CHS-114 shown to have an acceptable safety profile with no dose-limiting toxicities (DLTs) in heavily pretreated patients with solid tumors
Selective depletion of peripheral CCR8+ regulatory T cells (Tregs) was observed and depletion was maintained over the dosing interval, establishing proof of mechanism
Preclinical data and preliminary clinical results support further evaluation of CHS-114 in combination with the anti-programmed cell death protein 1 (PD-1) antibody, toripalimab-tpzi, and other immuno-oncology (IO) agents
REDWOOD CITY, Calif., May 23, 2024 (GLOBE NEWSWIRE) -- Coherus BioSciences, Inc. (Coherus, Nasdaq: CHRS), today announced clinical data from the CHS-114, single agent dose escalation stage of its Phase 1 study at the ASCO Annual Meeting, taking place May 31 to June 4, 2024, at McCormick Place in Chicago. CHS-114 is a novel afucosylated human immunoglobulin G1 (IgG1) monoclonal antibody (mAb) that selectively and potently targets human CCR8 with no off-target binding. CCR8 is a G protein-coupled receptor (GPCR) that shows preferential expression on tumor resident Treg cells and has promise as a drug target for selectively targeting immune suppression in the tumor microenvironment (TME) without broadly depleting Treg cells, which has the known unwanted side effect of autoimmune activation.
"The Phase 1 preliminary dose escalation results are an important milestone as we progress our innovative I-O pipeline. We are very pleased with the safety profile, the predictable dose proportional pharmacokinetic profile, and the selective depletion of peripheral CCR8+ Tregs that were observed," said Rosh Dias, M.D., Coherus' Chief Medical Officer. "By targeting CCR8, we believe CHS-114 has the potential to overcome Treg immune suppression in the TME and allows T cell recruitment, which turns cold tumors hot and enhances anti-tumor activity when combined with I-O agents. The data support further evaluation of CHS-114 in combination treatment with our anti-PD-1 antibody, toripalimab, and other I-O agents."
CCR8 is a chemokine receptor predominantly expressed by tumor infiltrating Tregs that suppress the body's natural anti-cancer immune response. Targeting CCR8 is a promising potential therapeutic strategy designed to selectively deplete intratumoral CCR8+ Tregs, reshape the tumor microenvironment by alleviating local immunosuppression, and enhance anti-tumor immune response when combined with I-O agents. Data presented at ASCO demonstrate proof of mechanism for selective depletion of CCR8+ Tregs and an acceptable safety profile to date.
Poster presentation:
Abstract # 2664: Preliminary Results of a Phase 1, First-in-human, Dose Escalation Study of the Anti-CCR8 Cytolytic Antibody, CHS-114 (formerly SRF114) in Patients with Advanced Solid Tumors.
Poster Session: Developmental Therapeutics - Immunotherapy
Date and Time: Saturday, June 1, 2024, 9:00 a.m. – 12:00 p.m. Central Daylight Time
Poster presentation data are summarized as follows:
CHS-114 has demonstrated an acceptable safety profile in 20 evaluable, heavily pre-treated patients with advanced solid tumors, with no DLTs reported to date. Treatment emergent adverse events (TEAEs) were generally low grade. One patient experienced a treatment-related serious adverse event (SAE) of Grade 2 colitis. There were no treatment related adverse events (AEs) leading to discontinuation or death.
CHS-114 PK exposure was approximately dose proportional, and the elimination appeared linear with a half-life of about 10 days (range 9-17 days).
Depletion of peripheral CCR8+ Treg cells was observed and depletion was maintained over the dosing interval, establishing proof of mechanism.
Preliminary results and acceptable safety profile support further evaluation of CHS-114 in combination treatment with toripalimab and other I-O agents. In 19 patients evaluable for response, no objective responses were yet noted, while the stable disease rate was 47%.
