CAR T-Cell Therapy for Brain Cancer

Recruiting in Palo Alto (17 mi)

Overseen by Reena Thomas, MD, PhD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Waitlist Available

Sponsor: Crystal Mackall, MD

Must not be taking: Anticoagulants, Immunosuppressants

Disqualifiers: Pregnancy, Uncontrolled infections, Autoimmune, others

No Placebo Group

Trial Summary

What is the purpose of this trial?

This is an open label, non-randomized, single site Phase I study to test the manufacturing feasibility and safety of locoregional (LR) administration of B7-H3CART into the central nervous system of adult subjects with recurrent IDH wild-type GBM using a standard 3+3 dose escalation design.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, you must limit steroid use to 4 mg of decadron daily and meet certain timing requirements after previous cancer treatments. It's best to discuss your specific medications with the trial team.

What data supports the effectiveness of the treatment B7-H3CART for brain cancer?

Research shows that B7-H3CART, a type of CAR T-cell therapy, has shown promise in treating glioblastoma (a type of brain cancer) by targeting the B7-H3 protein, which is often found in high levels in these tumors. Studies have demonstrated that this treatment can extend survival in animal models and has potential for use in pediatric brain tumors. ^{1 2 3 4 5}

Is CAR T-Cell Therapy targeting B7-H3 safe for brain cancer patients?

While CAR T-Cell Therapy targeting B7-H3 shows promise for treating brain cancer, there are concerns about severe side effects, including neurotoxicity (nerve damage) that can lead to serious conditions like encephalopathy (brain disease) and cerebral edema (brain swelling). The safety of this therapy is still being studied, and its effects can vary. ^{1 2 3 6 7}

What makes the B7-H3CART treatment unique for brain cancer?

B7-H3CART is a novel treatment that uses specially engineered immune cells (CAR T-cells) to target a protein called B7-H3, which is often found on brain cancer cells like glioblastoma. This approach is unique because it aims to directly attack cancer cells by recognizing this specific protein, potentially offering a new option for a condition with limited effective treatments. ^{1 2 3 4 5}

Research Team

Reena Thomas, MD, PhD

Principal Investigator

Stanford University

Eligibility Criteria

Adults aged 18-75 with recurrent high-grade glioblastoma, IDH wild-type, who have completed standard therapy and show tumor progression. They must be stable on low-dose steroids, have good organ function and performance status, not pregnant or breastfeeding, willing to use contraception, able to follow study procedures at Stanford Health Care.

Inclusion Criteria

My doctors believe most of my tumor can be surgically removed.

I use no more than 4 mg of decadron daily.

I am between 18 and 75 years old.

Exclusion Criteria

Pregnant or patients who are breastfeeding

I have HIV or hepatitis but it's under control.

In the investigator's judgment, the subject is unlikely to complete all protocol- required study visits or procedures, including follow-up visits, or comply with the study requirements for participation.

Treatment Details

Interventions

• B7-H3CART (CAR T-cell Therapy)

Trial Overview The trial is testing B7-H3CART cells delivered directly into the brain of patients with recurrent glioblastoma. It's a Phase I study focusing on safety and how well the treatment can be made using a '3+3 dose escalation' method where doses are increased slowly in small groups.

Participant Groups

Group I: Dose escalation Experimental Treatment 1 Intervention

All subjects will be assigned to a dose level. Does escalation will proceed sequentially via a standard 3+3 dose escalation design in subjects who receive at least one infusion of B7-H3CART. Each dose level will include 3 to 6 subjects, starting at Dose Level 1. If Dose Level 1 is considered too toxic, the dose may be de-escalated to Dose Level -1. If Dose Level 4 is completed with no dose limiting toxicity (DLT) in six subjects, a maximum tolerated dose (MTD) may not be determined, and Dose Level 4 will instead be the maximum administered dose (MAD). T

Group II: Dose Expansion Experimental Treatment 1 Intervention

After Maximum Tolerated Dose (MTD)/Recommended Phase 2 Dose (RP2D) is established, a total of 12 evaluable subjects (including the 6 subjects infused during the dose escalation phase) will be enrolled at the RP2D to further explore safety of repeat administrations at MTD/RP2D and conduct a preliminary assessment of benefit.

