Engineered T Cell Therapy for Brain Cancer

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: City of Hope Medical Center

Must not be taking: Cardiotoxic medications

Disqualifiers: Congestive heart failure, Dialysis, Active infection, others

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

Compensation: Varies

Number of Visits: 7

Duration: 3 weeks

29 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This phase I trial studies the side effects and best dose of memory-enriched T cells in treating patients with grade II-IV glioma that has come back (recurrent) or does not respond to treatment (refractory). Memory enriched T cells such as HER2(EQ)BBζ/CD19t+ T cells may enter and express its genes in immune cells. Immune cells can be engineered to kill glioma cells in the laboratory by inserting a piece of deoxyribonucleic acid (DNA) into the immune cells that allows them to recognize glioma cells. A vector called lentivirus is used to carry the piece of DNA into the immune cell. It is not known whether these immune cells will kill glioma tumor cells when given to patients.

Do I need to stop my current medications for the trial?

The trial requires a 'washout' period (time without taking certain medications) for some treatments. You must stop nitrosourea-containing chemotherapy for at least 6 weeks, Temodar for 23 days, and other non-nitrosourea chemotherapy for 4 weeks before starting the trial. If you are on a targeted agent, a 2-week waiting period is needed, except for bevacizumab, which requires a 4-week washout.

Is engineered T cell therapy for brain cancer safe?

Studies show that engineered T cell therapy, like HER2-targeting CAR-T cells, has been well tolerated in patients with brain tumors, with no severe side effects reported in initial trials. However, other CAR T-cell therapies have shown potential risks, such as immune system-related side effects, which need to be monitored. ^{1 2 3 4 5}

How is the treatment HER2(EQ)BBζ/CD19t+ T cells different from other brain cancer treatments?

This treatment is unique because it uses engineered T cells that specifically target the HER2 protein, which is often present in brain tumors. Unlike traditional treatments, these T cells are designed to recognize and kill cancer cells, potentially offering a more targeted and effective approach. ^{1 5 6 7 8}

What data supports the effectiveness of the treatment HER2(EQ)BBζ/CD19t+ T cells for brain cancer?

Research shows that HER2-targeting T cells have been effective in treating brain tumors, such as glioblastoma and medulloblastoma, by targeting and killing cancer cells. Additionally, HER2-CAR T cells have shown strong antitumor activity in brain metastases from breast cancer, suggesting potential effectiveness for brain cancer treatment. ^{1 5 6 9 10}

Who Is on the Research Team?

Behnam Badie

Principal Investigator

City of Hope Medical Center

Are You a Good Fit for This Trial?

This trial is for adults with recurrent or treatment-resistant Grade III-IV glioma. They must have good venous access, understand and consent to the study, not suffer from severe heart issues or uncontrolled seizures, and have certain blood levels within normal ranges. Participants need a confirmed diagnosis of HER2+ glioma, be able to tolerate minimal steroids during therapy, and agree to use contraception.

Inclusion Criteria

I have not had serious heart problems or treatments that could affect my heart in the last 6 months.

I've been checked by a heart specialist and passed tests for heart health before joining the study.

It's been over 2 weeks since my last cancer treatment, except possibly for local treatments into the CSF.

Exclusion Criteria

I have no other active cancers.

I am not currently being treated for a severe infection or recovering from major surgery.

I do not have any uncontrolled illnesses or active infections.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive autologous HER2(EQ)BBzeta/CD19t+ T cells via catheter over 5 minutes weekly for 3 weeks. Additional infusions may be given based on eligibility and product availability.

3 weeks

3 visits (in-person)

Optional Infusions

Participants may receive additional T cell infusions based on clinical response and eligibility.

Variable

Follow-up

Participants are monitored for safety and effectiveness after treatment completion.

Up to 3 years

Follow-up at 4 weeks, 3, 6, 8, 10, and 12 months, then annually

What Are the Treatments Tested in This Trial?

