Ciforadenant

引言 前列腺癌是全球男性中最常见的恶性肿瘤之一，尤其是晚期转移性去势抵抗性前列腺癌（mCRPC）。尽管免疫检查点抑制剂（ICIs）已被证明对多种癌症具有显著疗效，但对于mCRPC患者来说，这一治疗策略的效果却不尽人意。这背后的原因复杂且多样，而肿瘤微环境（TME）的免疫抑制性被认为是关键因素之一。 近年来，研究人员发现，肿瘤相关巨噬细胞（tumor-associated macrophages, TAMs）和髓系抑制细胞（MDSCs）在促进肿瘤生长和抑制免疫反应中扮演了重要角色。然而，这些髓系细胞种类多样、功能复杂，使得针对它们的治疗策略面临巨大挑战。例如，尽管CSF1R（集落刺激因子1受体）阻断剂曾被寄予厚望，但临床试验的结果却显示出有限的疗效。如何深入理解髓系细胞在前列腺癌免疫抑制中的具体机制，成为破解治疗耐药难题的关键。 12月4日Nature的研究报道“Evolution of myeloid-mediated immunotherapy resistance in prostate cancer”，研究人员利用单细胞RNA测序技术，分析了不同阶段前列腺癌患者肿瘤样本中的髓系细胞，发现了一种高度表达SPP1基因的巨噬细胞亚群（SPP1hi-TAMs）。这种特定细胞随着疾病进展逐渐富集，并通过腺苷信号通路抑制CD8+ T细胞活性，最终导致免疫治疗的耐药性。更令人振奋的是，研究进一步表明，阻断腺苷A2A受体（A2AR）不仅可以有效降低SPP1hi-TAMs的免疫抑制作用，还显著提高了免疫检查点抑制剂的疗效。 该研究不仅揭示了SPP1hi-TAMs在前列腺癌免疫治疗耐药中的核心作用，还提供了一种可能的联合治疗策略，为mCRPC患者带来了新的希望。这一发现强调了从肿瘤微环境入手的治疗潜力，并为未来的精准医学研究提供了重要的指引。 前列腺癌的挑战：为何免疫治疗对某些患者无效？ 前列腺癌是全球男性中最常见的恶性肿瘤之一，尤其在老龄化社会中，其发病率和死亡率居高不下。仅在美国，每年新增病例数就高达29万，导致约3.5万例患者不幸去世。尽管当前的治疗手段，如雄激素剥夺治疗（androgen deprivation therapy, ADT），在早期前列腺癌中表现出良好的疗效，但大多数患者最终会进入转移性去势抵抗性前列腺癌（metastatic castration-resistant prostate cancer, mCRPC）的阶段。此时，肿瘤不仅对ADT耐药，还常伴随治疗选择有限，患者预后极差。 近年来，免疫检查点抑制剂（immune checkpoint inhibitors, ICIs）的问世为癌症治疗带来了革命性突破。这种疗法通过阻断抑制T细胞活性的蛋白质（如PD-1、PD-L1和CTLA-4），使免疫系统重新激活，识别并清除肿瘤细胞。在某些癌症类型中，ICIs展现了前所未有的疗效。然而，遗憾的是，mCRPC患者对ICIs普遍反应较差，只有极少数具有特殊分子亚型的患者能够受益。 那么，为什么免疫疗法对mCRPC患者“束手无策”？研究表明，问题的核心在于肿瘤微环境（tumor microenvironment, TME）的免疫抑制特性。在mCRPC中，肿瘤微环境复杂且动态，包含了大量的免疫抑制性髓系细胞（如肿瘤相关巨噬细胞和髓系抑制细胞），它们通过多种机制削弱了T细胞的抗肿瘤活性。更糟糕的是，这些免疫抑制细胞在ADT治疗后会进一步富集，形成难以突破的“免疫屏障”。 尽管髓系细胞的存在是免疫治疗失败的关键原因之一，相关靶向策略却面临巨大挑战。例如，针对集落刺激因子1受体（CSF1R）的阻断剂在临床试验中未能显著改善患者的预后。这种失败反映了髓系细胞种群的异质性及其复杂的免疫调控网络。 揭开髓系细胞的神秘面纱：从复杂到精准 在癌症研究中，髓系细胞一直是一把“双刃剑”。它们在健康状态下负责维持免疫平衡，但在癌症环境中却常被肿瘤“招募”并“改造”，成为促进肿瘤生长和免疫抑制的帮凶。特别是在前列腺癌的肿瘤微环境中，髓系细胞不仅数量众多，功能也复杂多样，包括肿瘤相关巨噬细胞（tumor-associated macrophages, TAMs）、髓系抑制细胞（myeloid-derived suppressor cells, MDSCs）和树突状细胞（dendritic cells, DCs）等。 研究发现，这些髓系细胞通过释放多种免疫抑制因子（如IL-10、TGF-β）和代谢产物（如腺苷），削弱了T细胞和自然杀伤细胞（NK细胞）的抗肿瘤活性。然而，髓系细胞并不是单一的群体，而是一个异质性极高的“大家族”。例如，TAMs就分为M1型（促炎性、抗肿瘤性）和M2型（抗炎性、促肿瘤性），它们的比例和功能会随着肿瘤的进展而动态变化。这种复杂性使得针对髓系细胞的治疗策略面临巨大挑战。 幸运的是，单细胞技术的兴起为破解这一谜题带来了突破性进展。通过单细胞RNA测序（single-cell RNA sequencing, scRNA-seq），研究人员可以精确地解析肿瘤组织中每个细胞的基因表达特征。在这项研究中，研究人员对不同阶段前列腺癌患者的肿瘤样本进行了单细胞分析，共获得超过14万单细胞的转录组数据。结果显示，髓系细胞被细分为14种亚群，包括8种巨噬细胞亚群、2种髓系抑制细胞亚群和3种树突状细胞亚群等。 通过单细胞RNA测序（5′ scRNA-seq）技术，揭示了前列腺癌患者肿瘤样本中SPP1高表达的肿瘤相关巨噬细胞（SPP1hi-TAMs）的富集情况及其免疫抑制作用的动态变化（Credit: Nature） 研究对象与方法： 图a描述了研究对象的分类，包括未接受雄激素剥夺治疗（ADT）的局限性前列腺癌患者（n=13）、接受ADT治疗的转移性激素敏感型前列腺癌患者（HSPC, n=24）以及ADT治疗后进展为去势抵抗型前列腺癌患者（mCRPC, n=6）。通过对这些患者的肿瘤样本进行单细胞RNA测序（10x Genomics），研究人员深入分析了肿瘤微环境（TME）中髓系细胞的组成和功能。 髓系细胞的异质性： 图b展示了通过UMAP聚类图对肿瘤样本细胞类型和髓系细胞亚群的识别。研究共鉴定出多种髓系细胞亚群，包括8种巨噬细胞亚群、2种髓系抑制细胞（MDSC）亚群及3种树突状细胞（DC）亚群，进一步显示了髓系细胞在TME中的高度异质性。 SPP1hi-TAMs的动态富集： 图c和图d量化了髓系细胞亚群在前列腺癌疾病进展中的频率变化。研究发现，随着疾病从局限性前列腺癌进展至mCRPC，SPP1hi-TAMs的数量显著增加（与局限性前列腺癌相比P=0.002，与HSPC相比P=0.04）。这一结果表明SPP1hi-TAMs可能是晚期疾病阶段的重要免疫抑制因子。 免疫抑制基因表达特征： 图e和图f显示，SPP1hi-TAMs具有较高的免疫抑制基因表达分数，与其他髓系细胞亚群相比表现出更强的免疫抑制能力。研究还发现，这些基因特征在mCRPC患者中显著增强，进一步强化了SPP1hi-TAMs在抑制免疫反应中的作用。 与T细胞耗竭的关联： 图g揭示了SPP1hi-TAMs的富集程度与CD8+ T细胞耗竭特征之间的相关性。mCRPC患者中，这种相关性更为显著（P=0.07，R=0.780），表明SPP1hi-TAMs可能通过诱导T细胞耗竭促进免疫治疗耐药。 SPP1hi-TAMs的特异基因表达： 图h分析了SPP1hi-TAMs与其他髓系细胞亚群之间的差异基因表达。SPP1hi-TAMs显著上调了与免疫抑制和腺苷信号通路相关的基因（如SPP1、CD73），而关键巨噬细胞靶点基因（如CSF1R）的表达水平较低。这一特性可能解释了传统CSF1R阻断疗法对mCRPC疗效有限的原因。 SPP1hi-TAMs：免疫治疗耐药的“幕后推手” 在探究前列腺癌免疫治疗耐药性时，研究人员发现了一群关键的“幕后推手”——高度表达SPP1基因的肿瘤相关巨噬细胞（SPP1hi-TAMs）。这一髓系细胞亚群在疾病进展中逐渐占据主导地位，不仅数量显著增加，还展现出强大的免疫抑制功能。 通过单细胞RNA测序（scRNA-seq），研究人员识别出SPP1hi-TAMs在mCRPC患者肿瘤微环境中的富集程度远高于早期阶段的前列腺癌。组织染色实验进一步验证了这一发现：与早期激素敏感型前列腺癌相比，晚期去势抵抗性前列腺癌患者中SPP1hi-TAMs的数量显著增加。