ECT204 T-Cell Therapy for Liver Cancer
(ARYA-3 Trial)
Recruiting in Palo Alto (17 mi)
+4 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
Sponsor: Eureka Therapeutics Inc.
Must not be taking: Investigational agents
Disqualifiers: Congestive heart failure, Uncontrolled infection, others
No Placebo Group
Prior Safety Data
Approved in 1 Jurisdiction
Trial Summary
What is the purpose of this trial?
This trial is testing a new treatment where a patient's immune cells are modified to better fight liver cancer. It is for adults with a specific type of liver cancer who haven't had success with other treatments. The modified cells are designed to find and kill cancer cells with a particular marker.
Do I need to stop my current medications for the ECT204 T-Cell Therapy trial?
The trial protocol does not specify if you need to stop taking your current medications. However, you cannot be on other investigational agents or liver tumor-directed therapies while participating.
What data supports the effectiveness of the ECT204 T-cell therapy for liver cancer?
Research shows that T-cell therapies targeting glypican-3 (GPC3), a protein found in liver cancer cells, have shown promise in preclinical and early clinical trials. These therapies have demonstrated the ability to expand, persist, and effectively attack liver cancer cells in both laboratory and animal studies, suggesting potential effectiveness for treating liver cancer.12345
What safety data exists for ECT204 T-Cell Therapy for Liver Cancer?
Research on similar T-cell therapies targeting glypican-3 (GPC3) for liver cancer suggests that dual-targeting approaches may reduce the risk of harming healthy tissues while maintaining strong cancer-fighting abilities. However, specific safety data for ECT204 T-Cell Therapy in humans is not detailed in the available studies.23678
What makes ECT204 T-cell therapy unique for liver cancer treatment?
ECT204 T-cell therapy is unique because it targets glypican-3 (GPC3), a protein found on liver cancer cells, using engineered T cells that are designed to enhance their expansion and antitumor activity. This therapy is novel as it incorporates specific enhancements like the 4-1BB costimulatory domain, which improves T-cell proliferation and antitumor response, making it potentially more effective against solid tumors like liver cancer compared to traditional treatments.235910
Eligibility Criteria
Adults with advanced liver cancer (HCC) who have tried at least two treatments without success can join this trial. They should have a life expectancy of 4+ months, good organ function, and their cancer must show GPC3-positive expression. A score indicating mild liver disease (Child-Pugh A6 or better) and a performance status showing they're mostly independent are also required.Inclusion Criteria
Life expectancy of at least 4 months per Principal Investigator's opinion
My liver cancer cells test positive for GPC3.
I am able to care for myself but may not be able to do active work.
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Exclusion Criteria
My liver cancer affects more than half of my liver.
I have a serious health condition like heart failure.
I am currently undergoing or have recently finished (within 14 days) a treatment specifically targeting liver tumors.
See 5 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Phase 1 (Dose Escalation)
Completed; RP2D of ECT204 was determined
21 months
Phase 2 (Expansion)
Subjects receive ECT204 as monotherapy or with pre-treatment regorafenib
2 years
Long Term Follow-Up
Subjects are followed for assessment of treatment safety and overall survival
13 years
Treatment Details
Interventions
- ECT204 T cells (CAR T-cell Therapy)
Trial OverviewThe ECT204 T-cell therapy is being tested in adults with HCC that's not removable by surgery or has spread. This Phase I/II trial will determine the safest dose to use while checking how well it works against liver cancer.
Participant Groups
2Treatment groups
Experimental Treatment
Group I: Arm BExperimental Treatment2 Interventions
Approximately 10-15 subjects will receive ECT204 at the RP2D by intravenous infusion and preceded by cyclophosphamide and fludarabine chemotherapy for lymphodepletion. Arm B subjects will also receive pre-treatment with regorafenib (STIVARGA®) before ECT204 administration.
Group II: Arm AExperimental Treatment1 Intervention
Approximately 10-15 subjects will receive ECT204 at the RP2D by intravenous infusion and preceded by cyclophosphamide and fludarabine chemotherapy for lymphodepletion.
ECT204 T cells is already approved in United States for the following indications:
🇺🇸 Approved in United States as ECT204 for:
- Hepatocellular carcinoma (HCC) - Orphan drug designation
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Roswell Park Comprehensive Cancer CenterBuffalo, NY
Kansas University Cancer CenterWestwood, KS
City of HopeDuarte, CA
Kansas University Medical CenterWestwood, KS
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Who Is Running the Clinical Trial?
