CAR T Cell Therapy for Ependymoma

Recruiting at 4 trial locations

Overseen By Nina Butingan, MBS

Age: < 65

Sex: Any

Trial Phase: Phase 1

Sponsor: Pediatric Brain Tumor Consortium

Must not be taking: Corticosteroids, Herbal medications

Disqualifiers: HIV, Bulky tumors, Pregnancy, others

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

Compensation: Varies

Number of Visits: 2

Duration: 9 months

50 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a Phase I study to evaluate the safety profile of a type of immune therapy called HER2 CAR T cells (short for HER2 chimeric antigen receptor T cells). In addition to looking for side effects, we will study how well this treatment works against a brain tumor called ependymoma that has come back after treatment (recurrent) or has not responded well to treatment (progressive) in children. The HER2 CAR T cells used in this trial are made from the patient's own blood. A new gene, called the HER2 CAR, will be inserted into patient's T cells to allow them recognize a protein on the tumor called HER2. These HER2-specific CAR T cells may be able to target and kill ependymoma tumors that express HER2. This research is also studying how doable it is to provide this type of CAR T cell treatment to children being treated at different hospitals.

Will I have to stop taking my current medications?

The trial requires that patients stop taking certain medications before enrollment. Specifically, patients must not have received cytotoxic chemotherapy, biological, targeted, or investigational agents for at least 28 days prior to enrollment. Additionally, patients must stop using herbal medications and dietary supplements at least 7 days before enrollment.

What data supports the effectiveness of the treatment HER2 Specific CAR T Cell for ependymoma?

Research shows that HER2-specific CAR T cells can effectively target and kill HER2-positive tumor cells in medulloblastoma, a type of brain tumor, in both lab and animal studies. This suggests potential effectiveness for similar tumors like ependymoma, especially when delivered directly to the cerebrospinal fluid. ^{1 2 3 4 5}

Is HER2 CAR T cell therapy safe for humans?

HER2 CAR T cell therapy has been generally well tolerated in humans, with studies showing it can be safely delivered to the brain in patients with certain types of tumors. However, there is a risk of serious side effects, such as cytokine release syndrome, which is an intense immune reaction. ^{1 3 6 7 8}

How is the CAR T Cell Therapy for Ependymoma different from other treatments?

This treatment uses specially modified immune cells called CAR T cells that target a protein called HER2 on tumor cells, and it is delivered directly into the cerebrospinal fluid to bypass the blood-brain barrier, which is a unique approach compared to traditional treatments. ^{1 3 4 5 8}

Research Team

Meenakshi Hegde, MD

Principal Investigator

Baylor College of Medicine

Eligibility Criteria

This trial is for children aged 1 to 21 with recurrent or progressive ependymoma, a type of brain tumor. They must have had standard treatments and be HER2-positive. Kids need to be in good enough health with stable neurological conditions and not on other cancer treatments.

Inclusion Criteria

Patient or parent/guardian must be able to understand and sign a written informed consent document

My organs and bone marrow are functioning well.

I've had surgery and radiation for my condition as standard treatment.

Exclusion Criteria

Patient is living outside the US

I have had a condition where lymphocytes are produced in excessive amounts.

Patients with a history of allergic reactions attributed to compounds of similar chemical or biologic composition

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Lymphodepletion Chemotherapy

Patients receive lymphodepletion chemotherapy with cyclophosphamide and fludarabine prior to CAR T cell infusion

1 week

Daily visits for chemotherapy administration

Treatment

Patients receive HER2 CAR T cells infusion. Treatment repeats every 8 to 12 weeks for up to 3 cycles

9 months

1 visit per infusion cycle

Surgical Study

Patients undergo surgical tumor resection 4-6 weeks after CAR T cell infusion, followed by additional CAR T cell infusions

10 months

1 surgical visit, followed by infusion visits

Follow-up

Participants are monitored for safety and effectiveness after treatment

15 years

Treatment Details

Interventions

• HER2 Specific CAR T Cell

Trial Overview The study tests HER2 CAR T cells, which are the patient's own immune cells genetically modified to attack their tumor by recognizing a protein called HER2. It aims to see how safe this treatment is and how well it works against ependymoma in kids.

Participant Groups

Group I: Treatment (HER2 CAR T cells), Surgical Arm Experimental Treatment 1 Intervention

Patients receive lymphodepletion chemotherapy with cyclophosphamide IV daily on Days -7 to -6 and fludarabine IV daily on Days -5 to -1. Patients receive HER2 CAR T cells IV on Day 0 followed by surgical tumor resection 4-6 weeks following HER2 CAR T cell infusion. Treatment repeats every 8 to 15 weeks for 2 additional cycles in the absence of disease progression or unacceptable toxicity.

