CXCR3

该研究发现，瘤内注射CXCL9/10工程化树突状细胞（CXCL9/10-DC），增强了肿瘤微环境（TME）中的T细胞浸润和活化，在多个同源小鼠非小细胞肺癌模型中产生了有效的肿瘤抑制作用。 加州大学洛杉矶发现 Bin Liu、Steven Dubinett 等人在 Cell 子刊 Cell Reports Medicine 上发表了题为：CXCL9/10-engineered dendritic cells promote T cell activation and enhance immune checkpoint blockade for lung cancer 的研究论文。 该研究使用慢病毒载体构建了表达CXCL9和CXCL10的工程化树突状细胞（CXCL9/10-DC），瘤内注射CXCL9/10-DC能够增强肿瘤微环境中的T细胞浸润和激活，有效抑制小鼠非小细胞肺癌模型的肿瘤发展，瘤内注射CXCL9/10-DC与免疫检查点阻断（ICB）疗法结合，克服了治疗耐药性并建立了全身肿瘤特异性免疫。 这项研究提供了对CXCL9/10-DC介导的宿主免疫激活的机制理解，并支持瘤内注射CXCL9/10-DC的临床转化，以增强ICB疗法在非小细胞肺癌中的疗效。 趋化因子是招募T细胞进入肿瘤微环境的必不可少的可溶性介质。CXCL9和CXCL10（CXCL9/10）是干扰素γ（IFN-γ）诱导的趋化因子，主要由肿瘤内CD103+树突状细胞和肿瘤相关巨噬细胞分泌。 CXCL9/10通过CXCR3信号促进CXCR3+效应T细胞的肿瘤浸润，包括1型T细胞辅助细胞和CD8+细胞毒性T淋巴细胞。除了促进效应T细胞浸润到肿瘤中外，CXCL9/CXCL10/CXCR3信号级联是最佳T细胞激活所必需的。CXCL9表达是癌症患者对ICB反应的最强预测因子之一，此外，肿瘤活检中CXCL9、CXCL10和/或CXCR3的高表达与接受ICB治疗的患者总体生存率的改善相关。这些发现强调了CXCL9/10在肿瘤微环境中作为ICB诱导的抗肿瘤免疫介质的重要作用。 树突状细胞（DC）原位疫苗已成为克服ICB耐药的有前途的方法。瘤内疫苗接种为树突状细胞提供了获得所有可用肿瘤抗原的能力，以促进广泛的抗肿瘤T细胞反应。在临床前研究中，基因修饰的树突状细胞疫苗可以分泌趋化因子，调节肿瘤微环境中的可溶性介质和细胞介质，以促进良好的抗肿瘤反应。 值得注意的是，细胞因子基因工程化树突状细胞作为表达载体的表现优于成纤维细胞，强调了树突状细胞的抗原呈递功能对于最佳疗效的重要性。鉴于CXCL9/10在促进T细胞介导的抗肿瘤免疫反应中的关键作用，研究团队评估了CXCL9/10工程化树突状细胞（CXCL9/10-DC）原位疫苗在小鼠非小细胞肺癌（NSCLC）模型中增强免疫检查点阻断（ICB）疗法的效果。 该研究发现，瘤内注射CXCL9/10工程化树突状细胞（CXCL9/10-DC），增强了肿瘤微环境（TME）中的T细胞浸润和活化，在多个同源小鼠非小细胞肺癌模型中产生了有效的肿瘤抑制作用。瘤内注射CXCL9/10-DC的抗肿瘤效果依赖于CD4+T细胞和CD8+T细胞以及CXCR3介导的T细胞转运和淋巴结中的T细胞输出。 瘤内注射CXCL9/10-DC克服了低肿瘤突变负荷的Lkb1缺陷Kras突变小鼠非小细胞肺癌模型对PD-1/PD-L1阻断的耐药性。此外，瘤内注射CXCL9/10-DC增强了高肿瘤突变负荷的Lkb1缺陷，Kras突变小鼠NSCLC模型对PD-1/PD-L1阻断的相对中等疗效，导致部分肿瘤完全消灭并建立了肿瘤特异性免疫记忆。 这些发现为瘤内注射CXCL9/10-DC作为克服耐药性和增强非小细胞肺癌ICB免疫治疗临床疗效的潜在临床转化提供了证据。

A new study has found the immune system in the blood of Alzheimer's patients is epigenetically altered. That means the patients' behavior or environment has caused changes that affect the way their genes work. Many of these altered immune genes are the same ones that increase an individual's risk for Alzheimer's. Scientists now theorize the cause could be a previous viral infection, environmental pollutants or other lifestyle factors and behaviors. A new Northwestern Medicine study has found the immune system in the blood of Alzheimer's patients is epigenetically altered. That means the patients' behavior or environment has caused changes that affect the way their genes work. Many of these altered immune genes are the same ones that increase an individual's risk for Alzheimer's. Northwestern scientists theorize the cause could be a previous viral infection, environmental pollutants or other lifestyle factors and behaviors. "It is possible that these findings implicate the peripheral immune response in Alzheimer's disease risk," said lead investigator David Gate, assistant professor of neurology at Northwestern University Feinberg School of Medicine. "We haven't yet untangled whether these changes are reflective of brain pathology or whether they precipitate the disease." The study was published Feb. 9 in Neuron. Previous research showed that many of the mutated genes putting a person at higher risk for Alzheimer's are in the immune system. But scientists primarily studied the central immune system in the brain because Alzheimer's is a brain disease. They have largely ignored the immune system in the blood, also known as the peripheral immune system. Gate decided to study the blood. He and colleagues discovered every immune cell type in Alzheimer's patients has epigenetic changes, indicated by open chromatin. Chromatin is the packaging of the DNA within cells. When chromatin is open -- or exposed -- the cells' genome is vulnerable to alterations. Then, Gate examined which genes are more open in these immune cells. He discovered that a receptor -- CXCR3 -- on the T cells was more exposed. Gate believes CXCR3 functions like an antenna on T cells that allows the cells to enter the brain. T cells do not normally enter the brain because they can cause inflammation. "The brain is emitting a signal that it is damaged, and the T cells are homing to that signal by their antenna, CXCR3," Gate said. "T cells can be very toxic in the brain, but we also don't know if these cells might be attempting to repair the damage in the brain," Gate said. Gate also discovered epigenetic changes in inflammatory proteins in white blood cells called