ET140203 T Cells for Pediatric Liver Cancer (ARYA-2 Trial)
Palo Alto (17 mi)Age: < 65
Sex: Any
Travel: May be covered
Time Reimbursement: Varies
Trial Phase: Phase 1 & 2
Recruiting
Sponsor: Eureka Therapeutics Inc.
No Placebo Group
Approved in 1 jurisdiction
Trial Summary
What is the purpose of this trial?Open-label, dose escalation, multi-center, Phase I/II clinical trial to assess the safety/tolerability and determine the recommended Phase II Dose (RP2D) of ET140203 T-cells in pediatric subjects who are AFP-positive/HLA-A2-positive and have relapsed/refractory HB, HCN-NOS, or HCC.
Is the treatment ET140203 T Cells promising for pediatric liver cancer?Yes, ET140203 T Cells is a promising treatment for pediatric liver cancer. This type of treatment uses the body's own immune cells, called T cells, to fight cancer. Research shows that similar T cell therapies have been effective in treating liver cancer, with patients showing good survival rates and reduced disease recurrence. This suggests that ET140203 T Cells could be a valuable new option for treating pediatric liver cancer.14578
What data supports the idea that ET140203 T Cells for Pediatric Liver Cancer is an effective treatment?The available research does not provide specific data on ET140203 T Cells for Pediatric Liver Cancer. However, similar T-cell therapies have shown promise in treating liver cancer. For example, a study on autologous tumor-infiltrating lymphocytes (TIL) in liver cancer patients showed that 80% of patients had no evidence of disease after treatment, and all patients were alive after 14 months. This suggests that T-cell therapies can be effective in treating liver cancer, although specific data on ET140203 T Cells is not available.127911
Do I need to stop my current medications for this trial?Yes, you may need to stop certain medications. You cannot have received cytotoxic chemotherapy, radiation, other anti-cancer therapies, immunosuppressive therapy, or systemic corticosteroids at doses greater than 5 mg/day of prednisone within two weeks of leukapheresis or conditioning chemotherapy. Topical and inhaled corticosteroids in standard doses and physiological replacement doses for adrenal insufficiency are allowed.
What safety data is available for ET140203 T Cells for Pediatric Liver Cancer?The provided research does not directly mention ET140203 T Cells or its variants. However, it discusses related immunotherapies for liver cancer, such as autologous invariant natural killer T cells and tumor-infiltrating lymphocytes, which were found to be safe and well-tolerated with low toxicity. These studies suggest that similar T cell therapies, like ET140203, may also have a favorable safety profile, but specific data for ET140203 is not provided in the research.346710
Eligibility Criteria
This trial is for pediatric patients aged 1-21 with relapsed/refractory liver cancers (HB, HCN-NOS, or HCC) who are AFP-positive/HLA-A2-positive. They should have a life expectancy over 4 months and good performance status. Patients must not have had recent cancer treatments or other investigational therapies and should not be on systemic immunosuppressants.Inclusion Criteria
My disease came back after initial treatment or didn't respond to it.
I am between 1 and 21 years old.
My liver cancer has been confirmed and my blood test shows AFP levels over 200ng/ml.
I carry the HLA-A2 gene.
My liver function is relatively good.
I carry the HLA-A2 gene.
I am mostly active and can care for myself.
My liver function is fairly good.
My liver cancer has been confirmed and my blood test shows AFP levels over 200ng/ml.
My disease came back or didn't respond after standard treatment.
I am between 1 and 21 years old.
I am mostly active and can care for myself.
Exclusion Criteria
I am on medication to suppress my immune system due to an autoimmune disease.
I cannot take certain chemotherapy drugs like Fludarabine and Cyclophosphamide.
I have had an organ transplant.
More than half of my liver is affected by cancer.
Treatment Details
The trial tests ET140203 T-cells in children with specific liver cancers to find the safest dose that works best (Phase I/II). It's an open-label study where all participants receive the treatment, starting at lower doses which increase gradually to determine the optimal dose.