这些细胞不仅富集SPP1基因表达，还伴随CX3CR1和CSF1R等关键分子表达的下降，后者是传统抗巨噬细胞治疗的主要靶点之一。这种分子特性的变化可能解释了CSF1R阻断剂治疗失败的原因。 那么，SPP1hi-TAMs如何在肿瘤中发挥免疫抑制作用？研究表明，这一细胞亚群通过腺苷信号通路实现了强效的免疫抑制。腺苷是一种代谢产物，通过与腺苷A2A受体（A2AR）的结合，抑制了CD8+ T细胞的增殖和功能。SPP1hi-TAMs在高氧耗和缺氧环境中表现出显著的腺苷相关基因（如CD73）的过表达，释放了大量腺苷分子，从而进一步强化了肿瘤微环境的免疫抑制性。 研究中，小鼠实验清楚地展示了SPP1hi-TAMs的这一功能。当SPP1hi-TAMs与CD8+ T细胞共同培养时，T细胞的增殖率和活性显著下降，表明这些巨噬细胞通过腺苷信号阻碍了免疫反应的有效性。此外，SPP1hi-TAMs的富集与T细胞耗竭基因表达的上升高度相关，这表明其直接影响了抗肿瘤免疫反应的核心环节。 动物实验的启示：从分子机制到治疗策略 理解SPP1hi-TAMs在免疫治疗耐药中的作用，离不开动物模型的深入验证。在这项研究中，研究人员使用前列腺癌小鼠模型，不仅再现了人类肿瘤微环境的复杂性，还揭示了SPP1hi-TAMs的功能机制及其对治疗的影响。 研究团队通过移植MyC-CaP前列腺癌细胞建立小鼠模型，并通过单细胞RNA测序技术，在模型中成功识别出与人类SPP1hi-TAMs相对应的髓系细胞亚群。这些细胞以高度表达Spp1、Cd9和Lgals3基因为特征，同时显著缺乏CSF1R的表达，这一特性与临床观察中CSF1R阻断剂治疗无效的现象完全一致。 为了评估SPP1hi-TAMs的功能，研究人员采用了共培养实验和免疫检查点抑制剂（ICIs）联合治疗模型。在体外实验中，SPP1hi-TAMs通过腺苷信号途径抑制CD8+ T细胞的增殖和活性，进一步证实了其强大的免疫抑制作用。在体内，研究人员通过将SPP1hi-TAMs直接注射到接受ICIs治疗的小鼠肿瘤中，观察到ICIs的疗效显著下降，表明SPP1hi-TAMs是ICIs耐药的关键驱动因素。 更令人振奋的是，该研究还探索了腺苷A2A受体（A2AR）阻断剂在治疗中的潜力。研究发现，通过使用A2AR抑制剂ciforadenant，可以显著降低SPP1hi-TAMs的免疫抑制作用，同时增强CD8+ T细胞的抗肿瘤活性。在小鼠模型中，联合使用A2AR阻断剂和ICIs，不仅有效抑制了肿瘤生长，还显著延长了小鼠的生存期。 这些动物实验清楚地表明，SPP1hi-TAMs通过腺苷信号通路推动免疫治疗耐药，而A2AR阻断剂则为破除这一机制提供了有效的解决方案。 联合治疗的突破：腺苷阻断如何改变局面 在免疫治疗领域，联合疗法正在成为突破癌症治疗瓶颈的关键策略。针对SPP1hi-TAMs通过腺苷信号通路导致的免疫抑制，研究团队探索了腺苷A2A受体（A2AR）抑制剂与免疫检查点抑制剂（ICIs）联合治疗的可能性，初步结果振奋人心。 在临床前小鼠模型中，研究人员首先评估了单独使用A2AR抑制剂ciforadenant的效果。结果显示，A2AR抑制剂显著降低了肿瘤中SPP1hi-TAMs的数量，并减少了CD8+ T细胞的耗竭现象（标记为CD38+PD-1+），从而有效抑制了肿瘤的生长。当ciforadenant与PD-1抑制剂联合使用时，疗效进一步提升，肿瘤生长明显减缓，CD8+ T细胞的多功能性（如同时分泌IFN-γ和TNF-α的能力）显著增强。这表明腺苷阻断通过解除免疫抑制，为ICIs激发T细胞活性提供了更有利的环境。 这一成果在早期临床试验中也得到了验证。在一项针对晚期mCRPC患者的I期临床试验中，研究人员测试了ciforadenant与PD-L1抑制剂atezolizumab的联合疗法。24名患者中，有25%的患者在治疗后前列腺特异性抗原（PSA）水平显著下降，且部分患者的肿瘤体积明显缩小。进一步分析发现，治疗前肿瘤中SPP1hi-TAMs的高丰度可能预示着更好的治疗效果，这为开发基于生物标志物的精准治疗策略提供了线索。 联合疗法的成功不仅归功于A2AR抑制剂有效削弱了SPP1hi-TAMs的免疫抑制作用，还在于PD-1或PD-L1抑制剂激发了更强的抗肿瘤免疫反应。这种协同效应为治疗mCRPC开辟了新的路径，尤其是那些对单一ICIs治疗无反应的患者。 未来的治疗新思路 肿瘤治疗的未来，正在从“治愈肿瘤”向“重塑微环境”转变。在这场转变中，SPP1hi-TAMs的发现不仅为mCRPC患者的治疗带来了新的希望，也为精准医学提供了全新的思路。作为一种高度特异的肿瘤相关巨噬细胞亚群，SPP1hi-TAMs展现出了巨大的潜在价值。 首先，SPP1hi-TAMs可以作为一种重要的生物标志物，帮助预测免疫治疗的效果。在临床试验中，研究人员发现患者肿瘤组织中SPP1hi-TAMs的丰度与联合治疗的疗效显著相关。通过检测SPP1hi-TAMs的水平，医生或许能够筛选出更有可能受益于A2AR抑制剂与免疫检查点抑制剂联合治疗的患者群体，从而实现个性化治疗。这种基于生物标志物的精准医学策略，有望提升治疗的成功率，并避免无效治疗带来的经济和身体负担。 其次，SPP1hi-TAMs本身也是一个极具潜力的治疗靶点。研究显示，SPP1hi-TAMs通过腺苷信号通路抑制抗肿瘤免疫反应，同时还能通过其他促炎性因子（如IL-1β）进一步恶化肿瘤微环境。未来的研究可以进一步探索更多抑制SPP1hi-TAMs功能或减少其数量的方法，例如针对腺苷信号通路和炎症因子的双靶点治疗策略，从而从源头上瓦解免疫抑制。 此外，肿瘤微环境的复杂性决定了单一治疗手段往往难以完全奏效。未来的治疗应当注重多通路、多靶点的综合干预，尤其是结合免疫调控和代谢调节的策略，以彻底扭转TME的不利局面。研究表明，通过单细胞技术解析的微环境数据，不仅有助于发现新的细胞群体，还能推动新型药物的开发。 未来的医学图景或许将聚焦于重建一个“健康的”肿瘤微环境，为患者带来更长久的生存与更高的生活质量。这一方向充满挑战，但也充满希望。 参考文献 Lyu, A., Fan, Z., Clark, M. et al. Evolution of myeloid-mediated immunotherapy resistance in prostate cancer. Nature (2024). https://doi-org.libproxy1.nus.edu.sg/10.1038/s41586-024-08290-3 责编|探索君 排版|探索君 转载请注明来源于【生物探索】 声明：本文仅用于分享，不代表平台立场，如涉及版权等问题，请尽快联系我们，我们第一时间更正，谢谢！ End 往期精选 围观 Nature | 单细胞分析技术的革命性进展 热文 Nature | 环状RNA（circRNA）为何成为基因调控的新宠？ 热文 Cell | AI取代科研人员还有多远？ 热文 新英格兰 | 司美格鲁肽（semaglutide）又有新发现：助力关节炎治疗 热文 CRISPR技术进化史 | 24年Cell 综述