About the Phase 1 trial (NCT05635643):
SRF114-101 is a Phase 1, First-In-Human, open-label, dose escalation study, evaluating CHS-114 as a single agent and in combination with toripalimab. The study enrolled patients with advanced solid tumors who received more than one line of prior treatment (75% had more than three prior lines). Stage 1a of the study included CHS-114 administered intravenously (IV) on day one of each Q3W cycle as part of single-agent dose escalation and employed the Bayesian optimal interval (BOIN) design, including accelerated titration and 3+3 run-in. Stage 1b will enroll an additional five patients with advanced/metastatic Head and Neck Squamous Cell Carcinoma (HNSCC) at each of two dose levels.
Primary endpoints: rate of DLTs and TEAEs, with the overarching objective of determining two recommended doses for expansion (RDE).
Key secondary endpoints: objective response rate (ORR) based on Investigator review per RECIST v1.1, pharmacokinetics, pharmacodynamic assessments (changes in FOXP3 expression within tumor tissue –Stage 1b).
Exploratory pharmacodynamic endpoint: Changes in frequency of CCR8-expressing immune cell subsets in the periphery.
About CHS-114
CHS-114, a human, afucosylated anti-CCR8 monoclonal antibody, is designed to selectively target human CCR8 and preferentially deplete CCR8+ Tregs within the tumor microenvironment, while preserving effector T (Teff) cells in tumors or Tregs in normal tissue. In preclinical studies, CHS-114 induced antibody-dependent cellular cytotoxicity (ADCC) and/or antibody-dependent cellular phagocytosis (ADCP) to deplete tumoral CCR8+ Tregs. In addition, treatment with CHS-114 alone reduced tumor growth in murine models, and enhanced antitumor activity was observed in combination with anti-PD-1 treatment. CHS-114 is currently being evaluated in a Phase 1 clinical trial (NCT05635643) as a monotherapy and in combination with toripalimab in advanced solid tumors, including head and neck cancer. As reported in June 2023, early evidence of biological effect has been seen with CCR8+ Tregs depletion in blood following treatment with CHS-114, with no effect observed on non-CCR8+ Tregs.
在經過大量預處理的實體瘤患者中,CHS-114 的安全性可接受,且沒有劑量限制毒性 (DLT)
