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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment for individuals with a specific type of brain cancer called GPC3-positive glioblastoma. The treatment uses genetically modified T cells, known as GPC3-CAR T cells, designed to better recognize and kill cancer cells. The trial explores whether these modified cells can fight tumors more effectively than current options. Individuals with GPC3-positive glioblastoma who have undergone surgery to remove it may be suitable candidates for this study. As a Phase 1 trial, the research focuses on understanding 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, 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.

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

Research has shown that GPC3-CAR T cells, specially modified to fight cancer, have been tested in humans and initially appear safe. In earlier studies, these T cells grew the most about two weeks after administration. Importantly, no serious side effects were reported in these studies.

The treatment combines T cells with a protein called IL15, which helps the T cells grow and remain active longer in the body. This combination performed better in lab tests than T cells without IL15.

Additionally, a special drug can turn off the T cells if needed, and it has been tested in humans without causing adverse effects. This feature adds another layer of safety.

Overall, initial findings suggest that GPC3-CAR T cells are generally well-tolerated, with most participants not experiencing serious side effects from the treatment. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about GPC3-CAR T Cells for brain cancer because they offer a novel approach compared to standard treatments like surgery, radiation, and chemotherapy. Unlike these traditional options, GPC3-CAR T Cells are designed to specifically target and attack glioblastoma cells that express the GPC3 protein. This targeted mechanism could potentially lead to more effective elimination of cancer cells with fewer side effects. Additionally, the treatment includes IL15, which may enhance the persistence and activity of the CAR T Cells, providing a more sustained response against the tumor.

What evidence suggests that GPC3-CAR T cells might be an effective treatment for brain cancer?

Research has shown that combining GPC3-CAR and IL15 in T cells effectively kills cancer cells in the lab. This combination outperforms T cells without IL15. T cells, which are special blood cells that attack cancer, benefit from IL15 as it enhances their growth and prolongs their activity in the body. Although lab results are promising, human studies have not yet shown clear signs of tumor reduction. This trial will test this method in individuals with GPC3-positive brain tumors. ^{1 2 3 5 6}

Who Is on the Research Team?

Ganesh Rao, MD

Principal Investigator

Baylor College of Medicine

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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 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]

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 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]

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]

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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT06815432

Study Details | NCT06815432 | GPC-3 CAR T CELLS FOR ... 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 ...

2. trials.braintumor.org trials.braintumor.org/trials/NCT06815432

GPC-3 CAR T CELLS FOR Recurrent ... - Clinical Trial Finder 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 ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10705370/

Chimeric Antigen Receptor T-Cell Therapy for Glioblastoma This review explores the potential of chimeric antigen receptor (CAR) T-cell immunotherapy as a promising approach for treating GBM.

4. bcm.edu bcm.edu/news/car-t-cells-armed-with-il-15-show-promise-in-treating-solid-cancers

CAR T cells armed with IL-15 show promise in treating ... The GPC3-CAR T cells were found to be safe, with peak cell expansion at two-weeks post-infusion; however, no objective antitumor responses were ...

5. connect.careboxhealth.com connect.careboxhealth.com/en-US/trial/listing/573877

GPC-3 CAR T CELLS FOR Recurrent GPC-3 Positive ... 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 ...

6. 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 ... This report demonstrated the initial safety profile of CAR-GPC3 T-cell therapy. We observed early signs of antitumor activity of CAR-GPC3 T cells in patients ...