作者: Lesch, Stefanie ; Engel, Nils W ; Weiner, David ; O'Connell, Ryan P ; Gill, Saar I ; Rennels, Austin K ; Young, Regina M ; Herbst, Friederike ; Gonzales, Donna ; Garcia, K Christopher ; Wellhausen, Nils ; June, Carl H

In the absence of cell surface cancer-specific antigens, immunotherapies such as chimeric antigen receptor (CAR) T cells, monoclonal antibodies, or bispecific T cell engagers typically target lineage antigens. Currently, such immunotherapies are individually designed and tested for each disease. This approach is inefficient and limited to a few lineage antigens for which the on-target/off-tumor toxicities are clinically tolerated. Here, we sought to develop a universal CAR T cell therapy for blood cancers directed against the pan-leukocyte marker CD45. To protect healthy hematopoietic cells, including CAR T cells, from CD45-directed on-target/off-tumor toxicity while preserving the essential functions of CD45, we mapped the epitope on CD45 that is targeted by the CAR and used CRISPR adenine base editing to install a function-preserving mutation sufficient to evade CAR T cell recognition. Epitope-edited CD45 CAR T cells were fratricide resistant and effective against patient-derived acute myeloid leukemia, B cell lymphoma, and acute T cell leukemia. Epitope-edited hematopoietic stem cells (HSCs) were protected from CAR T cells and, unlike CD45 knockout cells, could engraft, persist, and differentiate in vivo. Ex vivo epitope editing in HSCs and T cells enables the safe and effective use of CD45-directed CAR T cells and bispecific T cell engagers for the universal treatment of hematologic malignancies and might be exploited for other diseases requiring intensive hematopoietic ablation.

2023-06-01·Journal for ImmunoTherapy of Cancer

Intratumoral pan-ErbB targeted CAR-T for head and neck squamous cell carcinoma: interim analysis of the T4 immunotherapy study

Article

作者: Andoniadou, Cynthia ; Maher, John ; Morton, Cienne ; Mitra, Arindam ; Reid, Fiona ; Guerrero-Urbano, Teresa ; Williams, Evangelia ; Cook, Gary J R ; Lyne, Mike ; Arif, Sefina ; Allen, Sarah ; Beckley-Hoelscher, Nicholas ; Parente-Pereira, Ana C ; Beatson, Richard ; Fisher, Christopher ; Papa, Sophie ; Henley-Smith, Rhonda ; Shivapatham, Dharshene ; Schurich, Anna ; Hope, Andrew ; Spicer, James ; Achkova, Daniela ; Elstad, Maria ; Davies, David M ; Douri, Abdel ; Delord, Marc ; Adami, Antonella ; George, Molly Sarah ; Gibson, Victoria ; Gooljar, Sakina ; Metoudi, Michael ; Santambrogio, Alice ; Gomm, Linda ; Farzaneh, Farzin ; Jeannon, Jean-Pierre ; Thavaraj, Selvam

BackgroundLocally advanced/recurrent head and neck squamous cell carcinoma (HNSCC) is associated with significant morbidity and mortality. To target upregulated ErbB dimer expression in this cancer, we developed an autologous CD28-based chimeric antigen receptor T-cell (CAR-T) approach named T4 immunotherapy. Patient-derived T-cells are engineered by retroviral transduction to coexpress a panErbB-specific CAR called T1E28ζ and an IL-4-responsive chimeric cytokine receptor, 4αβ, which allows IL-4-mediated enrichment of transduced cells during manufacture. These cells elicit preclinical antitumor activity against HNSCC and other carcinomas. In this trial, we used intratumoral delivery to mitigate significant clinical risk of on-target off-tumor toxicity owing to low-level ErbB expression in healthy tissues.MethodsWe undertook a phase 1 dose-escalation 3+3 trial of intratumoral T4 immunotherapy in HNSCC (NCT01818323). CAR T-cell batches were manufactured from 40 to 130 mL of whole blood using a 2-week semiclosed process. A single CAR T-cell treatment, formulated as a fresh product in 1–4 mL of medium, was injected into one or more target lesions. Dose of CAR T-cells was escalated in 5 cohorts from 1×107−1×109T4+T-cells, administered without prior lymphodepletion.ResultsDespite baseline lymphopenia in most enrolled subjects, the target cell dose was successfully manufactured in all cases, yielding up to 7.5 billion T-cells (67.5±11.8% transduced), without any batch failures. Treatment-related adverse events were all grade 2 or less, with no dose-limiting toxicities (Common Terminology Criteria for Adverse Events V.4.0). Frequent treatment-related adverse events were tumor swelling, pain, pyrexias, chills, and fatigue. There was no evidence of leakage of T4+T-cells into the circulation following intratumoral delivery, and injection of radiolabeled cells demonstrated intratumoral persistence. Despite rapid progression at trial entry, stabilization of disease (Response Evaluation Criteria in Solid Tumors V.1.1) was observed in 9 of 15 subjects (60%) at 6 weeks post-CAR T-cell administration. Subsequent treatment with pembrolizumab and T-VEC oncolytic virus achieved a rapid complete clinical response in one subject, which was durable for over 3 years. Median overall survival was greater than for historical controls. Disease stabilization was associated with the administration of an immunophenotypically fitter, less exhausted, T4 CAR T-cell product.ConclusionsThese data demonstrate the safe intratumoral administration of T4 immunotherapy in advanced HNSCC.

