The efficacy of airway stenting combined with PD-1/L1 immune checkpoint inhibitors for malignant central airway obstruction: A retrospective cohort study

Letter

作者: Tang, Hao ; Wei, Kunchen ; Feng, Xiao ; Hong, Hanhan

2024-04-15·Cancer

Cyclin‐dependent kinase inhibitors enhance programmed cell death protein 1 immune checkpoint blockade efficacy in triple‐negative breast cancer by affecting the immune microenvironment

Article

作者: Wang, Wei ; Shao, Xiying ; Wang, Xiaojia ; Gao, Lu ; Wu, Jiayi

ABSTRACTBackgroundClinical studies on programmed death‐ligand 1 (PD‐L1) immune checkpoint inhibitors for treating triple‐negative breast cancer (TNBC) have shown unsatisfactory efficacy due to low tumor‐infiltrating lymphocyte (TIL) levels. Inhibitors targeting cyclin‐dependent kinase (CDK) proteins can affect the immune microenvironment, increase TIL levels, and promote antitumor immunity, thus providing a new direction for TNBC treatment strategies.MethodsThe authors tested three CDK inhibitors on the TNBC cell lines MDA‐MB‐231 and 4T1 and validated their antitumor effects and impact on the immune microenvironment using multiple detection methods. They verified the efficacy and immune‐related mechanisms of different combination therapy experiments in a 4T1 cell‐transplanted BALB/c mouse model.ResultsTreatment with CDK inhibitors for 72 hours inhibited cell proliferation, clone formation, migration, and cell‐cycle arrest and induced apoptosis in human breast cancer MDA‐MB‐231 cells and mouse breast cancer 4T1 cells. CDK inhibitors suppressed DNA methylation by downregulating DNMT1, DNMT3a, and DNMT3b expression. These three inhibitors promoted the secretion of various chemokines, enhanced tumor cell antigen presentation, and increased PD‐L1 expression. CDK inhibitors improved the efficacy of immunotherapy in animal models and increased TIL levels.ConclusionsCombination therapy with CDK and PD‐L1 immune checkpoint inhibitors affects the immune microenvironment, promotes antitumor immunity, and improves the efficacy of immunotherapy for TNBC.

2024-04-05·JNCI: Journal of the National Cancer Institute

Platinum ineligibility and survival outcomes in patients with advanced urothelial carcinoma receiving first-line treatment

Article

作者: Andreev-Drakhlin, Alexander ; Gupta, Shilpa ; Wee, Christopher ; Garcia, Jorge A ; Schröder, Carsten ; Fassò, Marcella ; Fajardo, Otto

AbstractBackgroundThis study examined real-world patients with locally advanced or metastatic urothelial carcinoma considered ineligible for platinum-containing chemotherapy in the first-line setting.MethodsThis retrospective observational study used data from a nationwide (United States) de-identified patient-level electronic health record–derived database. Eligible adults (aged 18 years and older) had a locally advanced or metastatic urothelial carcinoma diagnosis on or after January 1, 2016, and initiated first-line systemic treatment at least 90 days before December 31, 2021. Platinum ineligibility was defined as Eastern Cooperative Oncology Group performance status of at least 3, creatinine clearance less than 30 mL/min, or Eastern Cooperative Oncology Group performance status of 2 and creatinine clearance of less than 45 mL/min. Overall survival and real-world progression-free survival (PFS) were summarized using the Kaplan–Meier method.ResultsThe overall population comprised 4270 patients; 477 (11%) were considered platinum ineligible, 262 (55%) received a first-line programmed cell death 1 or programmed cell death ligand 1 immune checkpoint inhibitor, and 118 (25%) received platinum-based chemotherapy. A total of 2335 (55%) patients were platinum eligible; 677 (29%) received a first-line programmed cell death 1 or programmed cell death ligand 1 inhibitor, and 1229 (53%) received platinum-based chemotherapy. Median overall survival was 13.3 months (95% confidence interval [CI] = 12.4 to 14.8 months) in platinum-eligible and 5.1 months (95% CI = 4.2 to 6.4 months) in platinum-ineligible patients. Median PFS was shorter in platinum-ineligible (3.4 months; 95% CI = 2.9 to 4.0 months) vs platinum-eligible patients (5.9 months; 95% CI = 5.5 to 6.2 months) overall and when stratified by first-line therapy type.ConclusionThis real-world study has shown for the first time the treatment patterns and outcomes in newly diagnosed patients with locally advanced or metastatic urothelial carcinoma ineligible for platinum-based chemotherapy. These findings provide quantitative benchmarks for platinum ineligibility in the first-line advanced or metastatic urothelial carcinoma setting and highlight the need for novel therapy options.

