CAR-T Cell Therapy for Liver Cancer

Overseen By Tim F Greten, M.D.

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: National Cancer Institute (NCI)

Must not be taking: Anticoagulants, Antiplatelets, Corticosteroids, others

Disqualifiers: Child-Pugh B/C, HIV, Autoimmune, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 8

38 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new personalized immune therapy called CAR-T cell therapy for individuals with Glypican-3 (GPC3) positive hepatocellular carcinoma (HCC), a specific type of liver cancer. The goal is to determine the safety of this treatment, which involves modifying a patient's own T cells to enhance their ability to fight cancer. Suitable candidates are adults with this liver cancer type, particularly those who have experienced issues with standard treatments. Participants will undergo various screenings and receive treatment in a hospital setting, followed by long-term follow-ups. As a Phase 1 trial, this research aims to understand how the treatment works in people, offering participants the opportunity to be among the first to receive this innovative therapy.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot participate if you are on certain medications like anticoagulants or systemic corticosteroids, or if you have had certain treatments like anti-PD-1 or anti-PD-L1 antibodies within specific time frames before starting the trial.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research has shown that CAR-T cell therapy, currently under testing for liver cancer, demonstrated promise in earlier studies. This treatment uses a person's own T cells, a type of white blood cell, modifying them to better combat cancer. Early results suggest that CAR-T cells targeting glypican-3 (GPC3) are well-tolerated by patients with hepatocellular carcinoma (HCC), a common type of liver cancer. In one study, this treatment significantly reduced tumor size for many patients.

Although specific safety data for this trial is not yet available, as a Phase 1 trial, researchers primarily focus on safety. Early trials typically monitor closely for any side effects or adverse reactions. Previous patients receiving similar CAR-T cell therapies generally tolerated the treatment well, with manageable side effects.

Each person's experience can differ, and joining a clinical trial always involves some risks. However, the structured environment of a clinical trial ensures that safety remains a top priority. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about CAR-T cell therapy for liver cancer because it offers a unique approach by using modified immune cells to specifically target and kill cancer cells. Unlike traditional treatments like surgery, chemotherapy, or radiation, which can affect both healthy and cancerous cells, CAR-T cells are engineered to recognize specific proteins on liver cancer cells, potentially reducing damage to normal tissues. Additionally, this therapy has shown promise in other cancers, suggesting it could offer new hope for liver cancer patients who have limited options.

What evidence suggests that this trial's treatments could be effective for liver cancer?

Research shows that CAR-T cell therapy, which modifies a person's T cells to better attack cancer cells, holds promise for some liver cancers. This trial will evaluate CAR-T cells targeting a protein called Glypican-3 (GPC3). Studies have shown that these cells successfully destroy GPC3-positive liver cancer cells in lab tests and in mice, removing tumors in these controlled settings. While CAR-T therapy has proven effective for blood cancers, its application for solid tumors like liver cancer remains under study. Early results are hopeful, suggesting that this therapy could become an important tool in fighting liver cancer. Participants in this trial will receive escalating doses of CAR-T cells or the maximum tolerated dose to further assess its effectiveness. ^{3 4 5 6 7}

Who Is on the Research Team?

Tim F Greten, M.D.

Principal Investigator

National Cancer Institute (NCI)

Are You a Good Fit for This Trial?

Adults over 18 with advanced liver cancer expressing GPC3, who have tried or can't tolerate standard chemotherapy. They must be able to undergo a tumor biopsy, have measurable disease not suitable for surgery or transplantation, and proper organ function. Pregnant women and those with severe illnesses or certain medical conditions are excluded.

Inclusion Criteria

I have hepatitis B, am on antivirals, and my HBV DNA level is below 100IU/mL.

Room air oxygen saturation of 92% or greater

Participants must be able to understand and sign a written informed consent

Exclusion Criteria

I am on blood thinners.

I haven't received anti-PD-1 or anti-PD-L1 treatments in the last 8 weeks.