Eureka Therapeutics Inc.Lead Sponsor
References
RUNX-3-expressing CAR T cells targeting glypican-3 in patients with heavily pretreated advanced hepatocellular carcinoma: a phase I trial. [2023]Label="Background" NlmCategory="UNASSIGNED">Glypican-3 (GPC3) is a well-characterized hepatocellular carcinoma (HCC)-associated antigen and a promising target for HCC treatment. CT017 CAR T cells were engineered to co-express CAR-GPC3 and runt-related transcription factor 3 (RUNX3), which triggers CD8+ T-cell infiltration into the cancer microenvironment.
Glypican-3-Specific CAR T Cells Coexpressing IL15 and IL21 Have Superior Expansion and Antitumor Activity against Hepatocellular Carcinoma. [2020]Hepatocellular carcinoma (HCC) is the fourth most common cause of cancer-related death in the world, and curative systemic therapies are lacking. Chimeric antigen receptor (CAR)-expressing T cells induce robust antitumor responses in patients with hematologic malignancies but have limited efficacy in patients with solid tumors, including HCC. IL15 and IL21 promote T-cell expansion, survival, and function and can improve the antitumor properties of T cells. We explored whether transgenic expression of IL15 and/or IL21 enhanced glypican-3-CAR (GPC3-CAR) T cells' antitumor properties against HCC. We previously optimized the costimulation in GPC3-CARs and selected a second-generation GPC3-CAR incorporating a 4-1BB costimulatory endodomain (GBBz) for development. Here, we generated constructs encoding IL15, IL21, or both with GBBz (15.GBBz, 21.GBBz, and 21.15.GBBz, respectively) and examined the ability of transduced T cells to kill, produce effector cytokines, and expand in an antigen-dependent manner. We performed gene-expression and phenotypic analyses of GPC3-CAR T cells and CRISPR-Cas9 knockout of the TCF7 gene. Finally, we measured GPC3-CAR T-cell antitumor activity in murine xenograft models of GPC3+ tumors. The increased proliferation of 21.15.GBBz T cells was at least in part dependent on the upregulation and maintenance of TCF-1 (encoded by TCF7) and associated with a higher percentage of stem cell memory and central memory populations after manufacturing. T cells expressing 21.15.GBBz had superior in vitro and in vivo expansion and persistence, and the most robust antitumor activity in vivo These results provided preclinical evidence to support the clinical evaluation of 21.15.GPC3-CAR T cells in patients with HCC.
[Construction and function of Glypican-3-targeted fourth-generation chimeric antigen receptor T cells (secreting IL-7 and CCL19)]. [2020]Adoptive immunotherapy based on chimeric antigen receptor-modified T cells (CAR-T) is one of the most promising strategies to treat malignant tumors, but its application in solid tumors is still limited. Glypican-3 (GPC3) is a meaningful diagnostic, therapeutic, and prognostic biomarker for hepatocellular carcinoma (HCC). The second/third generation GPC3-targeted CAR-T cells are generated to treat HCC. In order to improve the therapeutic effect, we constructed a fourth-generation lentiviral vector to express GPC3 CAR, human interleukin-7 (IL-7) and CCL19. Then the lentiviral vector and packaging plasmids were co-transfected into HEK293T cells to generate CAR lentiviral particles. Human T lymphocyte cells were transduced with CAR lentiviral to develop the fourth-generation GPC3-targeted CAR-T cells (GPC3-BBZ-7×19). In vitro, we used cell counting, transwell assay, luciferase bioluminescence assay and flow cytometry to compare the proliferation, chemotaxis, cytotoxicity and subtype distribution between GPC3-BBZ-7×19 CAR-T cells and the second generation GPC3-targeted CAR-T cells (GPC3-BBZ). In vivo, we established GPC3-positive HCC xenograft model in immunodeficient mice, then untransduced T cells (non-CAR-T) or GPC3-BBZ-7×19 CAR-T cells were injected. Tumor growth in mice was observed by bioluminescence imaging. Results showed that compared with GPC3-BBZ CAR-T, GPC3-BBZ-7×19 CAR-T cells had stronger proliferation, chemotactic ability, and higher composition of memory stem T cells (Tscm) (P values
Identification of glypican-3-derived long peptides activating both CD8+ and CD4+ T cells; prolonged overall survival in cancer patients with Th cell response. [2021]In a recent phase I clinical trial, a vaccine consisting of glypican-3 (GPC3)-derived CTL epitopes was found to be safe and induced measurable immune and clinical responses in patients with hepatocellular carcinoma (HCC). The aim of this study was to identify GPC3-derived long peptides (GPC3-LPs) carrying promiscuous HLA class II-restricted T helper (Th) cell epitopes. Using a computer algorithm, we predicted GPC3-LPs that can bind to promiscuous HLA class II molecules. Their antigenicity for induction of specific CD4+ T cells in healthy donors or patients with HCC, before and after vaccination with GPC3-SPs, was proven by IFNγ enzyme-linked immunospot assays. Natural processing of these epitopes was confirmed by the immune response of helper T cells to dendritic cells (DCs) loaded with GPC3 proteins. Cross-presentation capacity was assessed in vitro using human DCs and LPs encapsulated in liposomes and in vivo in HLA-A2 transgenic mice (Tgm). All five LPs could induce Th1 cells and were presented by several frequently occurring HLA class II molecules in vitro. Four of them were likely to be naturally processed. One of the LPs encapsulated in liposomes was well cross-presented in vitro; it cross-primed CTLs in HLA-A2 Tgm. LP-specific and HLA class II-restricted CD4+ T-cell responses were observed in 14 of 20 HCC patients vaccinated with GPC3-SPs. Repeated vaccinations enhanced GPC3-LP-specific responses in 8 of 13 patients with HCC. Moreover, the presence of the specific Th cell was correlated with prolonged overall survival (OS). GPC3-LPs can be useful for cancer immunotherapy.