Soquelitinib Atopic Dermatitis Phase 1 Clinical Trial Enrolling Patients in Second Dosing Cohort Interim Data from Atopic Dermatitis Trial Expected to be Announced December 2024 Registration Phase 3 Clinical Trial of Soquelitinib in Peripheral T Cell Lymphoma (PTCL) Enrolling with Multiple Clinical Sites Open Conference call today at 4:30 p.m. ET / 1:30 p.m. PT BURLINGAME, Calif., Nov. 12, 2024 (GLOBE NEWSWIRE) -- Corvus Pharmaceuticals, Inc. (Corvus or the Company) (Nasdaq: CRVS), a clinical-stage biopharmaceutical company, today provided a business update and reported financial results for the third quarter ended September 30, 2024. “There is strong interest from clinicians and patients in both of our clinical programs for soquelitinib – the registration Phase 3 clinical trial in PTCL and the Phase 1 clinical trial in atopic dermatitis – and we are pleased with ongoing enrollment in these trials,” said Richard A. Miller, M.D., co-founder, president and chief executive officer of Corvus. “ITK inhibition offers a novel mechanism of action that inhibits multiple parallel signaling pathways that modulate T cell function and immunity, giving it broad potential across a range of indications in oncology and immune disease. Its clinical potential has already been demonstrated in PTCL and we look forward to presenting interim data from our Phase 1 clinical trial in atopic dermatitis in December. We are excited for the potential of ITK inhibition to provide a new oral treatment option for atopic dermatitis, with the potential for improved efficacy, and with a more convenient and tolerable profile than biologics.” Business Update and Strategy Prioritized Program: Soquelitinib (Corvus’ selective ITK inhibitor) Soquelitinib for Immune Diseases Corvus continues to enroll patients at multiple clinical sites in its randomized, placebo-controlled Phase 1 clinical trial of soquelitinib in patients with moderate to severe atopic dermatitis. The trial is planned to enroll 64 patients that have failed at least one prior therapy across four different 28-day dosing regimens of soquelitinib compared to a placebo group. Patients are followed for an additional 30 days after completing the 28 day course of therapy. The endpoints include safety and improvement in the Eczema Area and Severity Index. Patients and physicians are blinded to the treatment assignment. Enrollment in the first cohort (100 mg, twice per day) has been completed and the data review committee has met and found no safety signals. The second cohort (200 mg, once-daily) is now enrolling patients. Corvus plans to announce interim data from the Phase 1 clinical trial in December 2024. In November, Corvus plans to present new preclinical data highlighting the potential of soquelitinib to prevent lung damage, inflammation and pulmonary hypertension caused by systemic sclerosis at ACR Convergence 2024, the annual meeting of the American College of Rheumatology.Corvus continues to advance its next-generation ITK inhibitor preclinical product candidates, which were designed to deliver precise T-cell modulation that is optimized for specific immunology indications. Soquelitinib for T Cell Lymphoma Corvus continues to enroll patients in a registrational Phase 3 clinical trial of soquelitinib in patients with relapsed PTCL at multiple sites. This randomized controlled trial is anticipated to enroll a total of 150 patients with relapsed PTCL and is evaluating soquelitinib versus physicians’ choice of either belinostat or pralatrexate. The primary endpoint of the trial is progression free survival.There are no FDA fully approved agents for the treatment of relapsed PTCL and the FDA has granted soquelitinib Orphan Drug Designation for the treatment of T cell lymphoma and Fast Track designation for treatment of adult patients with relapsed or refractory peripheral T cell lymphoma after at least 2 lines of systemic therapy. Collaboration with Kidney Cancer Research Consortium: