Eribulin mesylate

SHELTON, Conn., May 29, 2025 /PRNewswire/ -- Intensity Therapeutics, Inc. ("Intensity" or "the Company") (Nasdaq: INTS), a late-stage clinical biotechnology company focused on the discovery and development of proprietary, novel immune-based intratumoral cancer therapies designed to kill tumors and increase immune system recognition of cancers, announces that the Company will be presenting a Trials in Progress poster outlining its Phase 3 INVINCIBLE-3 clinical trial of INT230-6 for the treatment of metastatic soft tissue sarcomas. The poster will be shown at the American Society of Clinical Oncology (ASCO) 2025 Annual Meeting held at McCormick Place in Chicago May 30-June 5, 2025. The poster, titled, "A Multicenter, Randomized, Global Phase 3 Study to Assess the Efficacy and Safety of Intratumoral (IT) INT230-6 (SHAO, VINblastine, Cisplatin) as Monotherapy Compared with Standard of Care Systemic Chemotherapy in Adults with Locally Recurrent, InoperaBLE, or Metastatic Soft Tissue Sarcomas (STS) (INVINCIBLE-3)," will be presented by Sant P. Chawla M.D., Director, Sarcoma Oncology Center of Southern California, during the "Sarcoma" session to be held on Saturday May 31, 2025 from 9:30 AM to 12 PM on panel 66a. An abstract of the poster, which outlines the Company's Phase 3 study protocol, can be found here. "The INVINCIBLE-3 trial is breaking new ground in metastatic sarcoma with a unique, new, investigational product, INT230-6. Following direct intratumoral injection, this drug product results in significant necrosis and the formation of cysts within tumors, with little residual cancer remaining in those injected tumors. A successful outcome of the INVICIBLE-3 study will require practicing physicians to think differently about setting dose and disease endpoints. INT230-6's dose per tumor is set by the tumor size. In this protocol, survival advantage is the gold standard upon which the efficacy of a novel investigational agent such as INT230-6 would be ultimately based," said Dr. Chawla. "We have designed a unique Phase 3 protocol comparing our local therapy to the best systemic standard of care based on our completed Phase 1/2 trial. In our first study, refractory, metastatic sarcoma patients whose disease continued to progress following a median of three prior lines of therapy received INT230-6 alone," said Lewis H. Bender, Intensity Therapeutics Founder, President, and CEO. "Those sarcoma patients showed immune engagement post-dose, uninjected tumors regressing, a disease control rate of 93%, and a median overall survival of 21.3 months with minimal treatment-associated adverse events. Eight regulatory agencies, including the U.S. FDA, have authorized the Phase 3 study. Until sufficient additional funding is