Group II: Treatment (HER2 CAR T cells), Phase I Arm Experimental Treatment 1 Intervention

Patients receive lymphodepletion chemotherapy with cyclophosphamide IV daily on Days -7 to -6 and fludarabine IV daily on Days -5 to -1. Patients receive HER2 CAR T cells IV on Day 0. Treatment repeats every 8 to 12 weeks for 2 additional cycles in the absence of disease progression or unacceptable toxicity.

Who Is Running the Clinical Trial?

Pediatric Brain Tumor Consortium

Lead Sponsor

Trials

38

Recruited

1,600+

American Lebanese Syrian Associated Charities (ALSAC)

Collaborator

Trials

9

Recruited

670+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

American Lebanese Syrian Associated Charities

Collaborator

Trials

9

Recruited

670+

Texas Children's Cancer Center

Collaborator

Trials

8

Recruited

220+

Baylor College of Medicine

Collaborator

Trials

1,044

Recruited

6,031,000+

Findings from Research

Chimeric antigen receptor T cells targeting EPHA2, HER2, and interleukin 13 receptor α2 have been validated as effective treatments for recurrent medulloblastoma and ependymoma in mouse models, showing promise for bypassing the blood-brain barrier through intrathecal delivery.

The combination of these targeted T cells with azacytidine demonstrated high efficacy against multiple metastatic models of group 3 medulloblastoma and PFA ependymoma, suggesting a strong rationale for future clinical trials in humans.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Locoregional delivery of CAR T cells to the cerebrospinal fluid for treatment of metastatic medulloblastoma and ependymoma. Donovan, LK., Delaidelli, A., Joseph, SK., et al.[2022]

Patients with supratentorial extraventricular ependymoma (SEE) who underwent gross total resection (GTR) had significantly better progression-free survival compared to those who had subtotal resection (STR), with STR patients facing much higher recurrence risks over time.

The expression of PD-L1 was identified as an independent predictor of worse outcomes in SEE patients, suggesting that PD-L1 positivity correlates with increased recurrence rates and could serve as a reliable biological marker for prognosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The role of clinical factors and immunocheckpoint molecules in the prognosis of patients with supratentorial extraventricular ependymoma: a single-center retrospective study. Wang, L., Han, S., Yan, C., et al.[2021]

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]

CNS tumors are a major challenge in pediatric cancer, accounting for 25% of diagnoses and being the leading cause of cancer-related deaths in children, highlighting the urgent need for improved treatments.

CAR T cell therapy has shown promise in treating B-cell malignancies, but its effectiveness against pediatric CNS tumors is limited due to factors like tumor location, varied antigen expression, and the protective blood-brain barrier, necessitating innovative strategies to enhance its success.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Facing CAR T Cell Challenges on the Deadliest Paediatric Brain Tumours. Ferreras, C., Fernández, L., Clares-Villa, L., et al.[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 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]

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]

HER2-BBz-CAR T cells demonstrated strong anti-tumor efficacy against pediatric medulloblastoma in preclinical models, effectively clearing tumors in mice through both regional and intravenous delivery methods.

In non-human primates, intraventricular delivery of HER2-BBz-CAR T cells was well-tolerated without systemic toxicity, suggesting a safe approach for future clinical trials in children with relapsed medulloblastoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Durable regression of Medulloblastoma after regional and intravenous delivery of anti-HER2 chimeric antigen receptor T cells. Nellan, A., Rota, C., Majzner, R., et al.[2020]

References

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

Locoregional delivery of CAR T cells to the cerebrospinal fluid for treatment of metastatic medulloblastoma and ependymoma. [2022]

2. Germany pubmed.ncbi.nlm.nih.gov

The role of clinical factors and immunocheckpoint molecules in the prognosis of patients with supratentorial extraventricular ependymoma: a single-center retrospective study. [2021]

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

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

4. Switzerland pubmed.ncbi.nlm.nih.gov

Facing CAR T Cell Challenges on the Deadliest Paediatric Brain Tumours. [2022]

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

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

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

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

8. England pubmed.ncbi.nlm.nih.gov

Durable regression of Medulloblastoma after regional and intravenous delivery of anti-HER2 chimeric antigen receptor T cells. [2020]