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

24 Participants Needed

Trial Summary

What is the purpose of this trial?

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 and has come back (recurrent). HER2-CAR T cells delivered into the ventricles of the brain may recognize and kill tumor cells.

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.

What data supports the idea that CAR T-Cell Therapy for Brain Metastasis is an effective treatment?

The available research shows that CAR T-Cell Therapy, specifically HER2-CAR T cells, is effective in treating brain metastasis from breast cancer. In studies using mouse models, HER2-CAR T cells with a specific design showed improved targeting of tumors and reduced exhaustion of T cells, which means they stayed active longer. When delivered directly into the brain, these cells demonstrated strong anti-tumor activity. Additionally, in pediatric patients with central nervous system tumors, the treatment was well tolerated. This suggests that CAR T-Cell Therapy could be a promising option compared to other treatments that may not effectively target brain metastases. ^{1 2 3 4 5}

What data supports the effectiveness of the treatment HER2-CAR T Cells for brain metastasis?

Research shows that HER2-CAR T cells, especially when delivered directly into the brain, can effectively target and kill cancer cells in brain metastases from breast cancer. Similar treatments have also shown success in reducing tumors in other cancers like medulloblastoma and osteosarcoma, suggesting potential effectiveness for brain metastases. ^{1 2 3 4 5}

What safety data is available for HER2 CAR T-cell therapy?

HER2 CAR T-cell therapy has been associated with serious toxicities such as cytokine release syndrome and neurotoxicity, including severe neurologic adverse events like encephalopathy and cerebral edema. Intracranial delivery in pediatric CNS tumors was well tolerated in a small study. Strategies to improve safety are being explored, but the unpredictability of these toxicities remains a concern. ^{2 6 7 8 9}

Is HER2-CAR T-cell therapy safe for humans?

HER2-CAR T-cell therapy has shown potential in treating cancer, but it can cause serious side effects like cytokine release syndrome (a severe immune reaction) and neurotoxicity (nerve damage). Some studies have found it to be well-tolerated in specific cases, but the risk of severe side effects remains a concern. ^{2 6 7 8 9}

Is the treatment HER2-CAR T Cells a promising treatment for brain metastasis?

Yes, HER2-CAR T Cells are a promising treatment for brain metastasis. They have shown strong ability to target and kill cancer cells in the brain, especially when delivered directly to the brain area. This treatment has been effective in reducing tumor growth and improving outcomes in experimental models. ^{1 2 5 10 11}

How is the HER2-CAR T cell treatment different from other treatments for brain metastasis?

The HER2-CAR T cell treatment is unique because it involves genetically engineered immune cells that specifically target HER2-positive cancer cells in the brain, and it can be delivered directly into the brain's ventricles, which may enhance its effectiveness against multifocal brain metastases. ^{1 2 5 10 11}

Research Team

Jana Portnow, MD

Principal Investigator

City of Hope Medical Center

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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 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 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 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]

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]

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]

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]

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]

References

1. 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]

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

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

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

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

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

Immunotherapy for osteosarcoma: genetic modification of T cells overcomes low levels of tumor antigen expression. [2021]

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

HER2-specific T cells target primary glioblastoma stem cells and induce regression of autologous experimental tumors. [2022]

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

Clinical Predictors of Neurotoxicity After Chimeric Antigen Receptor T-Cell Therapy. [2021]

8. England 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. [2023]

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

Toxicity and management in CAR T-cell therapy. [2023]

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

Combination of tucatinib and neural stem cells secreting anti-HER2 antibody prolongs survival of mice with metastatic brain cancer. [2022]

11. France pubmed.ncbi.nlm.nih.gov

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