obtained, new enrollment for the Phase 3 has been paused. We are continuing to treat the enrolled patients, maintain pharmacovigilance, monitor sites, and look forward to reinitiating recruitment as soon as sufficient resources are available." About INT230-6 INT230-6, Intensity's lead proprietary investigational product candidate, is designed for direct intratumoral injection. INT230-6 was discovered using Intensity's proprietary DfuseRx℠ technology platform. The drug is composed of two proven, potent anti-cancer agents, cisplatin and vinblastine, and a penetration enhancer molecule (SHAO) that helps disperse potent cytotoxic drugs throughout tumors for diffusion into cancer cells. These agents remain in the tumor resulting in a favorable safety profile. In addition to local disease control, direct killing of the tumor by INT230-6 releases a bolus of neoantigens specific to the patient's malignancy, leading to immune system engagement and systemic anti-tumor effects. Importantly, these effects are mediated without immunosuppression, which so often occurs with systemic chemotherapy. About INVINCIBLE-3 INVINCIBLE-3 is a study to evaluate a novel, new drug product administered intratumorally by an interventional radiologist or an equivalently trained physician using image guidance compared to systemically dosed second- or third-line US standard of care chemotherapy. Patients will be randomized 2 to 1 to INT230-6 or pazopanib, trabectedin, or eribulin (selection of SOC depends on the sarcoma subtype). As this is a survival study, there is no crossover allowed between US SOC and INT230-6. Disease progression will be determined by the World Health Organization (WHO) Criteria in conjunction with evaluation of the post-treatment scans. Dosing beyond radiographic progression is allowed should tumors have low levels residual cancer on scans post baseline. Participants will be prospectively stratified into 1 of 3 histologically defined aSTS strata: leiomyosarcoma, liposarcoma (dedifferentiated, myxoid, round cell and pleomorphic) and undifferentiated pleomorphic sarcoma The participants will undergo in 4 phases: screening, treatment, maintenance, and follow-up in the study. Study visits, tumor and endpoint assessments will occur as indicated in the procedural outlines as part of a schedule of events. Important inclusion criteria include: histologically proven, unresectable, locally advanced, or metastatic STS only of the following Participant must have a pathology report indicating the diagnosis of their STS. Participants must have received at least 1 line of therapy for STS and must have progressed following anthracycline-based or alternative standard therapies, except if medically contraindicated or refused by the participant. A participant cannot