1Treatment groups
Experimental Treatment
Group I: ET140203 T CellsExperimental Treatment1 Intervention
ET140203 Autologous T Cells
ET140203 T Cells is already approved in United States for the following indications:
🇺🇸 Approved in United States as ET140203 for:
- Hepatoblastoma (HB)
Find a clinic near you
Research locations nearbySelect from list below to view details:
Dana Farber Cancer InstituteBoston, MA
UCSF Benioff Children's HospitalsSan Francisco, CA
Dana-Farber/Boston Children's Cancer and Blood Disorders CenterBoston, MA
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Who is running the clinical trial?
Eureka Therapeutics Inc.Lead Sponsor
References
[Prevention of cancer recurrence by infusion of activated autologous lymphocytes]. [2017]Activated and expanded autologous peripheral blood lymphocytes by cultivation with immobilized anti-CD3 antibody and IL-2 have been infused to the patients with hepatocellular carcinoma after culative operation as a randomized clinical trial. This study is on-going and primary efficacy endpoints of this study were disease-free survival and overall survival, and the sample size for the study was designed as a minimum of 146 patients. From interim analysis at the second year from start of the study, Eligible cases were 101, 49 cases in treated group and 52 cases in control. Recurrences were confirmed 13 cases from treated group and 22 cases from control group. Minor adverse reaction were observed in 28 cases (57%).
T-cell-based therapies for malignancy and infection in childhood. [2021]One major advance in T-cell-based immunotherapy in the last 20 years has been the molecular definition of numerous viral and tumor antigens. Adoptive T-cell transfer has shown definite clinical benefit in the prophylaxis and treatment of viral infections that develop in pediatric patients after allogeneic transplant and in posttransplant lymphoproliferative disease associated with the Epstein-Barr virus. Developing adoptive T-cell therapies for other malignancies presents additional challenges. This article describes the recent advances in T-cell-based therapies for malignancy and infection in childhood and strategies to enhance the effector functions of T cells and optimize the cellular product, including gene modification and modulation of the host environment.
A practical approach to immunotherapy of hepatocellular carcinoma using T cells redirected against hepatitis B virus. [2022]Hepatocellular carcinoma (HCC) cells often have hepatitis B virus (HBV)-DNA integration and can be targeted by HBV-specific T cells. The use of viral vectors to introduce exogenous HBV-specific T-cell receptors (TCR) on T cells to redirect their specificity is complex and expensive to implement in clinical trials. Moreover, it raises safety concerns related to insertional mutagenesis and potential toxicity of long-lived HBV-specific T cells in patients with persistent infection. To develop a more practical and safer approach to cell therapy of HCC, we used electroporation of mRNA encoding anti-HBV TCR. Approximately 80% of CD8(+) T cells expressed functional HBV TCR 24 hours postelectroporation, an expression efficiency much higher than that obtained by retroviral transduction (~18%). Antigen-specific cytokine production of electroporated T cells was efficient within 72-hour period, after which the redirected T cells lost their HBV-specific function. Despite this transient functionality, the TCR-electroporated T cells efficiently prevented tumor seeding and suppressed the growth of established tumors in a xenograft model of HCC. Finally, we established a method for large-scale TCR mRNA electroporation that yielded large numbers of highly functional clinical-grade anti-HBV T cells. This method represents a practical approach to cell therapy of HCC and its inherently self-limiting toxicity suggests potential for application in other HBV-related pathologies.Molecular Therapy-Nucleic Acids (2013) 2, e114; doi:10.1038/mtna.2013.43; published online 13 August 2013.
T cell receptor-therapy in HBV-related hepatocellularcarcinoma. [2022]Adoptive transfer of lymphocytes expressing engineered T cell receptors (TCR) is a promising option for cancer treatment and could include hepatocellularcarcinoma (HCC), where therapeutic options are limited. We have recently investigated whether hepatitis B viral antigens can act as a HCC-specific antigen and thus be targeted by adoptively transferred HBV-specific TCR redirected T cells.
