CAR-T Targeting GPC3, Mesothelin, Claudin18.2, GUCY2C, B7-H3, PSCA, PSMA, MUC1, TGFβ, HER2, Lewis-Y, AXL, or EGFR for Immunotherapy of Lung Cancer: Phase I Clinical Trial

The third generation of CAR-T cells that target GPC3, Mesothelin, Claudin18.2, GUCY2C, B7-H3, PSCA, PSMA, MUC1, TGFβ, HER2, Lewis-Y, AXL, or EGFR have been constructed respectively and their anti-cancer function has been verified by multiple in vitro and in vivo studies.Clinical studies will be performed to test the anti-cancer function of the these individual or combination of the CAR-T cells for immunotherapy of human cancer patients with GPC3, Mesothelin, Claudin18.2, GUCY2C, B7-H3, PSCA, PSMA, MUC1, TGFβ, HER2, Lewis-Y, AXL, or EGFR expressions. In this phase I study, the safety, tolerance, and preliminary efficacy of the GPC3/Mesothelin/Claudin18.2/GUCY2C/B7-H3/PSCA/PSMA/MUC1/TGFβ/HER2/Lewis-Y/AXL/EGFR
-CAR-T cell immunotherapy on human cancers will firstly be tested.

开始日期2017-07-01

申办/合作机构

广州医科大学附属第二医院

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项与 PSCA-CAR-T Cells(Guangdong Zhaotai InVivo Biomedicine) 相关的文献（医药）

2024-06-01·NATURE MEDICINE

PSCA-CAR T cell therapy in metastatic castration-resistant prostate cancer: a phase 1 trial

Article

作者: Tilakawardane, Dileshni ; Dorff, Tanya B ; Reiter, Robert E ; Luebbert, Laura ; Gerdts, Ethan ; Pachter, Lior ; Del Real, Marissa M ; D'Apuzzo, Massimo ; Chaudhry, Ammar ; Martinez, Catalina ; Leggett, Neena ; Budde, Lihua E ; Forman, Stephen J ; Rosa, Reginaldo ; Priceman, Saul J ; Paul, Jinny ; Dhapola, Gaurav ; Stiller, Tracey ; Macias, Alan ; Martirosyan, Hripsime ; Wagner, Jamie R ; Murad, John P ; Adkins, Lauren N ; Blanchard, M Suzette ; Pal, Sumanta ; Kuhn, Peter ; Egelston, Colt ; Shishido, Stephanie N

Abstract:

Despite recent therapeutic advances, metastatic castration-resistant prostate cancer (mCRPC) remains lethal. Chimeric antigen receptor (CAR) T cell therapies have demonstrated durable remissions in hematological malignancies. We report results from a phase 1, first-in-human study of prostate stem cell antigen (PSCA)-directed CAR T cells in men with mCRPC. The starting dose level (DL) was 100 million (M) CAR T cells without lymphodepletion (LD), followed by incorporation of LD. The primary end points were safety and dose-limiting toxicities (DLTs). No DLTs were observed at DL1, with a DLT of grade 3 cystitis encountered at DL2, resulting in addition of a new cohort using a reduced LD regimen + 100 M CAR T cells (DL3). No DLTs were observed in DL3. Cytokine release syndrome of grade 1 or 2 occurred in 5 of 14 treated patients. Prostate-specific antigen declines (>30%) occurred in 4 of 14 patients, as well as radiographic improvements. Dynamic changes indicating activation of peripheral blood endogenous and CAR T cell subsets, TCR repertoire diversity and changes in the tumor immune microenvironment were observed in a subset of patients. Limited persistence of CAR T cells was observed beyond 28 days post-infusion. These results support future clinical studies to optimize dosing and combination strategies to improve durable therapeutic outcomes. ClinicalTrials.gov identifier NCT03873805.

2014-12-01·BMC cancer2区 · 医学

Systemic treatment with CAR-engineered T cells against PSCA delays subcutaneous tumor growth and prolongs survival of mice

2区 · 医学

ArticleOA

作者: Mohanraj Ramachandran ; Magnus Essand ; Justyna Leja ; Victoria Hillerdal

Abstract:

Background:

Adoptive transfer of T cells genetically engineered with a chimeric antigen receptor (CAR) has successfully been used to treat both chronic and acute lymphocytic leukemia as well as other hematological cancers. Experimental therapy with CAR-engineered T cells has also shown promising results on solid tumors. The prostate stem cell antigen (PSCA) is a protein expressed on the surface of prostate epithelial cells as well as in primary and metastatic prostate cancer cells and therefore a promising target for immunotherapy of prostate cancer.

Methods:

We developed a third-generation CAR against PSCA including the CD28, OX-40 and CD3 ζ signaling domains. T cells were transduced with a lentivirus encoding the PSCA-CAR and evaluated for cytokine production (paired Student’s t-test), proliferation (paired Student’s t-test), CD107a expression (paired Student’s t-test) and target cell killing in vitro and tumor growth and survival in vivo (Log-rank test comparing Kaplan-Meier survival curves).

Results:

PSCA-CAR T cells exhibit specific interferon (IFN)-γ and interleukin (IL)-2 secretion and specific proliferation in response to PSCA-expressing target cells. Furthermore, the PSCA-CAR-engineered T cells efficiently kill PSCA-expressing tumor cells in vitro and systemic treatment with PSCA-CAR-engineered T cells significantly delays subcutaneous tumor growth and prolongs survival of mice.

Conclusions:

Our data confirms that PSCA-CAR T cells may be developed for treatment of prostate cancer.