My liver function is moderately to severely impaired.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Leukapheresis

Participants undergo leukapheresis to collect white blood cells for modification

1 day

1 visit (in-person)

Chemotherapy

Participants receive lymphocyte depleting chemotherapy conditioning regimen

3 days

Inpatient stay

CAR-T Cell Infusion

Participants receive the modified CAR-T cells and are monitored for toxicity

9 days

Inpatient stay

Follow-up

Participants are monitored for safety and effectiveness after treatment

15 years

Frequent visits initially, then every 6 months

What Are the Treatments Tested in This Trial?

Interventions

• CAR-T cell
• Cyclophosphamide
• Fludarabine

Trial Overview The trial is testing CAR-T cell therapy where patients' T cells are modified to fight liver cancer better. Participants will receive chemo drugs fludarabine and cyclophosphamide before getting their modified T cells back via IV. The study includes long-term follow-up.

How Is the Trial Designed?

Group I: 2/ Arm 2 Experimental Treatment 3 Interventions

MTD of CAR-T cells

Group II: 1/ Arm 1 Experimental Treatment 3 Interventions

Escalating doses of CAR-T cells

CAR-T cell is already approved in China, United States for the following indications:

Approved in China as CAR-GPC3 T-cell therapy for:

• Advanced hepatocellular carcinoma (HCC)

Approved in United States as Anti-GPC3 CAR-T cells for:

• Advanced hepatocellular carcinoma (HCC)

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

T cells engineered with GPC3-targeted chimeric antigen receptors (CAR) effectively kill GPC3-positive hepatocellular carcinoma (HCC) cells in vitro, demonstrating a strong correlation between their cytotoxic activity and the level of GPC3 expression in target cells.

In vivo studies showed that third-generation GPC3-targeted CAR T cells could eradicate HCC xenografts with high GPC3 expression and significantly prolong the survival of mice with established tumors, indicating their potential as a promising treatment for GPC3-positive HCC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Development of T cells redirected to glypican-3 for the treatment of hepatocellular carcinoma. Gao, H., Li, K., Tu, H., et al.[2022]

In a phase II study involving 40 patients with advanced solid tumors, high-dose chemotherapy (HDCT) using carboplatin, cyclophosphamide, and etoposide was administered safely without the need for peripheral blood progenitor cell (PBPC) support, demonstrating that this approach can reduce costs and potential tumor cell reinfusion risks.

The treatment resulted in a significant overall response rate of 72.5%, with median time to progression and overall survival of 29 and 38 months, respectively, indicating that HDCT can provide effective outcomes for patients with limited treatment options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

High-dose carboplatin, cyclophosphamide, etoposide with hematological growth factors, without stem cell support in patients with advanced cancer. Recchia, F., De Fillipis, S., Piccinini, M., et al.[2013]

Dual-targeted CAR-T cells that target both GPC3 and ASGR1 showed no cytotoxicity to tumor cells lacking GPC3, suggesting a reduced risk of on-target, off-tumor toxicity while effectively targeting hepatocellular carcinoma (HCC).

These dual-targeted CAR-T cells demonstrated enhanced anti-tumor activity, including higher cytokine secretion and proliferation, and effectively suppressed the growth of GPC3+ASGR1+ HCC tumors in xenograft models, outperforming single-targeted CAR-T cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Development of T cells carrying two complementary chimeric antigen receptors against glypican-3 and asialoglycoprotein receptor 1 for the treatment of hepatocellular carcinoma. Chen, C., Li, K., Jiang, H., et al.[2017]

In a clinical trial involving 32 adults with relapsed B cell non-Hodgkin's lymphoma, CD19 CAR-T cells showed significantly improved efficacy when administered after cyclophosphamide and fludarabine (Cy/Flu) lymphodepletion, achieving a 50% complete remission rate and a 72% overall response rate.

The study identified that the Cy/Flu regimen enhanced CAR-T cell expansion and persistence while minimizing immune responses that could limit efficacy, although it also resulted in severe cytokine release syndrome and neurotoxicity in a notable percentage of patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immunotherapy of non-Hodgkin's lymphoma with a defined ratio of CD8+ and CD4+ CD19-specific chimeric antigen receptor-modified T cells. Turtle, CJ., Hanafi, LA., Berger, C., et al.[2022]

In a study of 102 patients undergoing hematopoietic cell transplantation (HCT) with fludarabine and low-dose total body irradiation, significant variability was observed in pharmacological biomarkers related to fludarabine metabolism, indicating that individual responses to the drug can differ widely.