Engineered cytotoxic T lymphocytes with AFP-specific TCR gene for adoptive immunotherapy in hepatocellular carcinoma. [2022]Alpha-fetoprotein (AFP) is overexpressed in hepatocellular carcinoma (HCC) and could serve as a tumor-associated antigen (TAA) and potential target for adoptive immunotherapy. However, low frequency and severe functional impairment of AFP-specific T cells in vivo hamper adoptive infusion. TAA-specific T cell receptor (TCR) gene transfer could be an efficient and reliable alternation to generate AFP-specific cytotoxic T lymphocytes (CTLs). Autologous dendritic cells (DC) pulsed with AFP158-166 peptides were used to stimulate AFP-specific CTLs. TCR α/β chain genes of AFP-specific CTLs were cloned and linked by 2A peptide to form full-length TCR coding sequence synthesized into a lentiviral vector. Nonspecific activated T cells were engineered by lentivirus infection. Transgenetic CTLs were evaluated for transfection efficiency, expression of AFP158-166-specific TCR, interferon (IFN)-γ secretion, and specific cytotoxicity toward AFP+ HCC cells in vitro and in vivo. Flow cytometry revealed the AFP158-166-MHC-Pentamer positive transgenetic CTLs was 9.86 %. The number of IFN-γ secretion T cells and the specific cytotoxicity toward HpeG2 in vitro and in tumor-bearing NOD/SCID mice were significantly raised in transgenetic CTLs than that of AFP158-166-specific CTLs obtained by peptide-pulsed DCs or control group. TCR gene transfer is a promising strategy to generate AFP158-166-specific CTLs for the treatment of HCC.
Chimeric Antigen Receptor T Cell Therapy in Hematology. [2018]It is well demonstrated that the immune system can control and eliminate cancer cells. Immune-mediated elimination of tumor cells has been discovered and is the basis of both cancer vaccines and cellular therapies including hematopoietic stem cell transplantation. Adoptive T cell transfer has been improved to be more specific and potent and to cause less off-target toxicity. Currently, there are two forms of engineered T cells being tested in clinical trials: T cell receptor (TCR) and chimeric antigen receptor (CAR) modified T cells. On 1 July 2014, the United States Food and Drug Administration granted 'breakthrough therapy' designation to anti-CD19 CAR T cell therapy. Many studies were conducted to evaluate the benefits of this exciting and potent new treatment modality. This review summarizes the history of adoptive immunotherapy, adoptive immunotherapy using CARs, the CAR manufacturing process, preclinical and clinical studies, and the effectiveness and drawbacks of this strategy.
A phase I clinical trial utilizing autologous tumor-infiltrating lymphocytes in patients with primary hepatocellular carcinoma. [2018]This report describes an ongoing Phase I clinical trial testing the safety of adoptive cell therapy (ACT) using autologous tumor-infiltrating lymphocytes (TIL) in patients with primary hepatocellular carcinoma (HCC). Fifteen HCC patients were treated with their activated and expanded TILs following tumor resection. From a total of 17 patients with HCC, TIL were successfully expanded from 15 patients (88%), whereas two patients showed minimal or no expansion of TIL. Transient increase in the frequency of T cells was observed after adoptive transfer who was found only associated with grade I flu-like symptoms and malaise. After a median follow-up of 14 months, 15 patients (100%) were alive; and 12 patients (80%) showed no evidence of disease, 3 patients (patient 1,11,12) had tumor recurrence. The time to the diagnosis of tumor recurrence following therapy ranged from 105 to 261 days. These results indicate that immunotherapy with activated and expanded autologous TIL could be successfully performed with low toxicity, thus would serve as a novel treatment modality for patients with HCC.
