GPC3-CAR T Cells for Brain Cancer

Overseen By Ganesh Rao, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Baylor College of Medicine

Disqualifiers: Pregnancy, HIV, Organ transplant, others

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

Compensation: Varies

Number of Visits: 4

Duration: 1 day

27 Participants Needed

Trial Summary

What is the purpose of this trial?

The body has different ways of fighting infection and disease. No single way seems perfect for fighting cancers. This research study combines two different ways of fighting cancer: antibodies and T cells. Antibodies are types of proteins that protect the body from infectious diseases and possibly cancer. T-cells, also called T lymphocytes, are special infection-fighting blood cells that can kill other cells, including cells infected with viruses and tumor cells. Both antibodies and T cells have been used to treat participants with cancers. They have shown promise, but have not been strong enough to cure most participants. The study team has found from previous research that we can put a new gene (a tiny part of what makes-up DNA and carries the participants traits) into T cells that will make them recognize cancer cells and kill them. In the lab, the study team has made several genes called a chimeric antigen receptor (CAR), from an antibody called GC33. The antibody GC33 recognizes a protein found on the participants brain tumor. This CAR is called GPC3-CAR. To make this CAR more effective, the study has also added a gene that includes IL15. IL15 is a protein that helps CAR T cells grow better and stay in the blood longer so that they may kill tumors better. The mixture of GPC3-CAR and IL15 killed tumor cells better in the laboratory when compared with CAR T cells that did not have IL15. This study will test T cells with the IL15 GPC3-CAR (GO-CART T cells) in participants with GPC3-positive brain tumors. T cells made to carry a gene called iCasp9 can be killed when they encounter a specific drug called AP1903. The study team will insert the iCasp9 and IL15 together into the T cells using a virus that has been made for this study. The drug (AP1903) is an experimental drug that has been tested in humans with no bad side-effects. The study team will use this drug to kill the T cells if necessary due to side effects. This study will test T cells genetically engineered with a GPC3-CAR and IL15 (GO-CART T cells) in participants with GPC3-positive brain tumors. The GO-CART T cells are an investigational product not approved by the Food and Drug Administration.

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, it mentions that you must have a stable or decreasing dose of steroids for 7 days before surgery and therapy, and you must recover from the effects of any prior chemotherapy before starting the study.

What data supports the effectiveness of the GPC3-CAR T Cells treatment for brain cancer?

Research shows that GPC3-CAR T cells have been effective in treating other types of cancer, like liver and lung cancer, by targeting and destroying cancer cells that express a specific protein called glypican-3 (GPC3). This suggests that they might also work against brain cancer if the cancer cells have this protein. ^{1 2 3 4 5}

What safety data exists for GPC3-CAR T Cells in humans?

GPC3-CAR T cells have been studied primarily for liver cancer, showing strong antitumor activity, but there is limited information on their safety specifically for brain cancer. In general, CAR T cell therapies can have risks like severe cytokine release syndrome (a dangerous immune reaction) and neurological toxicities, which have been observed in other CAR T cell studies. ^{1 6 7 8 9}

How is the GPC3-CAR T Cells treatment different from other brain cancer treatments?

GPC3-CAR T Cells treatment is unique because it uses genetically engineered T cells to specifically target and attack cancer cells in the brain, potentially overcoming the challenges of traditional treatments that struggle with the brain's immune-privileged environment. This approach is part of a novel class of immunotherapies that aim to enhance the body's immune response against tumors, which is different from conventional therapies like chemotherapy or radiation. ^{2 8 10 11 12}

Eligibility Criteria

This trial is for individuals with recurrent GPC-3 positive glioblastoma, a type of brain cancer. Participants must have tumors that express the GPC-3 protein to be eligible. Specific inclusion and exclusion criteria details are not provided but would typically include factors like age, health status, prior treatments, and other medical conditions.

Inclusion Criteria

I can care for myself but may need occasional help.

Procurement: Informed consent explained to, understood by and signed by patient/guardian. Patient/guardian given copy of informed consent

I have had surgery for recurrent glioblastoma.

Exclusion Criteria

Procurement: History of organ transplantation

Procurement: Known HIV positivity

I am HIV positive.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a single dose of GO-CART T cells administered intracavitarily during scheduled surgical resection

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment, including regular blood tests and imaging

15 years

Regular visits every 3 months for 1 year, every 6 months for 4 years, then annually

Dose Escalation

Participants receive varying doses of GO-CART T cells to determine the maximum tolerated dose

4 weeks

Treatment Details

Interventions

• GPC-3 CAR T Cells

Trial Overview The trial is testing genetically engineered T cells called GO-CART T cells. These cells have been modified with a new gene to recognize and kill cancer cells by targeting the GPC-3 protein on brain tumors. The study also uses IL15 to help these CAR T cells grow better and an iCasp9 gene allowing controlled cell death if needed.