have received more than 2 prior regimens for unresectable, locally advanced or metastatic STS. Participants must have measurable disease per RECIST 1.1 criteria. Participants must have at least 1 target tumor ≥ 2 cm suitable for injection using routine image guidance, measurable by CT or MRI. Key exclusion criteria include: Prior primary or metastatic brain or meningeal tumors unless clinically and radiographically stable as well as off steroid therapy for at least 2 months. History of severe hypersensitivity reactions to US SOC agents and vinblastine or cisplatin or other products of the same class and their excipients. Histologically proven, unresectable, locally advanced or metastatic STS subtypes other than those specified, for example, excluded subtypes include liposarcoma (well differentiated), desmoid or dermatofibrosarcoma protuberans. Other prior malignancy, except for adequately treated basal or squamous cell skin cancer or superficial bladder cancer, or any other cancer from which the participant has been disease-free for at least 2 years. About Intensity Therapeutics Intensity is a late-stage clinical biotechnology company whose novel engineered chemistry enables aqueous cytotoxic-containing drug formulations to mix and saturate a tumor's dense, high-fat, pressurized environment following direct intratumoral injection. As a result of the saturation, Intensity's clinical trials have demonstrated the ability of the investigational new drug, INT230-6, to kill tumors and elicit an adaptive immune response within days of injection, representing a new approach to cancer cell death that holds the potential to shift the treatment paradigm and turn many deadly cancers into chronic diseases even for malignancies that do not respond to conventional immunotherapy. Intensity has completed two clinical studies and enrolled over 200 patients using INT230-6: a Phase 1/2 dose escalation study in metastatic cancers including sarcomas (NCT03058289), and a Phase 2 randomized control clinical trial in locally advanced breast cancer (the "INVINCIBLE-2 Study") (NCT04781725) in women without undergoing chemotherapy prior to their surgery. The Company initiated a Phase 3 trial in soft tissue sarcoma (the "INVINCIBLE-3 Study") (NCT06263231), testing INT230-6 as second or third-line monotherapy compared to the standard of care ("SOC") with overall survival as an endpoint. Intensity also initiated a Phase 2 study in collaboration with The Swiss Group for Clinical Cancer Research, SAKK (the "INVINCIBLE-4 Study") (NCT06358573) as part of a Phase 2/3 program evaluating INT230-6 followed by the SOC immunochemotherapy and the SOC alone for patients with presurgical triple-negative breast cancer. Pathological complete response ("pCR") is the endpoint. For