觀察到外周CCR8+調節性T細胞(Tregs)的選擇性耗竭,並在給藥間隔內保持消耗,從而證明了機制
臨床前數據和初步臨床結果支持進一步評估 CHS-114 與抗程序性細胞死亡蛋白 1 (PD-1) 抗體、toripalimab-tpzi 和其他免疫腫瘤學 (IO) 藥物聯合使用
加利福尼亞州雷德伍德城,2024年5月23日(GLOBE NEWSWIRE)——Coherus BioSciences, Inc.(Coherus,納斯達克股票代碼:CHRS)今天在2024年5月31日至6月4日在芝加哥味好美廣場舉行的ASCO年會上公佈了其1期研究的單一藥物劑量遞增階段 CHS-114 的臨床數據。CHS-114 是一種新型的核糖基化人免疫球蛋白 G1 (IgG1) 單克隆抗體 (mAb),可選擇性地有效靶向人類 CCR8,不會脫靶結合。CCR8是一種G蛋白偶聯受體(GPCR),在腫瘤駐留的Treg細胞上表現出優先表達,有望作爲選擇性靶向腫瘤微環境(TME)中的免疫抑制的藥物靶標,而不會廣泛消耗Treg細胞,而Treg細胞具有已知的自身免疫激活的不良副作用。
“隨着我們推進創新的I-O管道,第一階段的初步劑量遞增結果是一個重要的里程碑。我們對所觀察到的安全性、可預測的劑量比例藥代動力學特徵以及外周CCR8+ Treg的選擇性耗盡感到非常滿意。” Coherus首席醫學官羅什·迪亞斯醫學博士說。“通過靶向 CCR8,我們認爲 CHS-114 有可能克服 TME 中的 Treg 免疫抑制,並允許 T 細胞招募,這會使冷腫瘤變熱,與 I-O 藥物聯合使用時增強抗腫瘤活性。這些數據支持進一步評估使用我們的抗 PD-1 抗體、託瑞帕利單抗和其他 I-O 藥物聯合治療時的 CHS-114。”
CCR8 是一種趨化因子受體,主要由腫瘤浸潤 T 細胞表達,抑制人體自然的抗癌免疫反應。靶向CCR8是一種前景看好的潛在治療策略,旨在選擇性地消耗腫瘤內CCR8+ Treg,通過減輕局部免疫抑制重塑腫瘤微環境,並與I-O藥物聯合使用時增強抗腫瘤免疫反應。ASCO提供的數據證明了CCR8+ Tregs選擇性耗盡的機制以及迄今爲止可接受的安全性。
海報展示:
摘要 #2664:針對晚期實體瘤患者抗CCR8細胞溶解抗體 CHS-114(前身爲 SRF114)的1期人體首次劑量遞增研究的初步結果。
海報會議:發育療法-免疫療法
日期和時間:2024 年 6 月 1 日,星期六,上午 9:00 — 下午 12:00(中部夏令時間)
海報演示數據彙總如下:
在 20 名可評估、經過大量預治療的晚期實體瘤患者中,CHS-114 已顯示出可接受的安全性,迄今尚未報告 DLT。治療緊急不良事件(TEAE)的等級通常較低。一名患者出現了與治療相關的2級結腸炎嚴重不良事件(SAE)。未出現導致停藥或死亡的治療相關不良事件(AE)。
CHS-114 PK 暴露量與劑量成正比,消除效果呈線性變化,半衰期約爲 10 天(範圍爲 9-17 天)。
觀察到外周CCR8+ Treg細胞的耗竭,並在給藥間隔內維持消耗,從而證實了機制的證據。
初步結果和可接受的安全性概況支持進一步評估與託利單抗和其他 I-O 藥物聯合治療時的 CHS-114。在19名可評估反應的患者中,尚未發現客觀反應,而穩定的發病率爲47%。
關於 1 期試驗 (NCT05635643):
SRF114-101 是一項 1 期、首次進入人體、開放標籤、劑量遞增的研究,旨在評估 CHS-114 作爲單一藥物以及與託利單抗聯合用藥的情況。該研究招收了先前接受過超過一行治療的晚期實體瘤患者(75% 的患者先前接受過三系以上的治療)。該研究的第 1a 階段包括在每個 Q3W 週期的第一天靜脈注射 (IV),作爲單劑劑量遞增的一部分,並採用貝葉斯最佳間隔 (BOIN) 設計,包括加速滴定和 3+3 試驗。CHS-114第 1b 階段將再招收五名晚期/轉移性頭頸鱗狀細胞癌 (HNSCC) 患者,每種劑量水平各有五名。
主要終點:DLT和TEAE的比率,總體目標是確定兩種推薦的擴張劑量(RDE)。
關鍵次要終點:根據RECIST v1.1的研究者審查、藥代動力學、藥效學評估(腫瘤組織內 FOXP3 表達的變化——1b階段)得出的客觀反應率(ORR)。
探索性藥效學終點:外周表達 CCR8 的免疫細胞亞群頻率的變化。
關於 CHS-114
CHS-114 是一種人源化抗 CCR8 單克隆抗體,旨在選擇性地靶向人類 CCR8,優先消耗腫瘤微環境中的 CCR8+ Treg,同時保留腫瘤中的效應 T(Teff)細胞或正常組織中的 Treg 細胞。在臨床前研究中,CHS-114 誘導抗體依賴性細胞毒性 (ADCC) 和/或抗體依賴性細胞吞噬作用 (ADCP),從而消耗腫瘤 CCR8+ Treg。此外,單獨使用 CHS-114 治療可減少小鼠模型中的腫瘤生長,並且觀察到與抗 PD-1 治療聯合使用時抗腫瘤活性增強。CHS-114 目前正在 1 期臨床試驗(NCT05635643)中作爲單一療法進行評估,並與託利單抗聯合用於晚期實體瘤,包括頭頸癌。正如 2023 年 6 月報道的那樣,在使用 CHS-114 治療後,血液中 CCR8+ Tregs 的消耗已出現生物學效應的早期證據,對非 CCR8+ 的 Tregs 沒有觀察到任何影響。