Ciforadenant (adenosine A2a receptor inhibitor) Corvus is collaborating with the Kidney Cancer Research Consortium in a Phase 1b/2 clinical trial evaluating ciforadenant as a potential first line therapy for metastatic renal cell cancer (RCC) in combination with ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1). The efficacy endpoint for the trial is deep response rate, defined as CR plus PRs of greater than 50% tumor volume reduction. The clinical trial is expected to enroll up to 60 patients and as of September 30, 2024, a total of 46 patients were enrolled in the trial. The protocol defined, interim pre-specified statistical threshold for efficacy is a 50% increase above the 32% deep response rate seen with previous ipilimumab/nivolumab combination trials in RCC conducted by investigators at the Kidney Cancer Research Consortium. The analysis of the clinical trial continues to meet the threshold for efficacy and therefore enrollment continues. Along with our partners at the Kidney Cancer Research Consortium, we have decided to continue our follow-up of patients on the trial before presenting the data. Therefore, we will not be presenting this data at the GU Malignancy conference taking place in late November and will instead target a presentation sometime in 2025.The Phase 1b/2 clinical trial in patients with metastatic RCC is supported by data presented in November at the Society for Immunotherapy of Cancer (SITC) 39th Annual Meeting highlighting the potential of ciforadenant to overcome immunotherapy resistance in metastatic castration resistant prostate cancer. Financial Results As of September 30, 2024, Corvus had cash, cash equivalents and marketable securities of $41.7 million as compared to $27.1 million as of December 31, 2023. In October 2024, a holder of 1,677,220 common stock warrants early exercised all of their warrants resulting in cash proceeds of approximately $5.9 million. Corvus expects full year 2024 net cash used in operating activities to be between approximately $25 million and $26 million, resulting in a projected cash balance of between approximately $38 million and $39 million at December 31, 2024. Based on its current plans, Corvus expects its cash to fund operations into 2026. Research and development expenses for the three months ended September 30, 2024 totaled $5.2 million compared to $4.0 million for the same period in 2023. The increase of approximately $1.2 million was primarily due to higher clinical trial costs associated with the development of soquelitinib. The net loss for the three months ended September 30, 2024 was $40.2 million compared to a net loss of $6.0 million for the same period in 2023. Total stock compensation expense for the three months ended September 30, 2024 was $0.7 million compared to $0.5 million for the same period in 2023 and the non-cash loss from Corvus’ equity method investment in Angel Pharmaceuticals was $0.7 million for the three months ended September 30, 2024 compared to a loss of $0.9 million for the same period in 2023. In addition, the Company recorded a non-cash loss of $32.8 million related to an increase in the fair value of its warrant liability during the three months ended September 30, 2024 due an increase in the Company’s stock price from $1.82 at June 30, 2024 to $5.28 at September 30, 2024. The Company issued approximately 17.1 million common stock warrants in its May 2024 registered direct offering with an exercise price of $3.50 per common stock