CAR T Cell Therapy for Pediatric Brain Cancer

Overseen By Nicholas Vitanza, MD

Age: < 65

Sex: Any

Trial Phase: Phase 1

Sponsor: Seattle Children's Hospital

Must not be taking: Corticosteroids

Disqualifiers: DIPG, Cardiac dysfunction, Immunodeficiency, others

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

Compensation: Varies

Number of Visits: Unknown

10 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking all current medications, but you must stop certain treatments like chemotherapy, biologic therapy, and anti-tumor antibody therapy for specific periods before enrolling. Corticosteroid treatment must be stable or decreasing, with a maximum dose specified.

What data supports the effectiveness of the treatment HER2-specific CAR T Cell Locoregional Immunotherapy for pediatric brain cancer?

Research shows that HER2-specific CAR T cells can effectively target and kill HER2-positive medulloblastoma cells in lab tests and animal models, leading to tumor regression. Additionally, early clinical trials in children and young adults with brain tumors suggest that this treatment is well-tolerated and activates a local immune response, indicating potential effectiveness. ^{1 2 3 4 5}

Is HER2-specific CAR T Cell Therapy safe for children with brain cancer?

In early studies, HER2-specific CAR T Cell Therapy was well tolerated in children and young adults with brain tumors, with no severe side effects reported in the initial patients. ^{1 3 6 7 8}

How is HER2-specific CAR T Cell Locoregional Immunotherapy different from other treatments for pediatric brain cancer?

This treatment is unique because it involves delivering genetically engineered immune cells (CAR T cells) directly into the brain or spinal fluid, targeting a specific protein (HER2) found on cancer cells. This approach aims to activate a local immune response with potentially fewer side effects compared to traditional treatments like surgery, chemotherapy, and radiation. ^{1 3 4 7 8}

What is the purpose of this trial?

This is a Phase 1 study of central nervous system (CNS) locoregional adoptive therapy with autologous CD4 and CD8 T cells lentivirally transduced to express a HER2-specific chimeric antigen receptor (CAR) and EGFRt, delivered by an indwelling catheter in the tumor resection cavity or ventricular system in children and young adults with recurrent or refractory HER2-positive CNS tumors. A child or young adult with a refractory or recurrent CNS tumor will have their tumor tested for HER2 expression by immunohistochemistry (IHC) at their home institution or at Seattle Children's Hospital. If the tumor is HER2 positive and the patient meets all other eligibility criteria, including having a CNS catheter placed into the tumor resection cavity or into their ventricular system, and meets none of the exclusion criteria, then they can be apheresed, meaning T cells will be collected. The T cells will then be bioengineered into a second-generation CAR T cell that targets HER2-expressing tumor cells. The patient's newly engineered T cells will then be administered via the indwelling CNS catheter for two courses. In the first course they will receive a weekly dose of CAR T cells for three weeks, followed by a week off, an examination period, and then another course of weekly doses for three weeks. Following the two courses, patient's will undergo a series of studies including MRI to evaluate the effect of the CAR T cells and may have the opportunity to continue receiving additional courses of CAR T cells if the patient has not had adverse effects and if more of their T cells are available. The hypothesis is that an adequate amount of HER2-specific CAR T cells can be manufactured to complete two courses of treatment with three doses given on a weekly schedule followed by one week off in each course. The other hypothesis is that HER-specific CAR T cells safely can be administered through an indwelling CNS catheter to allow the T cells to directly interact with the tumor cells for each patient enrolled on the study safely can be delivered directly into the brain via indwelling catheter. Secondary aims of the study will include to evaluate CAR T cell distribution with the cerebrospinal fluid (CSF), the extent to which CAR T cells egress or traffic into the peripheral circulation or blood stream, and, if tissues samples from multiple time points are available, also evaluate the degree of HER2 expression at diagnosis versus at recurrence.

