CAR T-Cell Therapy for Brain Metastasis

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: City of Hope Medical Center

Must be taking: Corticosteroids

Must not be taking: Chemotherapy, Endocrine therapy

Disqualifiers: Congestive heart failure, Seizures, Autoimmune, 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 find the safest dose and identify any side effects of a new treatment called HER2-CAR T cells for cancer that has returned and spread to the brain or the fluid around the brain. The treatment uses modified immune cells to target and kill cancer cells. People with cancer that has returned in the brain after treatments like radiation, or those who haven't received treatment for brain or surrounding fluid cancer and chose not to undergo radiation, may be suitable candidates. As a Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this innovative therapy.

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

Yes, you will need to stop treatment with chemotherapy or endocrine therapy during the first 3 cycles of the HER2-CAR T cell study. Additionally, there are specific washout periods required for certain medications before starting the trial.

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

Yes, you will need to stop taking chemotherapy or endocrine therapy during the first 3 cycles of the HER2-CAR T cell study. Additionally, there are specific waiting periods required after your last dose of certain medications before starting the trial.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research has shown that HER2-CAR T cells have been tested for safety in treating cancer that has spread to the brain. One study improved these cells for brain cancer treatment by refining their design and delivery. Most patients tolerated the therapy well, though some experienced generally manageable side effects.

In another study, researchers tested HER2-CAR T cells in patients with glioblastoma, a type of brain cancer. The therapy proved relatively safe but did not perform as well as expected, indicating the need for further research to enhance its effectiveness. Overall, while HER2-CAR T cell therapy remains under study, early results suggest it is generally well-tolerated with some risks, which is common with new treatments. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about HER2-CAR T cell therapy for brain metastasis because it represents a novel approach compared to standard treatments like chemotherapy, radiation, and targeted therapies. Unlike these options, which act on the tumor or its environment, HER2-CAR T cells are engineered to specifically recognize and attack cancer cells expressing the HER2 protein. This therapy employs a new delivery method, administering the modified T cells directly into the brain's ventricles, potentially enhancing precision and minimizing systemic side effects. This targeted approach could offer a more effective and less toxic treatment option for patients with brain metastases.

What evidence suggests that HER2-CAR T cells might be an effective treatment for brain metastasis?

Studies have shown that HER2-CAR T cells can effectively fight cancer cells in both lab and animal studies. These cells are specially designed to target the HER2 protein, often found in certain cancers, including those that spread to the brain. Research indicates that HER2-CAR T cells exhibit strong anti-tumor activity, effectively attacking and killing cancer cells. This trial will evaluate the effectiveness of HER2-CAR T cells administered directly into the brain. Early studies suggest this method might enhance effectiveness by directly targeting cancer cells without harming healthy ones. ^{1 2 3 4 6}

Who Is on the Research Team?

Jana Portnow, MD

Principal Investigator

City of Hope Medical Center

Are You a Good Fit for This Trial?

This trial is for patients with recurrent brain or leptomeningeal metastases from HER2+ cancer, post-radiation therapy. They must have acceptable organ function, no severe heart issues, controlled seizures, not be on high-dose steroids or oxygen support, and agree to contraception if applicable. Excluded are those with active infections, other cancers, HIV, uncontrolled illnesses or requiring dialysis.

Inclusion Criteria

My brain cancer has returned after radiation treatment.

I have brain metastases and choose not to have radiation or chemotherapy.

I am able to care for myself but may not be able to do active work.

Exclusion Criteria

I have another active cancer besides the one being studied.

I am not willing to pause my chemotherapy or hormone therapy for the first 3 cycles of the HER2-CAR T cell study.

You have tested positive for HIV within the past 4 weeks.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive HER2-CAR T cells via intraventricular administration over 5 minutes once weekly for 3 doses

3 weeks

3 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 months

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

Long-term follow-up

Participants are monitored for long-term safety and survival outcomes

Up to 15 years

What Are the Treatments Tested in This Trial?

Interventions

• HER2-CAR T Cells

Trial Overview The study tests the safety and optimal dosage of HER2-CAR T cells injected into the brain's ventricles to target and destroy tumor cells in patients whose cancer has spread to the brain/leptomeninges and returned after treatment.

How Is the Trial Designed?