warrant. After the October 2024 early exercise of 1,677,220 common stock warrants, approximately 15.4 million common stock warrants remain outstanding. The common stock warrants expire on June 30, 2025. Conference Call DetailsCorvus will host a conference call and webcast today, Tuesday, November 12, 2024, at 4:30 p.m. ET (1:30 p.m. PT), during which time management will provide a business update and discuss the third quarter 2024 financial results. The conference call can be accessed by dialing 1- 800-717-1738 (toll-free domestic) or 1- 646-307-1865 (international) or by clicking on this link for instant telephone access to the event. The live webcast may be accessed via the investor relations section of the Corvus website. A replay of the webcast will be available on Corvus’ website for 90 days. About Corvus PharmaceuticalsCorvus Pharmaceuticals is a clinical-stage biopharmaceutical company pioneering the development of ITK inhibition as a new approach to immunotherapy for a broad range of cancer and immune diseases. The Company’s lead product candidate is soquelitinib, an investigational, oral, small molecule drug that selectively inhibits ITK. Its other clinical-stage candidates are being developed for a variety of cancer indications. For more information, visit www.corvuspharma.com. About SoquelitinibSoquelitinib (formerly CPI-818) is an investigational small molecule drug given orally designed to selectively inhibit ITK (interleukin-2-inducible T cell kinase), an enzyme that is expressed predominantly in T cells and plays a role in T cell and natural killer (NK) cell immune function. Based on interim results from a Phase 1/1b clinical trial in patients with refractory T cell lymphomas, which demonstrated tumor responses in very advanced, refractory, difficult to treat T cell malignancies, the Company initiated a registrational Phase 3 clinical trial of soquelitinib in patients with relapsed PTCL. Soquelitinib also is now being investigated in a randomized placebo controlled phase 1 clinical trial in patients with atopic dermatitis. The immunologic effects of soquelitinib lead to what is known as Th1 skewing and inhibition of Th2 and Th17 cells. Research on soquelitinib’s mechanism of action suggests that it has the potential to control differentiation of normal T helper cells and enhance immune responses to tumors by augmenting the generation of cytotoxic killer T cells and the production of cytokines that inhibit cancer cell survival. Soquelitinib has also been shown to prevent T cell exhaustion, a major limitation of current immunotherapy and CAR-T therapies. Soquelitinib has been shown to affect T cell differentiation and induce the generation of Th1 helper cells while blocking the development of both Th2 and Th17 cells and production of their secreted cytokines. Th1 T cells are required for immunity to tumors, viral infections and other infectious diseases. Th2 and Th17 helper T cells are involved in the pathogenesis of many autoimmune and allergic diseases. The Company believes the inhibition of specific molecular targets in T cells may be of therapeutic benefit for patients with cancers, including solid tumors, and in patients with autoimmune and allergic diseases. About Peripheral T Cell LymphomaPeripheral T cell lymphoma is a heterogeneous group of malignancies accounting for about 10% of non-Hodgkin’s lymphomas (NHL) in Western populations, reaching 20% to 25% of NHL in some parts of Asia and South America. The most common