CAR-T Cell Therapy for Liver Cancer

Overseen by Tim F Greten, M.D.

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Recruiting

Sponsor: National Cancer Institute (NCI)

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

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

No Placebo Group

Trial Summary

What is the purpose of this trial?

This trial tests a new treatment where a person's immune cells are modified to better fight liver cancer. It targets adults with a specific type of liver cancer that has a particular marker. The modified cells are designed to find and kill cancer cells. This marker is highly expressed in a common type of liver cancer and has been targeted in various innovative therapies for liver cancer.

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.

What data supports the effectiveness of this treatment for liver cancer?

Research shows that CAR-T cells targeting glypican-3 (GPC3) have demonstrated strong antitumor activity against liver cancer cells in laboratory studies. These CAR-T cells have been shown to effectively kill cancer cells and reduce tumor size in animal models, suggesting potential benefits for treating liver cancer in humans. ^{1 2 3 4 5}

Is CAR-T cell therapy for liver cancer safe for humans?

CAR-T cell therapy targeting glypican-3 (GPC3) has shown potential in treating liver cancer, but there is a risk of on-target, off-tumor toxicity, where the treatment might affect normal tissues that also express the target protein. Dual-targeting CAR-T cells, which target both GPC3 and another protein, may reduce this risk while maintaining strong antitumor activity. ^{4 5 6 7 8}

What makes CAR-T cell therapy for liver cancer unique compared to other treatments?

CAR-T cell therapy for liver cancer is unique because it uses genetically modified T cells to specifically target cancer cells, offering a personalized approach that can potentially improve outcomes. This therapy is combined with cyclophosphamide and fludarabine, which help prepare the body by reducing immune cells that might interfere with the treatment, enhancing the effectiveness of the CAR-T cells. ^{9 10 11 12 13}

Research Team

Tim F Greten, M.D.

Principal Investigator

National Cancer Institute (NCI)

Eligibility Criteria

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

My side effects from previous treatments are mild.

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.

Trial Timeline

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

Treatment Details

Interventions

• CAR-T cell (CAR T-cell Therapy)
• Cyclophosphamide (Alkylating agents)
• Fludarabine (Anti-metabolites)

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.

Participant Groups

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 for the following indications:

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

• Advanced hepatocellular carcinoma (HCC)

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Dr. Douglas R. Lowy

National Cancer Institute (NCI)

Chief Executive Officer since 2023

MD from New York University School of Medicine

Dr. Monica Bertagnolli

National Cancer Institute (NCI)

Chief Medical Officer since 2022

MD from Harvard Medical School

Findings from Research

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]

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 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]

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]

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]

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]

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]

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]

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 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]

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]

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]

References

1. England 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. [2023]

2. United States pubmed.ncbi.nlm.nih.gov

Development of T cells redirected to glypican-3 for the treatment of hepatocellular carcinoma. [2022]

3. United States pubmed.ncbi.nlm.nih.gov

Chimeric Antigen Receptor-Glypican-3 T-Cell Therapy for Advanced Hepatocellular Carcinoma: Results of Phase I Trials. [2021]

4. China pubmed.ncbi.nlm.nih.gov

[Construction and function of Glypican-3-targeted fourth-generation chimeric antigen receptor T cells (secreting IL-7 and CCL19)]. [2020]

5. United States 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. [2022]

6. United States pubmed.ncbi.nlm.nih.gov

Development of GPC3 and EGFR-dual-targeting chimeric antigen receptor-T cells for adoptive T cell therapy. [2021]

7. Germany 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. [2017]

8. United States pubmed.ncbi.nlm.nih.gov

Anti-glypican 3 antibody as a potential antitumor agent for human liver cancer. [2022]

9. United States 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. [2022]

10. Germany pubmed.ncbi.nlm.nih.gov

Association of fludarabine pharmacokinetic/dynamic biomarkers with donor chimerism in nonmyeloablative HCT recipients. [2018]

11. United States 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. [2021]

12. Greece pubmed.ncbi.nlm.nih.gov

High-dose carboplatin, cyclophosphamide, etoposide with hematological growth factors, without stem cell support in patients with advanced cancer. [2013]

13. England 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. [2023]