CAR T-Cell Therapy for Brain Cancer

(iCAR Trial)

Recruiting at 1 trial location

Overseen By Martha Arredondo

Age: Any Age

Sex: Any

Trial Phase: Phase 1

Sponsor: Baylor College of Medicine

Must not be taking: Steroids

Disqualifiers: DIPG, HIV, Pregnancy, others

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

Compensation: Varies

Number of Visits: 7

Duration: 6 weeks

10 Participants Needed

Trial Summary

What is the purpose of this trial?

This study is for patients that have brain cancer. 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 immune cells present in the blood that can kill other cells, including cells infected with viruses and tumor cells. Both antibodies and T cells have been used to treat patients with cancers. They have shown promise, but have not been strong enough to cure most patients. The antibody used in this study is called anti-HER2 (Human Epidermal Growth Factor Receptor 2). This antibody sticks to tumor cells because of a substance on the outside of these cells called HER2. Many types of brain tumors are positive for HER2 . HER2 antibodies have been used to treat people with HER2-positive cancers. For this study, the HER2 antibody has been changed so that instead of floating free in the blood it is now attached to T cells. When an antibody is joined to a T cell in this way it is called a chimeric antigen receptor (CAR). These CAR-T cells seem to be able to kill tumors like the one these patients have, but they don't last very long and so their chances of fighting the cancer are limited. Therefore, developing ways to prolong the life of these T cells should help them fight cancer. These HER2-CAR T cells are an investigational product not approved by the Food and Drug Administration. The purpose of this study is to find the largest safe dose of HER2-CAR T cells, to learn what the side effects are, and to see whether this experimental intervention might help patients with brain tumors who volunteer to test this new agent.

Will I have to stop taking my current medications?

The trial requires that you stop other investigational cancer treatments two weeks before the CAR T cell infusion, but you can continue taking Temozolomide up to 48 hours before the infusion. Dexamethasone is allowed up to a total dose of 2 mg per day if needed.

What data supports the effectiveness of the treatment HER2-specific T cells for brain cancer?

Research shows that HER2-specific T cells can effectively target and kill cancer cells in brain tumors like medulloblastoma and glioblastoma, leading to tumor regression in experimental models. Additionally, similar treatments have shown success in targeting HER2-positive tumors in other cancers, such as breast cancer metastasized to the brain, indicating potential effectiveness for brain cancer. ^{1 2 3 4 5}

Is CAR T-Cell Therapy safe for treating brain cancer?

Studies show that HER2-targeting CAR T-cells, when delivered directly to the brain, were generally well tolerated in both children and adults with brain tumors, with no severe side effects reported in initial trials. ^{1 4 6 7 8}

How is the CAR T-Cell treatment for brain cancer different from other treatments?

This treatment uses specially engineered T cells to target and kill cancer cells in the brain by recognizing a specific protein called HER2. Unlike traditional treatments, it involves delivering these T cells directly to the brain, which may enhance their effectiveness against tumors that are resistant to conventional therapies. ^{1 2 3 4 9}

Research Team

Meenakshi Hegde, MD

Principal Investigator

Baylor College of Medicine - Texas Children's Hospital

Nabil M Ahmed, MD

Principal Investigator

Baylor College of Medicine - Texas Children's Hospital

Shoba Navai, MD

Principal Investigator

Baylor College of Medicine - Texas Children's Hospital

Eligibility Criteria

This trial is for patients with brain cancer that tests positive for a protein called HER2. Participants should have recurrent or resistant tumors, be able to undergo surgery if needed, and have a moderate ability to perform daily activities (Karnofsky/Lansky score ≥60). They must understand and sign the consent form.

Inclusion Criteria

Inclusion criteria at the time of procurement.

I can care for myself but may need occasional help.

Informed consent explained to, understood by and signed by subject/guardian. Subject/guardian given copy of informed consent

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive three injections of HER2-CAR T cells two weeks apart, with dose escalation based on safety

6 weeks

3 visits (in-person) for T-cell injections, overnight observation after each injection

Follow-up

Participants are monitored for safety and effectiveness after treatment, with blood tests and imaging studies

6 weeks

Regular visits for blood tests and imaging studies

Long-term Follow-up

Participants are monitored for long-term side effects of gene transfer up to 15 years

15 years

Every 3 months for 1 year, every 6 months for 4 years, then yearly

Treatment Details

Interventions

• HER2-specific T cells

Trial Overview The study is testing T cells engineered with an antibody called anti-HER2 attached to them, known as HER2-CAR T cells. The goal is to determine the highest safe dose of these modified T cells, their side effects, and their effectiveness against brain tumors.

Participant Groups

Group I: HER2-specific T cells - Standard Risk Experimental Treatment 1 Intervention

All other patients not meeting the high risk description will be assigned to the Standard Risk arm. Three cell dosing schedules (1, 2, 3) consisting of combinations of three cell doses (A, B, C) will be evaluated.

Group II: HER2-specific T cells - High Risk Experimental Treatment 1 Intervention

Subjects with HER2 staining of Grade 3 (51-100% of cells staining for HER2) and intensity scores of 3+ will be assigned to the High Risk arm. Three cell dosing schedules (1, 2, 3) consisting of combinations of three cell doses (A, B, C) will be evaluated.

Who Is Running the Clinical Trial?