more information about Intensity, including publications, papers, and posters about its novel approach to cancer therapeutics, visit www.intensitytherapeutics.com Forward-Looking Statements Certain statements in this press release may constitute "forward-looking statements" within the meaning of the United States Private Securities Litigation Reform Act of 1995, as amended to date. These statements include, but are not limited to, statements relating to the Company's expected future plans, cash runway, development activities, projected milestones, business activities or results. When or if used in this communication, the words "may," "could," "should," "anticipate," "believe," "estimate," "expect," "intend," "plan," "predict" and similar expressions and their variants, as they relate to the Company or its management, may identify forward-looking statements. The forward-looking statements contained in this press release are based on management's current expectations and projections about future events. Nevertheless, actual results or events could differ materially from the plans, intentions, and expectations disclosed in, or implied by, the forward-looking statements. These risks and uncertainties, many of which are beyond our control, include: the initiation, timing, progress and results of future preclinical studies and clinical trials and research and development programs; the need to raise additional funding before the Company can expect to generate any revenues from product sales; plans to develop and commercialize product candidates; the timing or likelihood of regulatory filings and approvals; the ability of the Company's research to generate and advance additional product candidates; the implementation of the Company's business model, strategic plans for the Company's business, product candidates and technology; commercialization, marketing and manufacturing capabilities and strategy; the rate and degree of market acceptance and clinical utility of the Company's system; the Company's competitive position; the Company's intellectual property position; developments and projections relating to the Company's competitors and its industry; the Company's ability to maintain and establish collaborations or obtain additional funding; expectations related to the use of cash and cash equivalents and investments; estimates regarding expenses, future revenue, capital requirements and needs for additional financing; and other risks described in the section entitled "Risk Factors" in the Company's SEC filings, which can be obtained on the SEC website at www.sec.gov. Readers are cautioned not to place undue reliance on the forward-looking statements, which speak only as of the date on which they are made and reflect management's current