Chimeric Antigen Receptor-Glypican-3 T-Cell Therapy for Advanced Hepatocellular Carcinoma: Results of Phase I Trials. [2021]Our preclinical studies demonstrated the potential of chimeric antigen receptor (CAR)-glypican-3 (GPC3) T-cell therapy for hepatocellular carcinoma (HCC). We report herein the first published results of CAR-GPC3 T-cell therapy for HCC.
Development of T cells carrying two complementary chimeric antigen receptors against glypican-3 and asialoglycoprotein receptor 1 for the treatment of hepatocellular carcinoma. [2017]Adoptive immunotherapy leveraging chimeric antigen receptor-modified T (CAR-T) cells holds great promise for the treatment of cancer. However, tumor-associated antigens often have low expression levels in normal tissues, which can cause on-target, off-tumor toxicity. Recently, we reported that GPC3-targeted CAR-T cells could eradicate hepatocellular carcinoma (HCC) xenografts in mice. However, it remains unknown whether on-target, off-tumor toxicity can occur. Therefore, we proposed that dual-targeted CAR-T cells co-expressing glypican-3 (GPC3) and asialoglycoprotein receptor 1 (ASGR1) (a liver tissue-specific protein)-targeted CARs featuring CD3ζ and 28BB (containing both CD28 and 4-1BB signaling domains), respectively, may have reduced on-target, off-tumor toxicity. Our results demonstrated that dual-targeted CAR-T cells caused no cytotoxicity to ASGR1+GPC3- tumor cells, but they exhibited a similar cytotoxicity against GPC3+ASGR1- and GPC3+ASGR1+ HCC cells in vitro. We found that dual-targeted CAR-T cells showed significantly higher cytokine secretion, proliferation and antiapoptosis ability against tumor cells bearing both antigens than single-targeted CAR-T cells in vitro. Furthermore, the dual-targeted CAR-T cells displayed potent growth suppression activity on GPC3+ASGR1+ HCC tumor xenografts, while no obvious growth suppression was seen with single or double antigen-negative tumor xenografts. Additionally, the dual-targeted T cells exerted superior anticancer activity and persistence against single-targeted T cells in two GPC3+ASGR1+ HCC xenograft models. Together, T cells carrying two complementary CARs against GPC3 and ASGR1 may reduce the risk of on-target, off-tumor toxicity while maintaining relatively potent antitumor activities on GPC3+ASGR1+ HCC.
Development of GPC3 and EGFR-dual-targeting chimeric antigen receptor-T cells for adoptive T cell therapy. [2021]Adoptive transfer of T cells expressing specific anti-glypican-3 (GPC3) chimeric antigen receptors (CARs) has demonstrated therapeutic potential against hepatocellular carcinoma (HCC). However, normal tissues with low expression of neoplasm-associated antigens often show on-target, off-tumor toxicity. Previous studies have revealed that the development of HCC xenografts in mice could be inhibited effectively by GPC3-targeting CAR-T cells. However, these studies did not provide information regarding on-target, off-tumor toxicity. We hypothesized that on-target, off-tumor toxicity may decrease in dual-targeting CAR-T cells that co-express GPC3 with epidermal growth factor receptor (EGFR)-targeted CARs characterized by CD3ζ and 28BB expression. Our research confirmed that dual-targeting CAR-T (CARgpc3-egfr) cells exhibited similar proliferative ability and cytotoxicity to CARgpc3 T cells against GPC3+EGFR+ HCC in vitro. However, EGFR-targeting CAR-T (CARegfr) cells showed poor proliferation activity and cytotoxicity against GPC3+EGFR+ HCC cells, similar to mock CAR-T cells. CARgpc3 and CARgpc3-egfr T cells showed enhanced cytokine secretion compared to CARegfr and mock CAR-T cells in vitro. In vivo, tumor growth suppression was better for CARgpc3-egfr T cells than for CARgpc3 T cells in GPC3+EGFR+ HCC, while it was not observed for CARegfr or mock CAR-T cells. Taken together, our data indicated that dual-targeting CAR-T cells with two CARs against GPC3 and EGFR may maintain relatively effective anti-neoplasm functions in GPC3+EGFR+ HCC in vitro and in vivo, a strategy that may reduce off-tumor toxicity.