Baylor College of Medicine

Lead Sponsor

Trials

1,044

Recruited

6,031,000+

The Methodist Hospital Research Institute

Collaborator

Trials

299

Recruited

82,500+

Center for Cell and Gene Therapy, Baylor College of Medicine

Collaborator

Trials

114

Recruited

2,900+

Findings from Research

Intracranial delivery of HER2-targeting CAR-T cells was found to be well tolerated in a small group of 3 patients with central nervous system (CNS) tumors, indicating a potential safe application for this therapy.

This study suggests that targeting HER2 with CAR-T cells could be a promising approach for treating CNS tumors, although further research with larger patient groups is needed to confirm efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Locoregional Delivery of CAR-T Cells Is Feasible in Pediatric CNS Tumors. [2022]

HER2-specific T cells can effectively recognize and kill HER2-positive medulloblastoma cells, showing significant T-cell activation and proliferation in response to these tumors.

In vivo studies demonstrated that transferring HER2-specific T cells led to sustained regression of established medulloblastomas, suggesting that this approach could be a promising immunotherapy for treating this type of brain tumor.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Regression of experimental medulloblastoma following transfer of HER2-specific T cells. Ahmed, N., Ratnayake, M., Savoldo, B., et al.[2014]

HER2-specific T cells can be effectively generated from GBM patients, showing strong antitumor activity against both HER2-positive tumor cells and their resistant stem cell populations.

In preclinical models, these T cells not only proliferated and produced key immune signals upon encountering HER2-positive GBM cells but also led to significant tumor regression, suggesting that this immunotherapy could be a promising treatment for this aggressive brain cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

HER2-specific T cells target primary glioblastoma stem cells and induce regression of autologous experimental tumors. Ahmed, N., Salsman, VS., Kew, Y., et al.[2022]

Optimizing the design of HER2-CAR T cells, particularly using the 4-1BB costimulatory domain, enhances their ability to target tumors and reduces T-cell exhaustion, making them more effective against breast cancer metastases in the brain.

Local and regional delivery methods, especially intraventricular administration, demonstrated significant antitumor activity in mouse models with multifocal brain metastases, suggesting a promising approach for treating this challenging condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Regional Delivery of Chimeric Antigen Receptor-Engineered T Cells Effectively Targets HER2+ Breast Cancer Metastasis to the Brain. Priceman, SJ., Tilakawardane, D., Jeang, B., et al.[2020]

The chA21-4-1BBz CAR T cells demonstrated a strong ability to target and kill HER2 overexpressing gastric cancer cells in laboratory tests, showing a Th1 skewed cytokine response that correlates with HER2 levels on tumor cells.

In animal models, these CAR T cells significantly reduced tumor size and improved survival in mice with HER2 overexpressing tumors, while not affecting tumors with low HER2 expression, indicating a targeted and potentially safer treatment approach for gastric cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antitumor effects and persistence of a novel HER2 CAR T cells directed to gastric cancer in preclinical models. Han, Y., Liu, C., Li, G., et al.[2020]

HER2 CAR T-cell therapy shows promise for treating solid tumors, particularly in cancers like breast cancer, but it carries significant risks of severe side effects, such as cytokine release syndrome due to targeting HER2 on non-cancerous tissues.

The review highlights ongoing efforts to enhance the safety of HER2 CAR therapies through novel designs and alternative CAR host selections, aiming to minimize the risk of toxicities while maintaining therapeutic efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Driving better and safer HER2-specific CARs for cancer therapy. Liu, X., Zhang, N., Shi, H.[2019]

Engineering CAR T cells with a medium-length spacer significantly improves their effectiveness against HER2-positive pediatric CNS tumors, as demonstrated in a medulloblastoma model.

The ongoing BrainChild-01 trial shows that repeated locoregional delivery of HER2-specific CAR T cells in children and young adults is feasible and well tolerated, with initial patients showing no dose-limiting toxicity and signs of local immune activation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Locoregional infusion of HER2-specific CAR T cells in children and young adults with recurrent or refractory CNS tumors: an interim analysis. Vitanza, NA., Johnson, AJ., Wilson, AL., et al.[2021]

Engineered human neural stem cells (NSCs) that secrete antibodies against HER2 can effectively inhibit the growth of HER2-positive breast cancer brain metastases by targeting the PI3K-Akt signaling pathway, showing promise in laboratory settings.

Combining these anti-HER2-secreting NSCs with the tyrosine kinase inhibitor tucatinib significantly improved survival in mouse models of multiple HER2-positive brain metastases, suggesting a potential new treatment strategy for patients with this challenging condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination of tucatinib and neural stem cells secreting anti-HER2 antibody prolongs survival of mice with metastatic brain cancer. Cordero, A., Ramsey, MD., Kanojia, D., et al.[2022]

References

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

Locoregional Delivery of CAR-T Cells Is Feasible in Pediatric CNS Tumors. [2022]

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

Regression of experimental medulloblastoma following transfer of HER2-specific T cells. [2014]

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

HER2-specific T cells target primary glioblastoma stem cells and induce regression of autologous experimental tumors. [2022]

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

Regional Delivery of Chimeric Antigen Receptor-Engineered T Cells Effectively Targets HER2+ Breast Cancer Metastasis to the Brain. [2020]

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

Antitumor effects and persistence of a novel HER2 CAR T cells directed to gastric cancer in preclinical models. [2020]

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

Driving better and safer HER2-specific CARs for cancer therapy. [2019]

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

Locoregional infusion of HER2-specific CAR T cells in children and young adults with recurrent or refractory CNS tumors: an interim analysis. [2021]

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

Combination of tucatinib and neural stem cells secreting anti-HER2 antibody prolongs survival of mice with metastatic brain cancer. [2022]

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

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