Research Team

Rebecca Ronsley, MD

Principal Investigator

Seattle Children's Hospital

Eligibility Criteria

This trial is for children and young adults aged 1 to 26 with recurrent or refractory HER2-positive CNS tumors who have no standard therapy options left. They must have a CNS catheter in place, a life expectancy of at least 8 weeks, recovered from previous treatments, stable or decreasing steroid use, good organ function and lab values, not be pregnant or breastfeeding, and agree to use contraception.

Inclusion Criteria

My brain tumor is HER2 positive.

I can undergo apheresis or already have an apheresis product ready for use.

Your lab test results are within the normal range.

Exclusion Criteria

I have been diagnosed with a specific brain tumor known as DIPG.

I have severe heart issues or irregular heartbeats needing treatment.

I am showing signs of a possible herniation.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment Course 1

Participants receive weekly doses of CAR T cells for three weeks, followed by a week off and an examination period

4 weeks

Treatment Course 2

Participants receive another course of weekly doses of CAR T cells for three weeks

3 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment, including MRI evaluations

up to 6 months

Extension

Participants may continue receiving additional courses of CAR T cells if no adverse effects are observed and T cells are available

Treatment Details

Interventions

• HER2-specific CAR T Cell Locoregional Immunotherapy

Trial Overview The study tests HER2-specific CAR T cell therapy delivered through an indwelling CNS catheter over two courses. Each course involves weekly doses for three weeks followed by one week off. The treatment aims to allow engineered T cells to directly interact with tumor cells in the brain.

Participant Groups

Group I: ARM B (Ventricular System Infusion) Experimental Treatment 1 Intervention

patients with either infratentorial tumors or leptomeningeal tumors for which the CAR T cells will be delivered into the fourth ventricle or lateral ventricle, respectively Intervention: HER2-specific chimeric antigen receptor (CAR) T cell

Group II: ARM A (Tumor Cavity Infusion) Experimental Treatment 1 Intervention

patients with supratentorial tumors for which CAR T cells will be delivered into the tumor resection cavity Intervention: HER2-specific chimeric antigen receptor (CAR) T cell

Who Is Running the Clinical Trial?

Seattle Children's Hospital

Lead Sponsor

Trials

319

Recruited

5,232,000+

Findings from Research

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]

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]

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]

Brain tumors are the most common solid tumors in children and the leading cause of cancer-related deaths, highlighting the urgent need for more effective treatments.

Recent advancements in CAR T cell immunotherapy show promise for improving outcomes in pediatric brain cancer, with ongoing research focusing on specific targets and strategies to enhance the effectiveness of this treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Advances in CAR T cell immunotherapy for paediatric brain tumours. Rao, P., Furst, L., Meyran, D., et al.[2022]

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]

Malignant central nervous system tumors are the leading cause of cancer death in children, and while treatments like surgery and chemotherapy can be effective, they often lead to significant neurological and cognitive side effects.

Adoptive cell therapy using CAR T cells shows promise for treating pediatric brain tumors, but challenges such as tumor heterogeneity and the blood-brain barrier limit its effectiveness; recent preclinical studies are exploring ways to enhance the safety and efficacy of this approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CAR T Cell Therapy's Potential for Pediatric Brain Tumors. Thomas, P., Galopin, N., Bonérandi, E., et al.[2021]

CAR-T cell therapy, while currently approved only for B cell malignancies, shows promising potential for treating pediatric brain tumors, with early clinical trials indicating some positive responses.

Recent preclinical studies have identified new tumor antigens and combination strategies that enhance the effectiveness of CAR-T cells, particularly when administered directly to the tumor site.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CAR-T cells for pediatric brain tumors: Present and future. Leruste, A., Beccaria, K., Doz, F.[2021]

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

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

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

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

Advances in CAR T cell immunotherapy for paediatric brain tumours. [2022]

5. 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]

6. Switzerland pubmed.ncbi.nlm.nih.gov

CAR T Cell Therapy's Potential for Pediatric Brain Tumors. [2021]

7. France pubmed.ncbi.nlm.nih.gov

CAR-T cells for pediatric brain tumors: Present and future. [2021]

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]