项与 HW-CX04 相关的新闻（医药）

2024-03-15

·FiercePharma

Merck’s Keytruda claims digital marketing crown, holding off challenges from AstraZeneca, BMS

The report covers the digital footprints of treatment for NSCLC. Merck’s dominance of the PD-1/L1 checkpoint inhibitor space extends to the digital realm. That is the topline finding of a study of digital marketing trends, which found Merck has the highest traffic to patient and unbranded U.S. sites about non-small cell lung cancer (NSCLC). The ResearchAndMarkets.com report found “Merck's Keytruda.com achieved the highest total traffic across NSCLC patient sites in the U.S., with over 2.4 million visitors from October 2022 to September 2023.” Bristol Myers Squibb’s Opdivo.com and AstraZeneca’s Imfinzi.com trailed the frontrunner, racking up 1.7 million and 350,000 visits, respectively. The finding mirrors the products’ sales figures for 2023. Keytruda is the top dog in the checkpoint inhibitor world, generating $25 billion for Merck last year. Opdivo and Imfinzi lag well behind with, respectively, $9 billion and a little over $4 billion in sales. Merck’s dominance of the digital space is supported by a paid search campaign. Keytruda.com benefits from paid search engine optimization for more than 7,600 keywords, compared to 5,840 keywords for BMS’ Opdivo site, according to the report. The analysts found direct and organic sources accounted for the highest proportion of traffic to top branded patient NSCLC websites. The report covers the digital footprints of other types of treatment for NSCLC. AstraZeneca and Daiichi Sankyo’s website for Enhertu, a HER2-directed antibody-drug conjugate, is second on the list of paid search terms with 6,640 keywords. Merck also leads the way in the unbranded space. The drugmaker’s Understandcancertogether.com was by far the busiest NSCLC unbranded site in the U.S. from October 2022 to September 2023, attracting 94,000 visitors compared to 7,500 views for Pfizer's Thisislivingwithcancer.com. Merck spent more than its rivals on digital display advertising for the unbranded site, reportedly running up a bill of $94,000. Healthcare professional websites were the only area of the U.S. digital NSCLC landscape where Merck failed to claim the top spot. Visits to AstraZeneca's Imfinzihcp.com hit 300,000 over the analyzed period, beating Keytrudahcp.com into second place. The win was supported by 7,167 keywords, putting Imfinzihcp.com just ahead of Amgen’s Lumakrashcp.com and AstraZeneca’s own Enhertuhcp.com.

抗体药物偶联物

2024-01-04

·BioSpace

Sensei Biotherapeutics Provides Corporate Update and Highlights Key Upcoming Milestones