estimates, projections, expectations, and beliefs. The Company does not plan to update any such forward-looking statements and expressly disclaims any duty to update the information contained in this press release except as required by law. Investor Relations Contact: Justin Kulik Justin@coreir.com CORE IR (516) 222-2560 Media Contact: Jules Abraham CORE IR pr@coreir.com View original content to download multimedia:https://www.prnewswire.com/news-releases/intensity-therapeutics-incs-phase-3-invincible-3-sarcoma-study-selected-for-presentation-at-the-american-society-of-clinical-oncology-asco-2025-annual-meeting-302466668.html SOURCE Intensity Therapeutics Inc.

-01-引言肿瘤相关巨噬细胞（TAM）是免疫抑制细胞和细胞因子网络的核心，在肿瘤免疫逃避中起着至关重要的作用。因此，了解巨噬细胞和其他免疫细胞之间的相互作用以及增强现有抗癌治疗的因素至关重要。TAM在功能上是异质性的，分为两个主要亚群，M1和M2巨噬细胞。M1巨噬细胞是抵抗微生物感染的第一道防线，M1巨噬细胞还保持强大的抗原呈递能力，诱导强烈的Th1反应。相反，M2巨噬细胞在限制免疫反应、诱导血管生成和组织修复方面起着关键作用。因此，M2型TAM的存在与促肿瘤活性相关，而M1型TAM的存在与抗肿瘤活性相关。总之，TAM是产生免疫抑制性TME的关键，并且巨噬细胞与TME中的各种免疫细胞和细胞因子之间的串扰起着不可替代的作用。了解巨噬细胞参与肿瘤免疫逃逸的主要机制和相关靶向治疗，有助于我们改善临床方案，制定克服巨噬细胞相关免疫耐受的潜在新策略。-02-一、调节巨噬细胞吞噬的信号途径CD47/SIRPαCD47是一种广泛分布于正常细胞表面的免疫球蛋白，可通过抑制吞噬作用负调节抗肿瘤免疫，并参与介导细胞增殖、迁移、凋亡和免疫稳态。其主要配体信号调节蛋白α（SIRPα）是一种在髓细胞膜上高表达的跨膜蛋白，其胞外区的N末端可与CD47结合，导致免疫受体酪氨酸抑制基序（ITIM）上的酪氨酸磷酸化，释放“不要吃我”信号，从而抑制巨噬细胞介导的吞噬作用，保护正常细胞免受免疫系统的破坏。研究表明CD47在多种肿瘤中高表达，如恶性血液肿瘤和肝细胞癌（HCC），这也与不良预后相关。给予CD47阻断抗体或靶向灭活CD47基因可显著抑制肿瘤生长。此外，抗CD47治疗还可以改变TME中巨噬细胞的极化状态，诱导TAM转化为抗肿瘤状态。LILRB1/MHCI白细胞免疫球蛋白样受体B（LILRB）在大多数免疫细胞上表达，由细胞外Ig样区、跨膜区和含有ITIM的细胞内区组成。它与主要配体主要组织相容性复合体I（MHCI）结合后可介导免疫细胞激活的负调控。MHCI是由HLAα链和β2-微球蛋白（β2M）形成的复合体，某些肿瘤细胞高表达β2M，其可与巨噬细胞上的LILRB1结合以抑制吞噬作用，导致免疫监视丧失。因此，在肿瘤细胞上MHCI正常或高表达的患者中，靶向MHCI/LILRB1轴的药物可能促进抗肿瘤免疫反应，并与靶向CD47/SIRPα轴的药物发挥协同作用。CD24/Siglec-10CD24，也称为热稳定抗原，是一种高度糖基化的表面蛋白，由糖基磷脂酰肌醇锚定，可与唾液酸结合免疫球蛋白样凝集素-10（Siglec-10）相互作用，以减少感染或肝损伤引起的先天免疫介导的有害炎症。肿瘤细胞高表达CD24，而TAM高表达Siglec-10。与CD24结合后，Siglec-10的ITIM可招募并激活含有SH2结构域的酪氨酸磷酸酶SHP-1或SHP-2，从而阻断巨噬细胞吞噬所需的细胞骨架重排，触发抑制性信号转导级联。“不要吃我”发出CD47、β2M和CD24信号，所有这些信号都涉及基于ITIM的巨噬细胞信号，导致巨噬细胞耐药癌细胞亚群的免疫选择，使肿瘤细胞逃避巨噬细胞的监视和清除。因此，掌握肿瘤细胞表达抗吞噬信号的机制可以更好地预测治疗效果以及靶向治疗。-03- 二、巨噬细胞参与免疫逃避的机制巨噬细胞参与形成抑制性髓系微环境TME中的各种介质参与调节MDSC和单核细胞的募集，并通过不同的信号通路极化巨噬细胞，从而促进免疫抑制髓系微环境的形成。                此外，巨噬细胞、MDSC和树突状细胞之间的串扰进一步形成免疫抑制髓系微环境。卵巢癌细胞高表达CD39和CD73，有助于催化细胞外ATP转化为腺苷，腺苷可以招募单核细胞并诱导它们分化为分泌IL-10的TAM。TAM表达CD39和CD73，进一步增加MDSC和TAM的浸润，从而形成一种自我放大机制，促进局部免疫逃逸。肿瘤相关中性粒细胞（TAN）也是免疫抑制髓系微环境的重要组成部分。与巨噬细胞一样，中性粒细胞可以被描述为两个亚群，N1和N2，N1表现出抗肿瘤活性，N2被认为能促进肿瘤转移。在乳腺癌模型中，TAMs分泌的IL-1β诱导γδT细胞释放IL-17以调节G-CSF的释放并促进中性粒细胞的募集以刺激转移，表明TANs在肿瘤进展中与TAMs密切相关。然而，TAN和TAM在肿瘤发生和免疫逃逸中的特异性相互作用机制尚不清楚。巨噬细胞影响Th细胞巨噬细胞和辅助性T细胞之间存在相互调节作用。巨噬细胞依赖TGF-β和IL-10将Th1细胞转化为Th2细胞，以逆转CD8+细胞毒性T细胞和CD4+Th1细胞的抗肿瘤作用，这被认为是一种肿瘤免疫逃逸机制。而Th细胞通过改变巨噬细胞的极化方向影响肿瘤TME。Th1细胞分泌IFN-γ以诱导M1极化，而Th2细胞可分泌IL-4、IL-5和IL-10以促进M2巨噬细胞的生成。此外，Treg表型和功能对免疫抑制性TME发挥重要作用。最近的研究表明，巨噬细胞可以通过各种途径影响Treg的增殖、迁移和功能。