Despite the variability in biomarkers such as F-ara-A area under the curve and F-ara-ATP accumulation, no significant associations were found between these biomarkers and clinical outcomes like acute graft-versus-host disease or overall mortality, suggesting that these pharmacological measures may not predict treatment success.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Association of fludarabine pharmacokinetic/dynamic biomarkers with donor chimerism in nonmyeloablative HCT recipients. McCune, JS., Mager, DE., Bemer, MJ., et al.[2018]

In a study involving 26 patients with relapsed/refractory B cell acute lymphoblastic leukemia, the combination of decitabine (DAC) with fludarabine and cyclophosphamide (FC) significantly improved overall survival (92.3% vs. 41.7%) and leukemia-free survival (92.9% vs. 27.3%) compared to the FC regimen alone.

Despite the improved survival rates, the addition of DAC did not increase the incidence of cytokine release syndrome or delay recovery of blood cell counts, indicating that this combination therapy is both effective and safe.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Decitabine in combination with fludarabine and cyclophosphamide as a lymphodepletion regimen followed by CD19/CD22 bispecific targeted CAR T-cell therapy significantly improves survival in relapsed/refractory B-ALL patients. Ma, Y., Dai, H., Cui, Q., et al.[2023]

In a study of 89 hematopoietic cell transplantation recipients, higher levels of the active metabolite of cyclophosphamide (PM AUC0-8 hr) were linked to worse nonrelapse mortality and overall survival, indicating that careful monitoring of this metabolite is crucial for patient outcomes.

Patients with low levels of the active metabolite of fludarabine (F-ara-ADay-4) and low PM AUC0-8 hr had significantly lower nonrelapse mortality, suggesting that optimizing drug exposure could improve safety and efficacy in reduced-intensity conditioning regimens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Higher Fludarabine and Cyclophosphamide Exposures Lead to Worse Outcomes in Reduced-Intensity Conditioning Hematopoietic Cell Transplantation for Adult Hematologic Malignancy. Takahashi, T., Scheibner, A., Cao, Q., et al.[2021]

T cells engineered with GPC3-specific CARs demonstrated strong cytotoxic effects against various solid tumors, including hepatocellular carcinoma and malignant rhabdoid tumors, indicating their potential as an effective treatment option.

Among the different CAR constructs tested, the GBBz CAR showed superior T cell expansion and a Th1-biased cytokine profile, suggesting it may be the most promising candidate for further clinical development in treating GPC3-positive solid tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Redirecting T Cells to Glypican-3 with 4-1BB Zeta Chimeric Antigen Receptors Results in Th1 Polarization and Potent Antitumor Activity. Li, W., Guo, L., Rathi, P., et al.[2022]

The fourth-generation GPC3-targeted CAR-T cells (GPC3-BBZ-7×19) demonstrated enhanced proliferation and chemotactic abilities compared to second-generation CAR-T cells, indicating a potentially more effective treatment for hepatocellular carcinoma (HCC).

In vivo studies showed that GPC3-BBZ-7×19 CAR-T cells significantly eliminated GPC3-positive HCC tumors in immunodeficient mice, suggesting they could provide a durable and effective therapeutic option for HCC in future clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Construction and function of Glypican-3-targeted fourth-generation chimeric antigen receptor T cells (secreting IL-7 and CCL19)]. Huang, W., Liu, Y., Hu, Y., et al.[2020]

In two phase I studies involving 13 patients with advanced GPC3+ hepatocellular carcinoma, CAR-GPC3 T-cell therapy showed an initial safety profile, with manageable side effects like fever and cytokine release syndrome, and no severe neurotoxicity reported.

The therapy demonstrated early signs of antitumor activity, with overall survival rates of 50.3% at 6 months and 42.0% at 1 year, along with two partial responses observed, suggesting potential efficacy in treating this type of cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chimeric Antigen Receptor-Glypican-3 T-Cell Therapy for Advanced Hepatocellular Carcinoma: Results of Phase I Trials. Shi, D., Shi, Y., Kaseb, AO., et al.[2021]

Dual-targeting CAR-T cells that express both GPC3 and EGFR showed effective anti-tumor activity against hepatocellular carcinoma (HCC) in vitro and in vivo, suggesting a promising therapeutic approach.