- Completed SNS-101 monotherapy dose escalation through 15 mg/kg with no dose limiting toxicities - - Expands patient cohort in specific tumor types - - Multiple clinical milestones expected in 2024 - - Strong balance sheet with cash runway extended into the fourth quarter of 2025 - BOSTON, Jan. 04, 2024 (GLOBE NEWSWIRE) -- Sensei Bio, Inc. (Nasdaq: SNSE), a clinical stage immuno-oncology company focused on the discovery and development of next-generation therapeutics for cancer patients, today provided corporate updates on its research and development programs and upcoming milestones. “In 2023, we significantly advanced our lead clinical asset while prudently maintaining our strong balance sheet,” said John Celebi, President and Chief Executive Officer. “We believe SNS-101, which has demonstrated potentially best-in-class pharmacokinetics and tolerability at clinical doses far beyond other VISTA-targeted immunotherapies, has strong potential as a transformative option in multiple cancer indications. Given the favorable data thus far, we are expanding the SNS-101 Phase 1/2 clinical trial to include additional patients in a more focused set of indications as an intermediate stage to further optimize the Phase 2 study design with additional patient data while we prepare for an anticipated end of Phase 1 meeting with FDA by Q4 2024. As a result, we are dedicating additional resources to support this expanded clinical program while pausing the IND-enabling studies originally planned for our next TMAb product candidate. We expect these adjustments to extend our cash runway into the fourth quarter of 2025.” Highlights and Milestones SNS-101 SNS-101 is a conditionally active antibody harnessing the acidic tumor microenvironment to target the immune checkpoint VISTA (V-domain Ig suppressor of T cell activation). VISTA is implicated in numerous cancer indications and its expression correlates with low survival rates. Sensei is conducting a multi-center Phase 1/2 clinical trial to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy of SNS-101 as both a monotherapy and in combination with Regeneron’s PD-1 inhibitor Libtayo® (cemiplimab) in patients with advanced solid tumors. Recent updates include: As of January 2, 2024: A total of 25 patients have been treated with SNS-101 across various dose levels, with 16 patients in the monotherapy arm and nine patients in the combination arm. There have been no dose limiting toxicities (DLT) observed across both the monotherapy arm and the combination arm. In the monotherapy dose escalation arm, patients have cleared all planned dosing cohorts of 0.3, 1, 3, 10 and 15 mg/kg. In the combination dose escalation arm, six patients have been enrolled in the first cohort and have cleared the DLT period at a dose level of 3.0 mg/kg SNS-101 + Libtayo. The second cohort at a dose level of 10.0 mg/kg SNS-101 + Libtayo has been enrolled and is pending clearance of the DLT period as determined by the study safety monitoring committee. Following completion of dose escalation and prior to initiating the Phase 2 portion, the Company plans to enroll up to 40 additional patients in both monotherapy and in combination with Libtayo in specific tumor types to further optimize the design of the Phase 2 trial. In the monotherapy dose expansion arm, Sensei plans to enroll up to 10 patients with microsatellite stable (MSS) colorectal cancer (CRC) at a dose level of 15 mg/kg. In the combination dose expansion arm, Sensei plans to enroll up to 30 patients with MSS CRC, head and neck cancer (H&N), non-small cell lung cancer (NSCLC), and melanoma. The dose level will be determined following completion of the combination dose escalation phase of the study. The solid tumor types were selected to focus the cancer indications on a basket of more commonly occurring histologies, including both “hot” (NSCLC, H&N, Melanoma) and “cold” (CRC) tumors where we believe SNS-101 has potential to provide clinical benefit based on VISTA biology and supporting preclinical data. All patients with “hot” tumors enrolling into the expansion arm are expected to have been previously treated with a PD1/L1 checkpoint inhibitor. Additional tumor types and doses may be considered for both the monotherapy and combination expansion arms. Sensei expects to open enrollment in the monotherapy expansion arm later this month. The combination expansion arm will begin following completion of the combination dose escalation phase of this study. Anticipated milestones for the SNS-101 Phase 1/2 clinical trial include: Initial safety and pharmacokinetic data for the combination dose escalation arm of SNS-101 and Libtayo in Q1 2024 Topline data for the SNS-101 monotherapy dose escalation arm in Q2 2024 Topline data for the combination dose escalation arm of SNS-101 and Libtayo in Q3 2024 Initial data for the SNS-101 dose expansion cohorts by the end of 2024 Additional Corporate Updates Sensei announces that Ron Weitzman, M.D., F.A.C.P., has joined Sensei as part-time Chief Medical Officer. Dr. Weitzman joined Sensei as a consultant in August 2022 and has been instrumental in the design and implementation of the ongoing Phase 1/2 clinical trial. Dr. Weitzman brings over 25 years experience leading oncology clinical studies ranging from early to late-stage clinical development, including a pivotal study for cabozantanib that led to its FDA approval. Dr. Weitzman has held leadership roles at various global biopharmaceutical companies, including Exelixis, Genentech and Novartis, and has served as a consulting CMO to various biotechnology companies for nearly a decade. Dr