γδ T cell-mediated individualized immunotherapy for hepatocellular carcinoma considering clinicopathological characteristics and immunosuppressive factors. [2020]Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer. γδ T cells have been revealed to be promising candidates for immunotherapy in patients with HCC. However, the use of these cells in clinical practice has been demonstrated to be challenging. In the present study, γδ T cells isolated from the peripheral blood of patients with HCC (n=83) and healthy donors (n=15) were characterized. Flow cytometry was used to analyze the proportion, phenotype, tumor-killing capacity and cytokine secretion of regulatory T cells (Tregs) and γδ T17 cells in peripheral blood samples prior to and following amplification. Interleukin (IL)-17A levels in the supernatant was analyzed using an ELISA on days 3, 7, 10 and 14. The in vitro cytotoxicity of γδ T cells was measured using an MTT assay. It was revealed that zoledronate with IL-2 may efficiently expand γδ T cells sourced from the peripheral blood of patients with HCC. The amplification capacity of γδ T cells was associated with the clinicopathological characteristics of patients (clinical stage, levels of AFP and albumin, duration of disease, size and number of tumors, numbers of Tregs and γδ T17 cells, and levels of IL-17A). The proportion of γδ T cells positive for interferon-γ, tumor necrosis factor-α, granzyme B, perforin, and lysosome-associated membrane protein 1 was almost unchanged prior to and following amplification. Following amplification, the in vitro cytotoxicity of γδ T cells also remained unchanged. γδ T17 cells, Tregs and IL-17A levels were not altered during amplification. In summary, following in vitro amplification, circulating γδ T cells were revealed to possess features that may make them suitable for immunotherapy for HCC without increasing immunosuppressive factors. However, immunotherapy should be individualized according to the clinicopathological features of patients.
Selection of a Clinical Lead TCR Targeting Alpha-Fetoprotein-Positive Liver Cancer Based on a Balance of Risk and Benefit. [2021]Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer with a poor prognosis and limited therapeutic options. Alpha-fetoprotein (AFP), an established clinical biomarker of HCC, has been employed as an attractive target for T cell-based immunotherapy against this disease given its high expression in the tumor and restricted expression in normal tissues. We have identified a number of T cell receptors (TCRs) recognizing the HLA-A*02:01 restricted AFP158-166 peptide FMNKFIYEI, providing a TCR candidate pool for identifying TCRs with optimal clinical benefit. To select the ideal AFP TCR for clinical use, we evaluated the efficacy and safety profile of 7 TCRs by testing their potency toward AFP-expressing HCC cells and their specificity based upon reactivity to normal and transformed cells covering a wide variety of primary cell types and HLA serotypes. Furthermore, we assessed their cross-reactivity to potential protein candidates in the human genome by an extensive alanine scan (X-scan). We first selected three TCR candidates based on the in vitro anti-tumor activity. Next we eliminated two potential cross-reactive TCRs based on their reactivity against normal and transformed cells covering a variety of primary cell types and HLA serotypes, respectively. We then excluded the potential cross-reactivity of the selected TCR with a protein candidate identified by X-scan. At present we have selected an AFP TCR with the optimal affinity, function, and safety profile, bearing properties that are expected to allow AFP TCR redirected T cells to specifically differentiate between AFP levels on tumor and normal tissues. An early phase clinical trial using T cells transduced with this TCR to treat HCC patients (NCT03971747) has been initiated.
Adoptive Transfer of Autologous Invariant Natural Killer T Cells as Immunotherapy for Advanced Hepatocellular Carcinoma: A Phase I Clinical Trial. [2021]Label="LESSONS LEARNED">Administration of autologous invariant natural killer T (iNKT) cells was safe and well-tolerated in patients with hepatocellular carcinoma (Barcelona Clinic Liver Cancer stage B/C). Expanded iNKT cells produced T-helper 1-like responses with possible antitumor activity. No severe adverse events were observed in any of the enrolled patients, including one patient who received 1010 in vitro-expanded autologous iNKT cells as a single infusion.
Nonviral mcDNA-mediated bispecific CAR T cells kill tumor cells in an experimental mouse model of hepatocellular carcinoma. [2022]Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide and the adoptive immunotherapy of which is worth studying. CD133, a kind of cancer stem cell (CSC) antigen, together with glypican-3 (GPC3) has been proved to be highly expressed in HCC cells and both of them are used as targets to generate chimeric antigen receptor (CAR) T cells. But there are limitations like "off-target" toxicity, low transfection efficacy and weak antitumor ability in CAR T cells treatment.