T Cells Engineered to Express a T-Cell Receptor Specific for Glypican-3 to Recognize and Kill Hepatoma Cells In Vitro and in Mice. [2022]Cancer therapies are being developed based on our ability to direct T cells against tumor antigens. Glypican-3 (GPC3) is expressed by 75% of all hepatocellular carcinomas (HCC), but not in healthy liver tissue or other organs. We aimed to generate T cells with GPC3-specific receptors that recognize HCC and used them to eliminate GPC3-expressing xenograft tumors grown from human HCC cells in mice.
Redirecting T Cells to Glypican-3 with 4-1BB Zeta Chimeric Antigen Receptors Results in Th1 Polarization and Potent Antitumor Activity. [2022]T cells engineered to express CD19-specific chimeric antigen receptors (CARs) have shown breakthrough clinical successes in patients with B-cell lymphoid malignancies. However, similar therapeutic efficacy of CAR T cells in solid tumors is yet to be achieved. In this study we systematically evaluated a series of CAR constructs targeting glypican-3 (GPC3), which is selectively expressed on several solid tumors. We compared GPC3-specific CARs that encoded CD3ζ (Gz) alone or with costimulatory domains derived from CD28 (G28z), 4-1BB (GBBz), or CD28 and 4-1BB (G28BBz). All GPC3-CARs rendered T cells highly cytotoxic to GPC3-positive hepatocellular carcinoma, hepatoblastoma, and malignant rhabdoid tumor cell lines in vitro. GBBz induced the preferential production of Th1 cytokines (interferon γ/granulocyte macrophage colony-stimulating factor) while G28z preferentially induced Th2 cytokines (interleukin-4/interleukin-10). Inclusion of 4-1BB in G28BBz could only partially ameliorate the Th2-polarizing effect of CD28. 4-1BB induced superior expansion of CAR T cells in vitro and in vivo. T cells expressing GPC3-CARs incorporating CD28, 4-1BB, or both induced sustained tumor regressions in two xenogeneic tumor models. Thus, GBBz CAR endows T cells with superior proliferative potential, potent antitumor activity, and a Th1-biased cytokine profile, justifying further clinical development of GBBz CAR for immunotherapy of GPC3-positive solid tumors.
GPC3-targeted CAR-T cells secreting B7H3-targeted BiTE exhibit potent cytotoxicity activity against hepatocellular carcinoma cell in the in vitro assay. [2022]Hepatocellular carcinoma (HCC), the most common primary liver cancer has a high mortality in China, and it is usually diagnosed at a late stage, thereby leaving patients with few effective treatment options. Chimeric antigen receptor-T (CAR-T) cell therapy, a novel immunotherapy that has shown promising results in leukemia, lymphoma and multiple myeloma, is also expected to work well in solid tumors, including HCC. However, the ideal therapeutic efficacy has not yet been achieved, in part due to tumor antigen escape caused by antigen heterogeneity. To overcome such challenge, we screened a panel of biomarkers in HCC cell lines and found that GPC3 and B7H3 were highly expressed on HCC with expression heterogeneity. Then we developed a novel bispecific T cell engagers CAR-T (CAR.T-BiTEs) that drives the expression of a CAR specific for GPC3 and BiTEs against CD3 and B7H3, herein referred to as "GPC3-BiTE CAR." We found that BiTEs promoted the increased activation of untransduced T cells and IFN-γ release. Moreover, BiTEs secreted by GPC3-BiTE CAR-HEK293T cells promoted increased cytotoxicity activity of untransduced T cells against GPC3+/B7H3+ (GPC3 positive/B7H3 positive) and GPC3-/B7H3+(GPC3 negative/B7H3 positive) HCC cell lines. In vitro function assays showed that GPC3-BiTE CAR-T cells exhibited greater cytotoxicity activity against GPC3+/B7H3+ HCC cell lines than GPC3 CAR-T cells (GPC3-targeted CAR-T cells) and B7H3 CAR-T cells (B7H3-targeted CAR-T cells). Furthermore, GPC3-BiTE CAR-T cells exhibited superior cytotoxicity against GPC3 negative HCC cell lines compared with GPC3 CAR T cells. In conclusion, our study showed that GPC3-BiTE CAR T cells exhibited superior antitumor activity than single-target CAR-T cells and can overcome tumor escape induced by antigen heterogeneity, suggesting that this could be a promising therapeutic strategy for HCC.