monocytes. "Altogether, these findings indicate that immune function in Alzheimer's patients is significantly altered," Gate said. "It could be that environmental factors, like pollutants, or infections that a person has in their lifetime cause these epigenetic changes." The findings revealed several genes that may be therapeutic targets for manipulating the peripheral immune system. Next steps in the research are preclinical studies using in vitro culture systems and animal models to test these targets. Other Northwestern authors include Abhirami Ramakrishnan, Natalie Piehl, Brooke Simonton, Milan Parikh, Ziyang Zhang, Victoria Teregulova and Lynn van Olst. The title of the article is "Epigenetic dysregulation in Alzheimer's disease peripheral immunity." The research is supported by National Institute of Neurological Disorders and Stroke grant NS112458 and National Institute on Aging grant AG078713, both of the National Institutes of Health, Bright Focus Foundation, Alzheimer's Association and Cure Alzheimer's Fund.

Human proof of concept portion of the trial expected to begin in H1 2024; led by Georgetown Lombardi Comprehensive Cancer Center BXCL701 in combination with checkpoint inhibitor in preclinical studies demonstrated encouraging results in pancreatic cancer Initial study data expected in 2024 Feb. 06, 2024 -- BioXcel Therapeutics, Inc. (Nasdaq: BTAI), a biopharmaceutical company utilizing artificial intelligence to develop transformative medicines in neuroscience and immuno-oncology, today announced the completion of patient enrollment in the safety lead-in portion of the investigator-sponsored Phase 2 trial of BXCL701 in combination with KEYTRUDA® (pembrolizumab) in previously treated metastatic pancreatic ductal adenocarcinoma (PDAC). BioXcel Therapeutics, through its OnkosXcel Therapeutics immuno-oncology subsidiary, is collaborating with Georgetown Lombardi’s Dr. Louis M. Weiner, director of the cancer center, and Dr. Benjamin Weinberg, the study’s principal investigator. BioXcel Therapeutics and Merck & Co. are providing BXCL701 and KEYTRUDA for the trial, respectively. The trial is evaluating BXCL701, an investigational, oral innate immune activator designed to inflame the tumor microenvironment and thereby augment the activity of checkpoint inhibitors. As part of the trial’s safety lead-in, the first six patients have been enrolled and will be observed for a six-week safety window period. The trial is then expected to enroll approximately 39 patients in its efficacy phase in a Simon 2-stage single-arm, open-label design [19 + 20 patients]. The primary objective is to determine the 18-week progression-free survival rate. Patients will be monitored radiographically and by tumor markers for response assessment. Tumor biopsies and blood samples will also be collected over the course of treatment to better understand the mechanism of how the drug combination works in humans. The human proof of concept portion of the trial is expected to start in H1 2024. “Pancreatic cancer represents a significant unmet medical need, ranking as the third-leading cause of cancer deaths1, yet remains an exceptionally difficult cancer to treat. No novel therapies have emerged in decades, and overall survival for advanced disease has not improved in over 10 years,” said Dr. Weiner. “Building on results from the preclinical work conducted in our lab, we are excited to evaluate BXCL701 in this important trial as a potential treatment for advanced pancreatic cancer.” The American Cancer Society estimates that, in 2024, approximately 66,440 cases of pancreatic cancer will be diagnosed in the United States.2 Few therapeutic options are available for patients with this indication, which has a five-year survival rate of 13%, among the lowest of all cancers.3 Preclinical xenograft models of pancreatic cancer demonstrated strong synergy between BXCL701 and checkpoint inhibitors and reduced tumor growth and promoted an increase in intratumoral T cells, macrophages and NK cells, with induction of host-protective immunity. In addition, preclinical studies showed that BXCL701 has the potential to provide a marked anti-fibrotic effect, as seen in the tumor stroma. These findings have been published in the