subtypes are PTCL-not otherwise specified (PTCL-NOS) and T follicular helper cell lymphoma. First line treatment for these diseases is typically combination chemotherapy, however, approximately 75% of patients either do not respond or relapse within the first two years. Patients in relapse are treated with various chemotherapy agents but have poor overall outcomes with median progression-free survival in the three to four month range and overall median survival of six to 12 months. There are no approved drugs in relapsed PTCL based on randomized trials. PTCL is a disease of mature helper T cells that express ITK, often containing numerous genetic mutations and frequently associated with viral infection. Most often the malignant cells of PTCL express a Th2 phenotype. About Atopic DermatitisAtopic dermatitis, also called eczema, is a chronic disease that can cause inflammation, redness, scaly patches, blisters and irritation of the skin. It affects up to 20% of children and up to 10% of adults, and treatments include topical therapies, oral therapies and systemic injectable biologic therapies. It is frequently associated with other allergic disorders such as food allergies and asthma. Atopic dermatitis, like asthma and allergy, involves the participation of Th2 lymphocytes which secrete cytokines that result in inflammation. Soquelitinib has been shown in preclinical studies to inhibit cytokine production from Th2 lymphocytes. About CiforadenantCiforadenant (CPI-444) is an investigational small molecule, oral, checkpoint inhibitor designed to disable a tumor’s ability to subvert attack by the immune system by blocking the binding of adenosine to immune cells present in the tumor microenvironment. Adenosine, a metabolite of ATP (adenosine tri-phosphate), is produced within the tumor microenvironment where it may bind to the adenosine A2a receptor present on immune cells and block their activity. Ciforadenant has been shown to block the immunosuppressive effects of myeloid cells present in tumors and preclinical studies published in 2018 demonstrated synergy with combinations of anti PD1 and anti-CTLA4 antibodies. About MupadolimabMupadolimab (CPI-006) is an investigational, potent humanized monoclonal antibody that is designed to react with a specific site on CD73. In preclinical studies, it has demonstrated immunomodulatory activity resulting in activation of lymphocytes, induction of antibody production from B cells and effects on lymphocyte trafficking. While there are other anti-CD73 antibodies and small molecules in development for treatment of cancer, such agents react with a different region of CD73. Mupadolimab is designed to react with a region of the molecule that acts to stimulate B cells and block production of immunosuppressive adenosine. Mupadolimab is being studied in combination with pembrolizumab in a Phase 1b/2 clinical trial in patients with advanced head and neck cancers and in patients with NSCLC that have failed chemotherapy and anti-PD(L)1 therapy. It is postulated that the activation of B cells will enhance immunity within the tumors of these patients, leading to improved clinical outcomes. About Angel PharmaceuticalsAngel Pharmaceuticals is a privately held biopharmaceutical company developing a pipeline of precisely targeted investigational medicines for cancer, autoimmune, infectious and other serious diseases in China. Angel Pharmaceuticals was launched through a collaboration with U.S.