项与 PSCA-CAR-T Cells(Guangdong Zhaotai InVivo Biomedicine) 相关的新闻（医药）

2024-06-15

·生物制药小编

实体瘤CAR-T治疗的第28天

CAR-T细胞是一类创新的肿瘤治疗药物，被认为是继手术、化疗、放疗和骨髓移植后的“肿瘤治疗第五支柱”。在血液肿瘤上，CAR-T治疗已经取得成功，获批用于多种血液肿瘤；但是在实体瘤方面，CAR-T项目进度缓慢，障碍重重。近日，美国最大的癌症研究和治疗组织之一——希望之城（City of Hope）公布了其前列腺癌CAR-T项目的临床研究进展，研究显示：具有良好的治疗活性、积极的安全性、以及短暂的持久性。该研究发表于期刊Nature Medicine上，这也是PSCA CAR-T治疗转移性去势抵抗性前列腺癌（mCRPC）患者的首次人体研究结果。前列腺癌PSCA CAR-T 希望之城的这款实体瘤CAR-T靶向前列腺干细胞抗原（PSCA），PSCA在局部和转移性前列腺癌以及大部分膀胱癌和胰腺癌中均高表达，是潜在的肿瘤免疫疗法靶标。 PSCA-CAR构建体（图片来源：参考资料2）这款PSCA CAR-T没有制造失败，最终发布的产品中位数CAR百分比为86.8%。从单采到回输的中位时间为73天（范围：34-182），延迟主要由于在毒性评估和方案修定期间，协议强制暂停，等待研究活检以及监管对超出参数产品的批准。安全性数据这项由希望之城的Saul Priceman博士和Tanya Dorff博士团队发起的PSCA CAR-T针对前列腺癌的1期研究（NCT03873805），旨在评估PSCA CAR-T的安全性和剂量限制性毒性（DLT）。 DLT和CRS发生率（图片来源：参考资料2）在研究中，有14名患者接受了PSCA CAR-T。共有三个队列，初始剂量均为1亿个CAR-T细胞： DL1（n=3）患者无需接受淋巴细胞清除化疗，直接接受单次1亿个CAR-T细胞剂量的输注。由于该研究是该PSCA CAR-T的首次人体研究，评估单独使用CAR-T细胞的安全性非常重要。该队列中，并未观察到剂量限制性毒性（DLT）。 DL2（n=6）患者接受氟达拉滨/环磷酰胺（Flu/Cy）清淋后，再输注1亿个细胞剂量的PSCA CAR-T。该队列中，有两例DLT（非感染性膀胱炎）发生，膀胱炎的最高等级为2级。这是由于膀胱细胞也会表达PSCA，因此遭受到了CAR-T细胞的攻击导致炎症。两个DLT病例膀胱内治疗不是特别有效，都需要进行全身性类固醇治疗。为此，研究团队新增了DL3。 DL3（n=5）低剂量Flu/Cy后，输注1亿个细胞剂量的PSCA CAR-T。清淋化疗环磷酰胺的剂量从500mg m−2减少到300mg m−2，从而减少淋巴细胞耗竭；同时强制给药美司钠，更频繁地进行尿液分析，加强对膀胱炎的管理。在经过方案调整后的DL3中，未观察到DLT。在CRS和神经毒性方面，14例患者中有5例发生CRS，DL1发生1例（33%），DL2为2例，DL3为2例，没有达到3级的CRS；未发现高级别的CAR T细胞相关神经毒性或巨噬细胞活化综合征事件。有效性数据有效性数据主要由PSA水平来评估，PSA水平是前列腺癌患者疾病进展的血清标志物。在DL1中，1名患者（1/3）在治疗前至CAR-T输注后第28天期间观察到PSA水平下降；DL2中，3名患者（3/6）观察到PSA水平下降；DL3中，3名患者（3/5）观察到PSA水平下降。在全部14名患者中，有4名患者的PSA水平下降幅度超过30%，其中有一位在28天后维持PSA水平下降幅度超过30%。值得注意的是，DL2中的首位患者在CAR-T回输后第一周内实现了PSA水平下降幅度超过90%，骨骼和软组织的癌症也下降了，大约经历了8个月的积极缓解。 PSA水平下降情况（图片来源：参考资料1）此外，影像学检查显示一部分接受治疗的患者有治疗反应。同时在一部分患者中观察到外周血内源性和CAR-T细胞亚群激活、TCR库多样性和肿瘤免疫微环境的变化。持久性难关尽管在安全性和有效性上，希望之城的研究团队证明了PSCA CAR-T的潜力，但是在持久性上却遭难了。 PSCA-CAR T细胞数量情况（图片来源：参考资料1）根据研究显示，在28天的监测期后，PSCA CAR-T细胞没有维持高水平存在，这限制了CAR-T治疗的有效性。同时也是实体瘤CAR-T治疗的一个共同挑战。希望之城的研究团队即将以剂量优化、联合用药等方式以提高CAR-T治疗的持久性。小结根据报道，目前使用相同PSCA CAR-T细胞疗法的1b期试验已经启动，该试验将联合放疗以增强抗肿瘤活性，预计招募24名患者。参考资料： 1.Dorff, T.B., Blanchard, M.S., Adkins, L.N. et al. PSCA-CAR T cell therapy in metastatic castration-resistant prostate cancer: a phase 1 trial. Nat Med (2024). https://doi.org/10.1038/s41591-024-02979-8 2.https://www.businesswire.com/news/home/20240612751963/en/

免疫疗法细胞疗法临床结果临床2期ASH会议

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