Weitzman is board-certified by the American Board of Internal Medicine in Medical Oncology and is an active member of the American College of Physicians. Sensei has decided to realign its resources to fully support the Phase 1/2 clinical trial of SNS-101. As a result, Sensei will pause IND-enabling work on its preclinical-stage TMAb programs, including SNS-102 (VSIG4), SNS-103 (CD39) and SNS-201 (VISTAxCD28). During this time, preclinical work to characterize selected lead antibodies, including their mechanisms of action, and target biology is expected continue. In 2023, Sensei selected lead candidates for both SNS-102 and SNS-201. SNS-102 is a conditionally active antibody targeting VSIG4 that is 585-fold more selective for VSIG4 at low pH conditions. SNS-201 is a bispecific antibody incorporating a CD28 agonist arm and a pH-sensitive anti-VISTA arm designed to conditionally activate CD28 under low pH conditions, such as those found in the tumor microenvironment, leading to T cell activation in the tumor while minimizing off-tumor toxicity. This realignment of resources is expected to extend cash runway into the fourth quarter of 2025. About Sensei Biotherapeutics Sensei Biotherapeutics (Nasdaq: SNSE) is a clinical stage immuno-oncology company focused on the discovery and development of next-generation therapeutics for cancer patients. Through its TMAb™ (Tumor Microenvironment Activated biologics) platform, Sensei develops conditionally active therapeutics designed to disable immunosuppressive signals or activate immunostimulatory signals selectively in the tumor microenvironment. Sensei’s lead investigational candidate is SNS-101, a conditionally active antibody designed to block the V-domain Ig suppressor of T cell activation (VISTA) checkpoint selectively within the low pH tumor microenvironment, where VISTA acts as a suppressor of T cells by binding the receptor PSGL-1. The company is also developing SNS-102, a conditionally active monoclonal antibody targeting V-Set and Immunoglobulin Domain Containing 4 (VSIG-4); SNS-103, a conditionally active monoclonal antibody targeting ecto-nucleoside triphosphate diphosphohydrolase-1 (ENTPDase1), also known as CD39; and SNS-201, a conditionally active VISTAxCD28 bispecific antibody consisting of a CD28 agonist arm and a pH-sensitive anti-VISTA arm. For more information, please visit , and follow the company on Twitter @SenseiBio and LinkedIn. Cautionary Note Regarding Forward-Looking Statements Any statements contained in this press release that do not describe historical facts may constitute forward-looking statements as that term is defined in the Private Securities Litigation Reform Act of 1995. These statements may be identified by words and phrases such as “believe”, “designed to,” “expect”, “may”, “plan”, “potential”, “will”, and similar expressions, and are based on Sensei’s current beliefs and expectations. These forward-looking statements include expectations regarding the development and potential therapeutic benefits of Sensei’s product candidates, the timing of Sensei’s Phase 1/2 clinical trial of SNS-101, including reporting of data therefrom, the expansion of the Phase 1 clinical trial to include additional patients with specific tumor types, the expected timing of an end of Phase 1 meeting with the FDA for SNS-101, preclinical activities related to the Company’s preclinical TMAb product candidates, and its belief that its existing cash and cash equivalents will be sufficient to fund its operations at least into the fourth quarter of 2025. These statements involve risks and uncertainties that could cause actual results to differ materially from those reflected in such statements. Risks and uncertainties that may cause actual results to differ materially include uncertainties inherent in the development of therapeutic product candidates, such as the risk that any one or more of Sensei’s product candidates will not be successfully developed or commercialized; the risk of delay or cessation of any planned clinical trials of Sensei’s product candidates; the risk that prior results, such as signals of safety, activity or durability of effect, observed from preclinical trials and early results from the clinical trial of SNS-101, will not be replicated or will not continue in ongoing or future studies or clinical trials involving Sensei’s product candidates, including SNS-101; the risk that Sensei’s product candidates or procedures in connection with the administration thereof will not have the safety or efficacy pro Sensei anticipates; risks associated with Sensei’s dependence on third-party suppliers and manufacturers, including sole source suppliers, over which Sensei may not always have full control; risks regarding the accuracy of Sensei’s estimates of expenses, capital requirements and needs for additional financing; and other risks and uncertainties that are described in Sensei’s Quarterly Report on Form 10-Q filed with the U.S. Securities and Exchange Commission (SEC) on or about November 7, 2023 and Sensei’s other Periodic Reports filed with the SEC. Any forward-looking statements speak only as of the date of this press release and are based on information available to Sensei as of the date of this release, and Sensei assumes no obligation to, and does not intend to, update any forward-looking statements, whether as a result of new information, future events or otherwise. Investor Contact: Michael Biega Senior Director, Investor Relations Sensei Biotherapeutics mbiega@senseibio.com Media Contact: Joyce Allaire LifeSci Advisors Jallaire@lifesciadvisors.com