-based Corvus and investments from investors in China. Angel Pharmaceuticals licensed the rights to develop and commercialize Corvus’ three clinical-stage candidates – soquelitinib, ciforadenant and mupadolimab – in greater China and obtained global rights to Corvus’ BTK inhibitor preclinical programs. Under the collaboration, Corvus currently has a 49.7% equity stake in Angel Pharmaceuticals excluding 7% of Angel’s equity reserved for issuance under the Angel ESOP, and Corvus has designated three individuals on Angel’s five-person Board of Directors. For more information, visit www.angelpharma.com. Forward-Looking StatementsThis press release contains forward-looking statements, including statements related to the potential safety and efficacy of the Company’s product candidates including soquelitinib, ciforadenant and mupadolimab; the potential use of soquelitinib to treat a variety of hematological cancers and autoimmune diseases; the potential of ciforadenant to overcome immunotherapy resistance in metastatic castration resistant prostate cancer; the potential of ITK inhibition to provide a new oral treatment option for atopic dermatitis; the Company’s ability and its partners’ ability, as well as the timing thereof, to develop and advance product candidates into and successfully complete preclinical studies and clinical trials, including the Company’s registrational Phase 3 clinical trial for PTCL with soquelitinib and its Phase 1 clinical trial for atopic dermatitis with soquelitinib; the timing of and the Company’s ability to launch clinical trials, including the soquelitinib Phase 1 clinical trial for solid tumors; the design of clinical trials, including the timeline for initiation, target or expected number of patients to be enrolled, expected number of sites and certain other product development milestones, including in regards to the Phase 1 clinical trial for atopic dermatitis with soquelitinib and the registrational Phase 3 clinical trial for PTCL with soquelitinib; the availability and timing of clinical and preclinical data announcements and clinical readouts, including interim data from the Phase 1 clinical trial for atopic dermatitis with soquelitinib and preclinical data highlighting the potential of soquelitinib to prevent lung damage, inflammation and pulmonary hypertension caused by systemic sclerosis; the estimated amount of net cash used in operating activities for 2024 and its ability to fund operations into 2026. All statements other than statements of historical fact contained in this press release are forward-looking statements. These statements often include words such as “believe,” “expect,” “anticipate,” “intend,” “plan,” “estimate,” “seek,” “will,” “may” or similar expressions. Forward-looking statements are subject to a number of risks and uncertainties, many of which involve factors or circumstances that are beyond the Company’s control. The Company’s actual results could differ materially from those stated or implied in forward-looking statements due to a number of factors, including but not limited to, risks detailed in the Company’s Quarterly Report on Form 10-Q for the three months ended September 30, 2024, filed with the Securities and Exchange Commission on or about the date hereof, as well as other documents that may be filed by the Company from time to time with the Securities and Exchange Commission. In particular, the following factors, among others, could cause results to differ materially from those expressed or implied