This dual-targeting strategy may help reduce on-target, off-tumor toxicity, which is a common issue with therapies targeting specific antigens, as demonstrated by improved tumor suppression compared to single-target CAR-T cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Development of GPC3 and EGFR-dual-targeting chimeric antigen receptor-T cells for adoptive T cell therapy. Li, K., Qian, S., Huang, M., et al.[2021]

The CT017 CAR T cell therapy, targeting the GPC3 antigen in patients with advanced hepatocellular carcinoma (HCC), demonstrated a manageable safety profile, with all patients experiencing cytokine release syndrome (CRS) that resolved after treatment, but no cases of neurotoxicity were observed.

Among the six heavily pretreated patients, there was a 16.7% objective response rate and a 50% disease control rate, indicating promising antitumor activity, with a median overall survival of 7.9 months, suggesting potential efficacy that warrants further investigation in larger trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

RUNX-3-expressing CAR T cells targeting glypican-3 in patients with heavily pretreated advanced hepatocellular carcinoma: a phase I trial. Fu, Q., Zheng, Y., Fang, W., et al.[2023]

The monoclonal antibody GC33 effectively inhibits tumor growth in liver cancer models expressing glypican 3 (GPC3), demonstrating its potential as a targeted therapy for GPC3-positive tumors.

Humanized GC33 (hGC33) retains similar efficacy to GC33 in inhibiting tumor growth, with its antitumor activity primarily driven by antibody-dependent cellular cytotoxicity (ADCC), particularly involving natural killer cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-glypican 3 antibody as a potential antitumor agent for human liver cancer. Ishiguro, T., Sugimoto, M., Kinoshita, Y., et al.[2022]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05003895

Study Details | NCT05003895 | GPC3 Targeted CAR-T Cell ... To see if a personalized immune treatment, anti-GPC3 CAR-T cells, is safe. Eligibility: Adults aged 18 years and older who have Glypican-3 (GPC3) positive HCC, ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11576447/

CAR-T cell therapy for hepatocellular carcinoma This review synthesizes recent findings and clinical advancements in the use of CAR T-cell therapies for HCC treatment.

3. aacrjournals.org aacrjournals.org/clincancerres/article/26/15/3979/82521/Chimeric-Antigen-Receptor-Glypican-3-T-Cell

Chimeric Antigen Receptor-Glypican-3 T-Cell Therapy for ... Recently, we demonstrated that GPC3-targeted CAR T cells could eliminate GPC3+ HCC cells in vitro and eradicate GPC3+ HCC tumor xenografts in mice (36–38).

4. jnanobiotechnology.biomedcentral.com jnanobiotechnology.biomedcentral.com/articles/10.1186/s12951-025-03512-w

Advancing liver cancer treatment with dual-targeting CAR-T ... Chimeric antigen receptor (CAR)-T cell therapy targeting glypican-3 (GPC3) has shown promise in the treatment of hepatocellular carcinoma ...

5. cell.com cell.com/molecular-therapy-family/oncology/fulltext/S2950-3299(24)00059-6

Bispecific CAR-T cells targeting FAP and GPC3 have the ... CAR-T cell therapy achieves striking success in the treatment of patients with hematological malignancies, but no such efficacy has been observed in solid ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11179089/

Bispecific CAR-T cells targeting FAP and GPC3 have the ... Li and colleagues found that CAR-T cell therapy targeting FAP and GPC3 has the potential to treat HCC by avoiding HCC antigen escape, which may solve the ...

7. gioncologynow.com gioncologynow.com/post/new-car-t-cell-therapy-shows-promise-for-treating-advanced-hepatocellular-carcinoma

New CAR T-Cell Therapy Shows Promise for Treating ... New trial shows C-CAR031 CAR T-cell therapy promising for advanced hepatocellular carcinoma, with 90.9% tumor reduction rate.