Participant Groups

Group I: 15.GPC3-CAR T cells Experimental Treatment 1 Intervention

GPC3-CAR and IL15 will be administered to patients with GPC3-positive glioblastoma.

Who Is Running the Clinical Trial?

Baylor College of Medicine

Lead Sponsor

Trials

1,044

Recruited

6,031,000+

Baylor St. Luke's Medical Center

Collaborator

Trials

4

Recruited

500+

Center for Cell and Gene Therapy, Baylor College of Medicine

Collaborator

Trials

114

Recruited

2,900+

Findings from Research

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]

Clinical trials of CAR-T cell therapy for glioblastoma (GBM) have identified significant challenges, such as incomplete antigen coverage and the immunosuppressive tumor microenvironment, which limit the effectiveness of the treatment.

Novel modifications to CAR-T cells aim to enhance their function and resilience against immunosuppression, potentially transforming GBM from a 'cold tumor' into a more responsive one, thereby improving tumor clearance and reducing CAR-T cell exhaustion.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CAR-T Therapy in GBM: Current Challenges and Avenues for Improvement. Pant, A., Lim, M.[2023]

Glypican 3 (GPC3) is expressed in 66.3% of lung squamous cell carcinoma (LSCC) samples, making it a promising target for therapy, as it is rarely found in normal lung tissues.

CARgpc3 T cells, engineered to target GPC3, showed strong antitumor activity by effectively eliminating GPC3-positive LSCC cells in vitro and in two xenograft models, suggesting they could be a novel treatment option for LSCC patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adoptive immunotherapy using T lymphocytes redirected to glypican-3 for the treatment of lung squamous cell carcinoma. Li, K., Pan, X., Bi, Y., et al.[2020]

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]

The study engineered CAR-T cells that can express IL-12, which significantly enhances their ability to target and destroy GPC3+ tumor cells, showing improved efficacy in both laboratory and animal models.

Inducible IL-12 expression not only boosts the antitumor response but also reduces regulatory T cell infiltration, suggesting a safer profile for CAR-T therapy, making it a promising option for patients who cannot undergo traditional lymphodepletion chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Armored Inducible Expression of IL-12 Enhances Antitumor Activity of Glypican-3-Targeted Chimeric Antigen Receptor-Engineered T Cells in Hepatocellular Carcinoma. Liu, Y., Di, S., Shi, B., 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-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]

Infusion of GD2-specific fourth-generation safety-designed chimeric antigen receptor (4SCAR)-T cells in eight patients with GD2-positive glioblastoma (GBM) was found to be safe and well tolerated, with no severe adverse events reported.

Of the eight patients, four experienced a partial response lasting between 3 to 24 months, indicating that 4SCAR-T cells can exert anti-GBM activity, with a median overall survival of 10 months post-infusion.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and antitumor activity of GD2-Specific 4SCAR-T cells in patients with glioblastoma. Liu, Z., Zhou, J., Yang, X., et al.[2023]

In a study involving 1,926 subjects from 17 clinical trials, patients with acute lymphocytic leukemia (ALL) were found to have a higher risk of severe cytokine release syndrome (sCRS) and severe neurological toxicities (sNTX) compared to those with non-Hodgkin's lymphoma (NHL) or multiple myeloma (MM).

The use of CAR T cells produced with gammaretrovirus vectors containing CD28 sequences was linked to increased rates of sNTX, while administering cytokine-directed therapies and corticosteroids at lower toxicity grades was associated with reduced rates of sCRS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cross-study safety analysis of risk factors in CAR T cell clinical trials: An FDA database pilot project. Foster, M., Negash, Y., Eberhardt, L., et al.[2022]

References

1. 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]

2. Switzerland pubmed.ncbi.nlm.nih.gov

CAR-T Therapy in GBM: Current Challenges and Avenues for Improvement. [2023]

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

Adoptive immunotherapy using T lymphocytes redirected to glypican-3 for the treatment of lung squamous cell carcinoma. [2020]

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

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

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

Armored Inducible Expression of IL-12 Enhances Antitumor Activity of Glypican-3-Targeted Chimeric Antigen Receptor-Engineered T Cells in Hepatocellular Carcinoma. [2020]

6. 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]

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. England pubmed.ncbi.nlm.nih.gov

Safety and antitumor activity of GD2-Specific 4SCAR-T cells in patients with glioblastoma. [2023]

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

Cross-study safety analysis of risk factors in CAR T cell clinical trials: An FDA database pilot project. [2022]

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

CSPG4 Shows Promise for Glioblastoma CAR T Therapy. [2019]

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

CRISPR Screening of CAR T Cells and Cancer Stem Cells Reveals Critical Dependencies for Cell-Based Therapies. [2022]

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

Engineering Chimeric Antigen Receptor T cells to Treat Glioblastoma. [2020]