by such forward-looking statements: the Company’s ability to demonstrate sufficient evidence of efficacy and safety in its clinical trials of soquelitinib and its other product candidates; the accuracy of the Company’s estimates relating to its ability to initiate and/or complete preclinical studies and clinical trials and release data from such studies and clinical trials; the results of preclinical studies and interim data from clinical trials not being predictive of future results; the Company’s ability to enroll sufficient numbers of patients in its clinical trials; the unpredictability of the regulatory process; regulatory developments in the United States, and other foreign countries; the costs of clinical trials may exceed expectations; the Company’s ability to accurately estimate the amount of net cash used in operating activities for 2024 and cash on hand providing funding into 2026 and the Company’s ability to raise additional capital. Although the Company believes that the expectations reflected in the forward-looking statements are reasonable, it cannot guarantee that the events and circumstances reflected in the forward-looking statements will be achieved or occur, and the timing of events and circumstances and actual results could differ materially from those projected in the forward-looking statements. Accordingly, you should not place undue reliance on these forward-looking statements. All such statements speak only as of the date made, and the Company undertakes no obligation to update or revise publicly any forward-looking statements, whether as a result of new information, future events or otherwise. The Company’s results for the quarter ended September 30, 2024 are not necessarily indicative of its operating results for any future periods. CORVUS PHARMACEUTICALS, INC.CONDENSED CONSOLIDATED STATEMENTS OF OPERATIONS (in thousands, except share and per share data) Three Months Ended September 30, Nine Months Ended September 30, 2024 2023 2024 2023 (unaudited) (unaudited)Operating expenses: Research and development $5,222 $3,965 $13,411 $12,527 General and administrative 2,033 1,595 6,032 5,229 Total operating expenses 7,255 5,560 19,443 17,756 Loss from operations (7,255) (5,560) (19,443) (17,756)Interest income and other expense, net 566 425 1,316 1,204 Change in fair value of warrant liability (32,846) — (31,030) — Sublease income - related party — — — 56 Loss from equity method investment (682) (865) (1,023) (3,880)Net loss $(40,217) $(6,000) $(50,180) $(20,376)Net loss per share, basic and diluted$(0.60) $(0.12) $(0.86) $(0.43)Shares used to compute net loss per share, basic and diluted 66,701,086 48,971,246 58,513,303 47,683,792 CORVUS PHARMACEUTICALS, INC.CONDENSED CONSOLIDATED BALANCE SHEETS (in thousands) September 30,December 31, 2024 2023 (unaudited) Assets Cash, cash equivalents and marketable securities$41,651 $27,149Operating lease right-of-use asset 284 1,149Other assets 1,693 1,132Investment in Angel Pharmaceuticals 15,187 16,123Total assets$58,815 $45,553Liabilities and stockholders' equity Accounts payable and accrued liabilities and other liabilities$6,088 $5,495Operating lease liability 354 1,374Warrant liability 39,964 —Stockholders' equity 12,409 38,684Total liabilities and stockholders' equity$58,815 $45,553 INVESTOR CONTACT:Leiv LeaChief Financial OfficerCorvus Pharmaceuticals, Inc.+1-650-900-4522llea@corvuspharma.com MEDIA CONTACT:Sheryl SeapyReal Chemistry+1-949-903-4750sseapy@realchemistry.com