Journal for ImmunoTherapy of Cancer4, and recently presented at the 2023 annual meeting of the Society for Immunotherapy of Cancer5 “The major challenge in immuno-oncology is cold tumors and their lack of sensitivity to checkpoint therapy,” said Vincent J. O’Neill, M.D., Executive Vice President, Chief of Product Development and Medical Officer of BioXcel Therapeutics. “We have already demonstrated encouraging response rates and survival data in two aggressive forms of prostate cancer: small cell neuroendocrine cancer (SCNC) and adenocarcinoma, as highlighted in our Key Opinion Leader Day presentation last year. This Phase 2 trial marks the third cold tumor setting where we are testing BXCL701 in combination with KEYTRUDA. Based on encouraging preclinical results, we look forward to the results from the human proof of concept efficacy trial evaluating BXCL701 in combination with pembrolizumab in patients with PDAC.” BXCL701 is an investigational, oral innate immune activator designed to initiate inflammation in the tumor microenvironment. Approved and experimental immunotherapies often fail to address cancers that appear “cold.” Therefore, BXCL701 is being evaluated to determine if it can render “cold” tumors “hot,” making them more detectable by the adaptive immune system and thereby facilitating the development of a strong anticancer immune response. OnkosXcel Therapeutics’ preclinical data support BXCL701’s potential synergy with both current checkpoint inhibitors and emerging immunotherapies directed to activate T-cells. BXCL701 is currently being developed as a potential therapy for the treatment of aggressive forms of prostate cancer and advanced solid tumors that are refractory or treatment naïve to checkpoint inhibitors. BXCL701 has received Orphan Drug Designation from the U.S. Food and Drug Administration in four indications: acute myelogenous leukemia, pancreatic cancer, stage IIb to IV melanoma, and soft tissue sarcoma. An 800+-subject clinical database, with data collected by the Company and others, supports the ongoing development of BXCL701. BioXcel Therapeutics, Inc. (Nasdaq: BTAI) is a biopharmaceutical company utilizing artificial intelligence to develop transformative medicines in neuroscience. Its wholly owned subsidiary, OnkosXcel Therapeutics, is focused on the development of medicines in immuno-oncology. The Company’s drug re-innovation approach leverages existing approved drugs and/or clinically validated product candidates together with big data and proprietary machine learning algorithms to identify new therapeutic indications. For more information, please visit bioxceltherapeutics.com. References American Cancer Society: 2024 Estimated Cancer Deaths. https://cancerstatisticscenter.cancer.org/, accessed February 5, 2024 American Cancer Society: Key Statistics for Pancreatic Cancer. https://www.cancer.org/cancer/types/pancreatic-cancer/about/key-statistics.html, accessed February 5, 2024 American Cancer Society: 5-year relative survival rates for pancreatic cancer.https://www.cancer.org/cancer/types/pancreatic-cancer/detection-diagnosis-staging/survival-rates.html, accessed February 5, 2024 Fitzgerald AA, Wang S, Agarwal V, et al. DPP inhibition alters the CXCR3 axis and enhances NK and CD8+ T cell infiltration to improve anti-PD1 efficacy in murine models of pancreatic ductal adenocarcinoma. Journal for ImmunoTherapy of Cancer 2021;9:e002837. doi:10.1136/jitc-2021-002837).https://jitc.bmj.com/content/9/11/e002837.info, accessed February 5, 2024 Dipeptidyl peptidase 4 (DPP4) inhibition is not solely responsible for the antitumor effects of BXCL701, an inhibitor of multiple DPPs, in a murine model of pancreatic ductal adenocarcinoma (PDAC). Alexander Lekan, Rachael Maynard, Zoe X. Malchiodi, Annie Zuo, Sandra A. Jablonski, Veena Agarwal, Moses Donkor, Vincent O’Neill, and Louis M. Weine. Poster presented at the 38th Annual Meeting of the Society for Immunotherapy of Cancer, November 01-05, 2023, San Diego, CA. chrome-extension://efaidnbmnnnibpcajpcglclefindmkaj/https:/ir.bioxceltherapeutics.com/static-files/d10d0294-9156-4fe5-8e2a-5f8f665f2e75, accessed February 5, 2024 The content above comes from the network. if any infringement, please contact us to modify.