microsatellite instability. A total of 15 patients were enrolled, 14 of whom were evaluated for therapeutic efficacy. The overall response rate was 21.4% and the disease control rate was 57.1%. Median overall survival and median progression-free survival were 17.9 months and 2.5 months, respectively. The objective response rate for patients with exonuclease domain mutations was 66.7 (2/3) and the disease control rate was 66.7 (2/3). The incidence of non-exonuclease domain mutations was 9.1%(1/11) and 54.5%(6/11), respectively.It is worth noting that,PBRM1The effect of gene mutation patients onTreplimabThe reaction rate was as high as 75.0%(3/4).
Cancer is one of the leading causes of disease-related death in the world.Recent global cancer statistics show a staggering 20 million new cancer diagnoses and nearly 10 million cancer-related deaths each year, and these numbers are increasing. While traditional treatments such as surgery, chemotherapy, and radiotherapy have made progress in improving overall survival for some cancers, their overall effectiveness for most cancers remains inadequate. Recently, immune checkpoint inhibitors (ICIs), specifically programmed cell death -1/Programmed Cell Death Ligand 1(PD-1/PD-L1) antibodies, showing considerable potential in the treatment of various types of cancer, such as melanoma, non-small cell lung cancer, and renal cell carcinoma. However, in most tumor types, the efficacy of ICIs is relatively low, and the difference between unselected and selectively treated patients is significant.Therefore, it is important to identify specific biomarkers to distinguish patients who really benefit from ICIs.
Various possible indicators have been found to predict the effectiveness of ICI treatment,Examples are high levels of microsatellite instability/mismatch repair deficiency (MSI-H/dMMR) or high tumor mutational burden (TMB-H), and increased expression of PD-L1 in certain tumors. TMB is also a predictive biomarker for the efficacy of ICI for different cancers. In the KEYNOTE-158 phase II study, patients in the TMB-H state showed a higher response rate than patients in the TMB-l state. Although an association between TMB and immunotherapy response was observed, TMB by itself did not clearly distinguish responders. There are some patients with TMB-L states that respond to ICI and vice versa. Previous studies have also identified other possible predictive biomarkers, including tumor-infiltrating lymphocyte density, T-cell receptor clonality, peripheral blood markers, immune gene signatures, transcriptome and epigenetic features, and commensal microbiota. Like MSI/MMR and TMB, these biomarkers have their own limitations.Thus, improved biomarkers are needed to distinguish between patients who may benefit from immunotherapy and those who may not.
The polymerase epsilon (POLE) and polymerase δ 1 (POLD1) genes are responsible for encoding the major catalytic subunits of the DNA polymerases Polε and Polδ, which are involved in different proofreading and DNA repair processes,Such as nucleotide excision, double strand break repair, base excision and mismatch repair. The exonuclease regions of Pol ε and Pol δ are responsible for the recognition and elimination of mismatched bases formed during DNA replication. Thus, mutations in the exonuclease region (POL-EDMs) of the POLE/POLD1 gene lead to a loss of proofreading ability, resulting in an increase in genetic mutations and the production of new antigens in the cell. More and more studies have reported that destructive germline or somatic mutation of POLE/POLD1 gene may lead to genomic instability, increased mutation rate and carcinogenesis of various malignant tumors.Therefore, POLE/POLD1 mutations (POL-MUTs) may enhance tumor sensitivity to immunotherapy and may serve as a biomarker for ICI therapy.
Previous studies have pointed to POL-MUTs as an independent predictive marker for the effectiveness of ICI in different types of cancer.In a comprehensive analysis of a large data set, compared with patients without these mutations,POL-MUTsPatients had higher TMB. Overall survival was significantly improved in ICI-treated patients with POL-MUTs compared to patients without these mutations (34 and 18 months, respectively). Of note, POL-MUTs outside the exonuclease domain (POL-non-EDMs) also showed a comparable correlation with overall survival in patients treated with ICI. Further studies have shown that domain location does not determine the predictive significance of POL-MUTs. In the combined group of 2862 cancer patients receiving immunotherapy,The study found that the unselectedPOL-non-EDMsandPOL-non-EDMscan be used as identificationPOL-EDMsbiomarkers in patients who may benefit from ICI therapy. The remission rate of POL-non-EDM type patients was significantly higher than that of wild type patients.
POL-non-EDMsIt is also associated with an immune response, even in patients with low TMB status.Nevertheless,POL-non-EDMsThe potential benefits of immunotherapy in patients remain controversial. Some researchers believe that tumors will respond to anti-PD-1 monotherapy only if they have specific POLE pathogenic mutations in the DNA binding site or the catalytic site of the exonuclease domain. Because mostPOL-MUTsLocated outside the exonuclease domain, it is therefore necessary to study the effectiveness of ICIs in treating this subgroup of patients.To this end, the study conducted a single-arm prospective phase II clinical trial to examineTreplimabin advanced solid cancers and non-MSI-HPOL-MUTseffectiveness in patients.
Chongqing Chongfan Technology Co., Ltd. Optical platform film thickness meter OCT optical coherence tomography LabVIEW control
LATEST NEWS
Thank you for visiting the official website of Chongfan Technology. If you have cooperation intentions or suggestions, please contact us through the following methods, and we will reply as soon as possible, thank you!
Address: Room 403, Building 6, Phase III of R&D, No. 36 Xiyong Avenue, High tech Zone, Chongqing, China.
Telephone: +86-13658337211
E-mail: Sales@cfkeji.net
Website: www.cfkeji.net
Mobile Version