2018-11-01·Cancer Immunology, Immunotherapy2区 · 医学

Chemotherapy-induced apoptosis, autophagy and cell cycle arrest are key drivers of synergy in chemo-immunotherapy of epithelial ovarian cancer

2区 · 医学

Article

作者: Smith, J Richard ; Lam, Eric W-F ; Whilding, Lynsey M ; Maher, John ; Parente-Pereira, Ana C ; Wahba, John ; Jung, Youngrock ; Zona, Stefania ; Ghaem-Maghami, Sadaf ; Natoli, Marina

Epithelial ovarian cancer (EOC) is the most lethal of all gynecological malignancies in the UK. Recent evidence has shown that there is potential for immunotherapies to be successful in treating this cancer. We have previously shown the effective application of combinations of traditional chemotherapy and CAR (chimeric antigen receptor) T cell immunotherapy in in vitro and in vivo models of EOC. Platinum-based chemotherapy synergizes with ErbB-targeted CAR T cells (named T4), significantly reducing tumor burden in mice. Here, we show that paclitaxel synergizes with T4 as well, and look into the mechanisms behind the effectiveness of chemo-immunotherapy in our system. Impairment of caspase activity using pan-caspase inhibitor Z-VAD reveals this chemotherapy-induced apoptotic pathway as an essential factor in driving synergy. Mannose-6-phosphate receptor-mediated autophagy and the arrest of cell cycle in G2/M are also shown to be induced by chemotherapy and significantly contributing to the synergy. Increased expression of PD-1 on T4 CAR T cells occurred when these were in culture with ovarian tumor cells; on the other hand, EOC cell lines showed increased PD-L1 expression following chemotherapy treatment. These findings provided a rationale to look into testing PD-1 blockade in combination with paclitaxel and T4 immunotherapy. Combination of these three agents in mice resulted in significant reduction of tumor burden, compared to each treatment alone. In conclusion, the mechanism driving synergy in chemo-immunotherapy of EOC is multifactorial. A deeper understanding of such process is needed to better design combination therapies and carefully stratify patients.