免疫疗法临床1期临床2期

2023-12-11

·FierceBiotech

Affimed stops enrolling multiple tumor types as data disappoint but forges ahead in other settings

Affimed shared the update alongside the latest data on AFM13. Affimed is slashing the list of opportunities open to its bispecific innate cell engager AFM24. The failure of data in multiple tumor types to clear its bar for continuation drove the biotech to narrow its focus to lung cancer—but there are signs of encouragement in that setting and for lead candidate AFM13. AFM24 is designed to turn the immune system against tumors by binding to CD16A on innate immune cells and EGFR on cancer cells. Evidence that the molecule drives an uptick in T-cell activity, while also activating the innate immune system, has led Affimed to identify opportunities to combine the therapy with checkpoint inhibitors. The company is continuing to pursue some AFM24 opportunities but is pulling back from multiple indications. A look at phase 1/2a data from a gastric cancer arm and basket cohort, which targeted pancreatic cancer, biliary tract cancer and hepatocellular carcinoma, led the biotech to stop enrollment in the indications. The early data revealed “clinical activity” in both cohorts, Affimed said, but the predicted response rates fell short of the biotech’s internal criteria for further development. Affimed also framed the jettisoning of the indications as supporting its desire to advance in another setting—non-small cell lung cancer (NSCLC)—as quickly as possible. Affimed made NSCLC a priority for AFM24 after reviewing data on 15 patients from the EGFR-wildtype NSCLC expansion arm. The patients had received a median of two lines of prior therapy. All the subjects had previously progressed while on a PD-1/L1 checkpoint inhibitor. Affimed treated them with AFM24 and Tecentriq, Roche’s PD-L1 checkpoint inhibitor. The biotech saw four responses in the patients, although only one is confirmed. One of the unconfirmed responses is a complete response. Although there is no control arm to reveal what AFM24 is contributing to the efficacy of the combination, the fact the patients previously progressed after taking drugs similar to Tecentriq suggests Affimed’s asset may be enhancing the efficacy of the checkpoint inhibitor. Affimed shared the update alongside the latest data on AFM13, the CD30 innate cell engager also known as acimtamig. In 32 relapsed or refractory Hodgkin lymphoma patients, the biotech reported objective and complete response rates of 97% and 78%, respectively. The median duration of response in the heavily pretreated population was 8.8 months. The findings, which are consistent with results shared last year, come from patients who received the recommended phase 2 dose. Affimed recently began a phase 2 trial of acimtamig that is shaping up to be a key event. The biotech’s stock has traded below $1 for much of the year, and fell 8% to below 40 cents in premarket trading Monday.