Interventions

• HER2(EQ)BBζ/CD19t+ T cells
• Leukapheresis

Trial Overview The trial tests memory-enriched T cells (HER2(EQ)BBζ/CD19t+ T cells), which are engineered immune cells designed to target and kill glioma tumor cells. It's in phase I to determine side effects and optimal dosing. The process includes leukapheresis (blood filtering) and laboratory biomarker analysis.

How Is the Trial Designed?

Group I: Arm II (dual delivery Tcm enriched) Experimental Treatment 3 Interventions

Patients receive autologous HER2(EQ)BBzeta/CD19t+ Tcm cells via intratumoral/intracavitary catheter and intraventricular catheter over 5 minutes weekly for 3 weeks. Beginning as early as 1 week later, patients may receive additional T cell infusions as long as patients continue to remain eligible and there is product available. Based on clinical response after the first 3 infusions, the study principal investigator may decide to continue with the optional infusions at either one or both sites (instead of requiring injections at both sites).

Group II: Arm I (intratumoral/intracavitary delivery) Experimental Treatment 3 Interventions

Patients receive autologous HER2(EQ)BBzeta/CD19t+ Tcm cells via intratumoral/intracavitary catheter over 5 minutes weekly for 3 weeks. Beginning as early as 1 week later, patients may receive additional T cell infusions as long as patients remain eligible and there is product available. Patients who progress on intracavitary or intratumoral administration may move to alternative delivery routes for the optional infusions.

Group III: ARM III (dual delivery Tn/mem enriched) Experimental Treatment 3 Interventions

Patients receive autologous HER2(EQ)BBzeta/CD19t+ Tn/mem cells via intratumoral/intracavitary catheter and intraventricular catheter over 5 minutes weekly for 3 weeks. Beginning as early as 1 week later, patients may receive additional T cell infusions as long as patients continue to remain eligible and there is product available. Based on clinical response after the first 3 infusions, the study principal investigator may decide to continue with the optional infusions at either one or both sites (instead of requiring injections at both sites).

Who Is Running the Clinical Trial?

City of Hope Medical Center

Lead Sponsor

Trials

614

Recruited

1,924,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

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 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]

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]

CD19+ CAR T-cells have shown high effectiveness against various cancers, but their complete risk profile, including complications, was not fully understood during initial clinical trials.

Emerging evidence from post-approval studies reveals significant complications associated with CD19+ CAR T-cell therapy, such as cytokine release syndrome and neurotoxicity, indicating that these therapies can affect multiple organ systems and may lead to long-term health issues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Complications after CD19+ CAR T-Cell Therapy. Penack, O., Koenecke, C.[2020]

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]

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]

The engineered T1E28z chimeric antigen receptor effectively activates T cells against various tumor cells by targeting multiple ErbB receptor combinations, demonstrating its potential for broad application in cancer therapy.

In mouse models with established tumors overexpressing ErbB1/2 or ErbB2/3, T1E28z⁺ T cells showed significant antitumor activity, suggesting this immunotherapeutic approach could overcome resistance seen with traditional ErbB-targeted therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Flexible targeting of ErbB dimers that drive tumorigenesis by using genetically engineered T cells. Davies, DM., Foster, J., Van Der Stegen, SJ., et al.[2022]

Citations

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

Bioactivity and Safety of IL13Rα2-Redirected Chimeric Antigen Receptor CD8+ T Cells in Patients with Recurrent Glioblastoma. [2023]

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

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

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

Complications after CD19+ CAR T-Cell Therapy. [2020]

7. Switzerland pubmed.ncbi.nlm.nih.gov

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

8. 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]

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

Immunotherapy of cancer using systemically delivered gene-modified human T lymphocytes. [2014]

10. England pubmed.ncbi.nlm.nih.gov

Flexible targeting of ErbB dimers that drive tumorigenesis by using genetically engineered T cells. [2022]