项与 CD45靶向CAR-T(University of Pennsylvania) 相关的新闻（医药）

2023-10-18

·佰傲谷BioValley

明星背景，泛血液瘤CD45 CAR-T

近日，Cimeio Therapeutics宣布，将与宾夕法尼亚大学Perelman医学院细胞免疫疗法中心的Saar Gill博士开展临床前合作，以研究和评估一种靶向CD45的通用CAR-T细胞的血液肿瘤治疗潜力。CD45是较少见的药物开发靶点，主要原因是其在除红细胞和血小板外的所有造血干细胞(HSCs)中均有表达。因此，尽管CD45具有控制免疫系统信号通路的作用，以及在血液肿瘤细胞中高表达，具有作为药物靶标开发潜力，但还是鲜有人去开发CD45。CD45 CAR-T的开发策略如果按照传统的CAR-T细胞治疗去设计和开发CD45 CAR-T细胞，是不行的。因为会导致CD45 CAR-T无差别攻击表达CD45的细胞，无论是肿瘤细胞还是正常细胞，会造成严重的毒副作用。但也有一个好处就是，CD45 CAR-T可以攻击所有表达CD45的细胞，即可以用于所有的血液肿瘤，成为一种血液肿瘤通用的CAR-T细胞治疗，因为几乎所有血细胞上都高度表达CD45。延伸阅读：CD45: 不再只是一个marker为了实现CD45 CAR-T的肿瘤杀伤作用，同时保证安全性，Cimeio公司和宾大团队进行合作，结合Cimeio公司专有的Shielded Cell & Immunotherapy Pairs™（细胞屏蔽技术和配对免疫技术），开发CD45 CAR-T细胞与配对的CD45表位编辑造血干细胞（HSC）组合疗法。利用基因编辑工具对健康HSC细胞进行工程化，改变HSC表面的CD45的某单一氨基酸，使其成为一种CD45变体，并不影响原本的功能；但是CD45 CAR-T并不会结合该CD45变体，从而实现CD45 CAR-T能够杀死表达CD45的肿瘤细胞，而不影响正常的HSC。这种CAR-T细胞与工程化HSC的组合被称为细胞屏蔽与配对免疫技术，目前Cimeio公司已经在多种靶标上（例如CD45、CD123、CD117等）上进行了相关的研究，表明通过对HSC细胞表面蛋白的工程，可以保护其免受靶向疗法（包括抗体、T细胞接合剂、ADC和CAR-T）的攻击。除了CD45 CAR-T，Cimeio公司还在开发CD45靶向抗体偶联药物，配合其配对免疫HSC技术，用于治疗血液肿瘤和自身免疫性疾病等适应症。小编简评：尽管在这种组合疗法在概念上可以成立，临床前研究也提供了一定的数据支持；但是真正用到人体上，存在的风险因素还是很大；此外其复杂的治疗方案可能会产生更高的治疗成本和研发支出，以及监管的挑战。简而言之，临床转化具有较大的挑战。上个月，Saar Gill博士和Carl June教授合作发表在Science Translational Medicine上的一篇文章，展示了这种CAR-T细胞与CD45表位编辑HSC的临床前数据。利用CRISPR腺嘌呤碱基编辑技术在HCS上进行表位编辑，使其成为CD45变体，CD45表位编辑的HSC在体内具有持续和分化能力，且不会被CD45 CAR-T所识别和攻击，且CD45 CAR-T能够正常识别肿瘤细胞，包括急性髓系白血病、B细胞淋巴瘤和急性T细胞白血病细胞。然后将工程HSC与CD45 CAR-T配合回输小鼠，观察到这种方法成功杀死血液系统恶性肿瘤并重建了造血系统。小编简评：尽管在这种组合疗法在概念上可以成立，或许在临床前研究中也可以提供一定的数据支持；但是真正用到人体上，存在的风险因素还是很大；此外其复杂的治疗方案可能会产生更高的治疗成本和研发支出，以及监管的挑战。小结事实上，基于CD45的广泛表达以及生物学功能，能够通过调节淋巴细胞存活、细胞因子反应和TCR信号传导来控制免疫功能，也正在成为部分研究团队和公司所关注的治疗靶点。总部位于马萨诸塞州的Magenta Therapeutics，正在开发CD45 ADC药物。正在进行IND申请，用于自身免疫性疾病，移植排斥反应等；Fred Hutchinson Cancer Center使用抗体（Anti-CD45 Monoclonal Antibody BC8-B10）进行非恶行疾病的临床研究；Perron等正在开发CD45抑制剂211 (2-[(4-acetylphenyl) amino]−3- chloronaphthoquinone)。参考资料：1.https://www.cimeio.com/2023/10/16/cimeio-therapeutics-announces-research-collaboration-with-the-university-of-pennsylvania/2.https://www.cimeio.com/3.https://www.science.org/doi/10.1126/scitranslmed.adi1145?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed本周好文推荐如需转载请联系佰傲谷并在醒目位置注明出处﹀‍‍ ········

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100 项与 CD45靶向CAR-T(University of Pennsylvania) 相关的药物交易

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