Who Is Running the Clinical Trial?

Crystal Mackall, MD

Lead Sponsor

Trials

6

Recruited

240+

California Institute for Regenerative Medicine (CIRM)

Collaborator

Trials

70

Recruited

3,300+

Jonathan Thomas

California Institute for Regenerative Medicine (CIRM)

Chief Executive Officer

BA in Biology and History from Yale University, JD from Yale Law School, PhD in Commonwealth History from Oxford University

Rosa Canet-Avilés

California Institute for Regenerative Medicine (CIRM)

Chief Medical Officer since 2024

PhD in Neuroscience from Leeds University, BS in Organic Chemistry from Central University of Barcelona

Findings from Research

B7-H3 is frequently overexpressed in glioblastoma (GBM) and correlates with higher malignancy and poorer survival rates, making it a promising target for treatment.

CAR T cells engineered to target B7-H3 showed significant antitumor effects in both laboratory tests and in animal models, leading to longer survival compared to control groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

B7-H3 as a Novel CAR-T Therapeutic Target for Glioblastoma. Tang, X., Zhao, S., Zhang, Y., et al.[2020]

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]

B7-H3 is highly overexpressed in glioblastoma (GBM) compared to normal brain tissue, making it a promising target for CAR-T cell therapy, as shown by immunohistochemistry in 76% of analyzed specimens.

B7-H3-redirected CAR-T cells effectively targeted and controlled tumor growth in GBM cell lines and patient-derived neurospheres in both in vitro and in vivo models, indicating their potential as a new treatment strategy for GBM.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

B7-H3-redirected chimeric antigen receptor T cells target glioblastoma and neurospheres. Nehama, D., Di Ianni, N., Musio, S., et al.[2021]

In a study of 49 pediatric brain tumor patient-derived xenografts, B7-H3 was identified as a promising target for CAR T-cell therapy due to its high and consistent expression across various tumor types, while HLA class I expression was found in all high-grade gliomas but only in 57.1% of other tumor subtypes.

B7-H3-CAR T cells demonstrated effective tumor recognition and induced significant tumor regression in both in vitro and in vivo models, suggesting a potential survival advantage for patients with pediatric brain tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cell-surface antigen profiling of pediatric brain tumors: B7-H3 is consistently expressed and can be targeted via local or systemic CAR T-cell delivery. Haydar, D., Houke, H., Chiang, J., et al.[2023]

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]

CAR T-cell therapy appears to be a relatively safe treatment for patients with recurrent glioblastoma, with only 9.5% of patients experiencing mild cytokine release syndrome and 25.4% having non-critical neurological events.

However, the therapy shows marginal efficacy, with a pooled objective response rate of only 5.1% and a median overall survival of 8.1 months, indicating that more research is needed to improve its effectiveness in treating this type of brain cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and Efficacy of Chimeric Antigen Receptor T-Cell Therapy for Glioblastoma: A Systemic Review and Meta-Analysis. Jang, JK., Pyo, J., Suh, CH., et al.[2023]

References

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

B7-H3 as a Novel CAR-T Therapeutic Target for Glioblastoma. [2020]

2. France pubmed.ncbi.nlm.nih.gov

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

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

CAR T Cells Targeting B7-H3, a Pan-Cancer Antigen, Demonstrate Potent Preclinical Activity Against Pediatric Solid Tumors and Brain Tumors. [2021]

4. Netherlands pubmed.ncbi.nlm.nih.gov

B7-H3-redirected chimeric antigen receptor T cells target glioblastoma and neurospheres. [2021]

5. England pubmed.ncbi.nlm.nih.gov

Cell-surface antigen profiling of pediatric brain tumors: B7-H3 is consistently expressed and can be targeted via local or systemic CAR T-cell delivery. [2023]

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

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

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

Safety and Efficacy of Chimeric Antigen Receptor T-Cell Therapy for Glioblastoma: A Systemic Review and Meta-Analysis. [2023]