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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine the safest dose and possible side effects of a new T cell therapy for brain cancer patients with glioma that has either returned or isn't responding to treatment. The therapy uses engineered T cells, which are immune cells modified to target and potentially kill cancer cells. Participants with a grade III or IV glioma, or a grade II glioma that has progressed and has specific tumor characteristics, may qualify for this study.

As a Phase 1 trial, participants will be among the first to receive this new treatment, aiding researchers in understanding how it works in people.

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 there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that HER2-targeting CAR-T cells, similar to the HER2(EQ)BBζ/CD19t+ T cells used in this trial, have been effective against tumors in past studies. Patients generally tolerated these cells well, although some experienced mild side effects like headaches or tiredness, which are common with such treatments.

For HER2(EQ)BBζ/CD19t+ Tn/mem cells, research is closely examining their safety and effectiveness. In earlier studies with similar treatments, these cells were administered safely, and side effects were usually mild and manageable.

Since this trial is in an early stage, it primarily focuses on identifying the safest dose and understanding any side effects. The treatment is still being tested for safety, and any serious risks are not fully known yet. However, other studies suggest that these T cells are generally well-tolerated. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about this treatment for brain cancer because it uses engineered T cells, specifically HER2(EQ)BBζ/CD19t+ T cells, which offer a fresh approach compared to traditional therapies like chemotherapy and radiation. Unlike standard treatments, these T cells are delivered directly into the tumor or brain cavities, potentially increasing their effectiveness by targeting cancer cells more precisely. Additionally, the ability to continue infusions based on patient response allows for a more personalized treatment strategy, which could lead to better outcomes and fewer side effects. This innovative method of using the body’s own immune cells to fight cancer is a promising advancement that sets it apart from current therapies.

What evidence suggests that this trial's treatments could be effective for brain cancer?

Research has shown that CAR-T cells targeting HER2 proteins effectively combat tumors in both lab tests and living organisms. These cells are designed to attack specific proteins on cancer cells, aiding in their destruction. In this trial, participants may receive HER2(EQ)BBζ/CD19t+ Tcm cells, known for their ability to target and kill glioma cells, a type of brain cancer. Another trial arm involves HER2(EQ)BBζ/CD19t+ Tn/mem cells, which are part of ongoing research into new cancer treatments. These cells show promise by harnessing the body's immune system to fight tumors. Although evidence is still emerging, these treatments offer hope for addressing hard-to-treat brain cancers. ^{2 3 6 7 8}

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

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]

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]

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]

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]

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]

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]

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