Group I: Treatment (HER2-CAR T cells) Experimental Treatment 1 Intervention

Patients receive HER2-CAR T cells via intraventricular administration over 5 minutes once weekly for 3 doses in the absence of disease progression or unacceptable toxicity. If patients continue to meet all eligibility criteria, they may receive additional cycles of HER2-CAR T cells at principal investigator's discretion.

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+

California Institute for Regenerative Medicine (CIRM)

Collaborator

Trials

70

Recruited

3,300+

Published Research Related to This Trial

HER2 is commonly expressed in osteosarcoma but at low levels, making traditional HER2 monoclonal antibody treatments ineffective; however, genetically modified T cells with HER2-specific chimeric antigen receptors (CARs) can effectively target these tumors.

In mouse models, the adoptive transfer of HER2-specific T cells led to significant regression of established osteosarcoma tumors, demonstrating the potential of CAR T-cell therapy in treating cancers with low antigen expression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immunotherapy for osteosarcoma: genetic modification of T cells overcomes low levels of tumor antigen expression. Ahmed, N., Salsman, VS., Yvon, E., et al.[2021]

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]

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]

CAR T cells have shown significant clinical effectiveness in treating blood cancers, but their success in solid tumors has been less impressive, highlighting the need for further research in this area.

While CAR T cell therapy can lead to serious side effects like cytokine release syndrome and neurological toxicity, some theoretical risks have not yet been observed in clinical settings, emphasizing the importance of managing known toxicities for safe treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Toxicity and management in CAR T-cell therapy. Bonifant, CL., Jackson, HJ., Brentjens, RJ., et al.[2023]

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]

A study involving 204 patients undergoing CAR T-cell therapy identified clinical and laboratory parameters that can predict the risk of neurotoxicity, which affects over half of the patients treated.

A prognostic score developed from early admission data showed a 74% area under the curve and 77% accuracy in predicting neurotoxicity, potentially allowing for better patient management and earlier hospital discharge.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical Predictors of Neurotoxicity After Chimeric Antigen Receptor T-Cell Therapy. Rubin, DB., Al Jarrah, A., Li, K., et al.[2021]

Radiolabeling CAR-T cells with 89Zr-oxine is an effective method that allows for tracking their distribution in the body using PET imaging, while maintaining the cells' viability and functional characteristics for at least 8 days.

The study found that radiolabeled CAR-T cells retain their ability to target and kill IL-13Rα2 positive tumor cells without significant changes in activation or exhaustion markers, indicating that this labeling technique could enhance our understanding of CAR-T cell behavior in vivo.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Characterization of chimeric antigen receptor modified T cells expressing scFv-IL-13Rα2 after radiolabeling with 89Zirconium oxine for PET imaging. Leland, P., Kumar, D., Nimmagadda, S., et al.[2023]

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]

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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7685198/

Regional Delivery of Chimeric Antigen Receptor–Engineered ... We have optimized HER2-CAR T cells for the treatment of breast to brain metastases, and determined optimal second-generation CAR design and route of ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT03696030

NCT03696030 | HER2-CAR T Cells in Treating Patients ... This phase I trial studies the side effects and best dose of HER2-CAR T cells in treating patients with cancer that has spread to the brain or leptomeninges ...

3. nature.com nature.com/articles/s41435-024-00275-6

HER2-targeting CAR-T cells show highly efficient anti- ... HER2-CAR-T cells showed effective anti-tumor activity both in vitro and in vivo. Furthermore, HER2-specific CAR-T cells exhibited strong ...

4. frontiersin.org frontiersin.org/journals/immunology/articles/10.3389/fimmu.2025.1514994/full

Research progress on HER2-specific chimeric antigen ... A recent study constructed third-generation CAR-T cells targeting the HER2 antigen in glioblastoma, demonstrating effective anti-tumor activity ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12133747/

Research progress on HER2-specific chimeric antigen ... This review will delineate the structure and cytotoxic mechanism of HER2-CAR-T cells, elucidate the difficulties and optimization strategies for HER2-CAR-T ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9178287/

Safety and Efficacy of Chimeric Antigen Receptor T-Cell ... Although CAR T-cell therapy is a relatively safe therapeutic option in patients with glioblastoma, it shows marginal efficacy, suggesting that further research ...