首先，TAMs可分泌IL-23，促进Treg的增殖以及IL-10和TGF-β的表达，抑制CTL杀伤肿瘤细胞；其次，巨噬细胞过度表达CCL1，即Treg上表达的CCR8的配体，以吸引Treg进入肿瘤区域；类似地，巨噬细胞分泌CCL22以诱导Treg迁移到卵巢癌的肿瘤区域，抑制T细胞免疫并促进肿瘤生长。巨噬细胞与CAF 的相互作用CAF是TME中最丰富的基质细胞，可释放大量细胞因子，合成和重塑细胞外基质，形成促瘤纤维微环境。CAF可分泌IL-6、M-CSF、MCP-1和基质细胞衍生因子-1，以促进巨噬细胞的浸润和分化。而M2可分泌TGF-β，以促进内皮细胞向间质细胞的转化，并增加CAF的反应性，从而增强癌细胞的侵袭性。巨噬细胞通过PD-1/PD-L1轴介导免疫逃逸TAMs调节肿瘤细胞上PD-L1和CD8+T细胞上PD-1的表达。PD-L1在多种肿瘤组织中高表达，可被TAM衍生的TNF-α上调，并与肿瘤基质中的巨噬细胞浸润呈正相关。在TME中，PD-L1在TAMs上的表达也受到许多因素的影响。IL-27/STAT3轴在淋巴瘤浸润巨噬细胞中诱导PD-L1/2过表达。Progranulin可以通过STAT3途径上调TAMs上的PD-L1，从而促进乳腺癌的免疫逃避。同时，PD-1/PD-L1轴对巨噬细胞功能有着深刻的影响。TAMs上PD-1表达的增加可抑制其吞噬作用，并在结构上作用于mTOR途径，对巨噬细胞的增殖和活化起负调节作用。因此，PD-1/PD-L1阻断也可直接影响巨噬细胞。PD-1/PD-L1阻断剂可促进巨噬细胞的促炎极化，增强效应T细胞的活性，并与其他免疫检查点抑制剂合作限制肿瘤扩散。除了PD-1/PD-L1轴外，一些实验结果表明TAM还可以与其他免疫检查点（如CTLA/CD86轴和TIM3/galectin-9轴）一起诱导免疫逃逸，但仍缺乏确切的证据。巨噬细胞与这些免疫检查点在免疫逃逸中的相互作用值得进一步研究。巨噬细胞有助于形成免疫无反应部位免疫无应答是肿瘤组织逃避免疫监视的重要原因，巨噬细胞可能通过以下机制参与肿瘤组织的免疫豁免。首先，巨噬细胞可以通过聚集CAF到肿瘤区域，CAF沉积纤维胶原、透明质酸、纤维连接蛋白和其他物质，并分泌赖氨酰氧化酶刺激I型胶原交联，从而形成物理屏障。其次，与肿瘤细胞类似，诱导的TAM可表达Fas-L并释放活性可溶性Fas-L，诱导Fas+淋巴细胞凋亡，而CAF可通过MHC-1抗原交叉呈递上调Fas-L和PD-L2，抑制CD8+T细胞的活性，从而形成缺乏淋巴细胞浸润的TME。此外，肿瘤细胞分泌的透明质酸可与巨噬细胞表面的TLR4结合，诱导TAM迁移至肿瘤相关区域，并通过miR935抑制C/EBPβ的表达，促进巨噬细胞向M2表型的分化，从而促进恶性肿瘤细胞逃避免疫监视并“冷却”免疫反应。-04-三、巨噬细胞免疫治疗的临床进展靶向TAM越来越多的证据表明TAM有助于化疗耐药性,以TAM为靶点的单一疗法或联合化疗的治疗方法正在临床前和临床中进行试验。TAM被CSF-1招募到TME中，促进乳腺癌的发展和转移。因此，用单克隆抗体或小分子化合物靶向CSF-1/CSF-1R轴的治疗方法正在试验中。RG7155是一种靶向CSF-1R的单克隆抗体，在一项1期临床试验（NCT01494688）中对7名诊断为弥漫型巨细胞瘤的患者进行治疗，所有患者均出现PR，2名患者出现CR。此外，在RG7155治疗的患者肿瘤活检中，CD68+CD163+巨噬细胞的数量减少，表明TAM向TME的募集减少。靶向CSF-1R、c-Kit和Flt3的酪氨酸激酶抑制剂PLX3397通过使TAM的M2表型去极化来阻断肿瘤进展。PLX3397正在包括黑色素瘤（NCT02071940、NCT02975700）、前列腺癌（NCT0149043）和胶质母细胞瘤（NCT01349036）患者中进行临床试验。其他CSF-1R抑制剂，如ARRY-382（NCT01316822）、BLZ945（NCT02829723）、AMG820（NCT01444404）和IMC-CS4（NCT01346358）也正在各种实体瘤患者中进行测试。除了单药治疗外，针对CSF-1或CSF-1R的抑制剂还与化疗联合进行测试。例如，PLX3397与紫杉醇联合用于晚期实体瘤患者（NCT01525602）；PLX3397与eribulin联合用于乳腺癌患者的试验（NCT01596751）；PLX3397与vemurafenib用于BRAF突变黑色素瘤患者（NCT01826448）；PLX3397联合sirolimus用于晚期肉瘤患者（ NCT02584647）等。此外，TAM的靶向剂和免疫检查点抑制剂的联合应用也在开发中。IMC-CS4与durvalumab或tremelimumab联合用于实体瘤患者的临床试验（NCT02718911）正在进行中。还有PLX3397与pembrolizumab联合用于各种肿瘤患者的1期临床试验（NCT02452424），ARRY-382与pembrolizumab的联合试验（NCT02880371），BLZ945与PDR001（一种针对PD-1的单克隆抗体）的联合试验（NCT02829723），RG7155与atezolizumab的联合试验（NCT02323191），以及AMG820与使用pembrolizumab的联合试验（NCT02713529）。CAR-巨噬细胞直到2020年11月，两个基于CAR-M策略的临床试验已经获得FDA的批准。第一个是来自CARISMA Therapeutics的候选药物CT-0508，它用抗HER2的CAR-M治疗复发/难治性HER2过度表达的肿瘤患者（I期临床试验）。另一个是Maxyte的MCY-M11，它利用mRNA转染PBMC表达靶向间皮素的CAR（包括CAR-M），治疗复发/难治性卵巢癌和腹膜间皮瘤患者，目前正在招募志愿者进行I期临床试验。-05-结语越来越多的研究表明巨噬细胞在肿瘤发展、转移、免疫调节、肿瘤血管形成、TME重塑和癌症治疗反应中起着关键作用。巨噬细胞靶向治疗有望成为肿瘤免疫治疗的下一个前沿，阐明其相互作用模式将有助于对免疫抑制性TME形成更全面的认识，避免免疫反弹，减少肿瘤免疫逃避，促进相关研究的发展。参考资料：1.Next frontier in tumor immunotherapy:macrophage-mediated immune evasion. Biomark Res. 2021; 9: 72.公众号内回复“ADC”或扫描下方图片中的二维码免费下载《抗体偶联药物：从基础到临床》的PDF格式电子书！公众号已建立“小药说药专业交流群”微信行业交流群以及读者交流群，扫描下方小编二维码加入，入行业群请主动告知姓名、工作单位和职务。