CAR T-Cell Therapy for Brain Cancer

Overseen By Kelly Tanner

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Stanford University

Must not be taking: Anticoagulants, Immunosuppressants

Disqualifiers: Pregnancy, Uncontrolled infections, Autoimmune, others

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

Compensation: Varies

Number of Visits: Unknown

39 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment called B7-H3CART, a type of CAR T-cell therapy, to determine its safety and production effectiveness. It targets brain cancer, specifically IDH wild-type glioblastoma, a common and aggressive tumor that has recurred after standard treatments. The trial explores different doses to identify the safest and most effective amount. Individuals whose brain cancer has returned after treatment and are considering surgery might be suitable candidates. As a Phase 1 trial, this research aims to understand how the treatment works in people, offering participants the opportunity to be among the first to receive this new therapy.

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.

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, it mentions that you must be at least 3 weeks post-chemotherapy or 5 half-lives, whichever is shorter, since any prior systemic therapy, and at least 4 weeks from certain treatments like bevacizumab. It's best to discuss your specific medications with the trial team.

Is there any evidence suggesting that B7-H3CART is likely to be safe for humans?

Research shows that B7-H3 CAR T-cell therapy appears promising in terms of safety. Earlier studies often found B7-H3 in brain tumors, making it a suitable target for this therapy. In one study, children and young adults with a specific type of brain tumor received repeated doses of B7-H3 CAR T cells and tolerated it well, experiencing no severe side effects.

Another study examined the safety of these B7-H3 targeted cells in patients with glioblastoma, a type of brain cancer. The study suggested that the therapy is relatively safe, but more research is needed to assess its effectiveness.

Since this trial is in an early phase, the main goal is to test the treatment's safety. This phase typically involves administering low doses to determine tolerability. While these early studies are promising, further research is necessary to confirm the safety and effectiveness of B7-H3 CAR T-cell therapy. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

CAR T-Cell Therapy for brain cancer is unique because it uses genetically engineered T-cells to specifically target and attack cancer cells expressing the B7-H3 protein. Unlike standard treatments like surgery, radiation, and chemotherapy, which can affect healthy brain tissue, CAR T-Cell Therapy aims for precision by honing in on cancer-specific markers, potentially reducing collateral damage to healthy cells. Researchers are excited about this treatment because it represents a novel approach that could lead to more effective and less harmful options for patients with brain cancer.

What evidence suggests that B7-H3CART might be an effective treatment for brain cancer?

Research shows that a new treatment using B7-H3-targeted CAR T cells could help fight brain tumors. In lab studies, these cells have effectively shrunk tumors. For instance, in mice, B7-H3 CAR T cells significantly reduced tumor size compared to other treatments. Early tests in children demonstrated that this treatment can be used safely at certain doses. In this trial, participants will receive B7-H3 CAR T cells in either a dose escalation or dose expansion phase to determine the optimal dosing. This treatment targets a protein called B7-H3, often found in tumors like GBM, a severe type of brain cancer. Overall, these findings suggest that B7-H3 CAR T cells could be a promising new option for treating brain cancer. ^{1 5 6 7 8}

Who Is on the Research Team?

Reena Thomas, MD, PhD

Principal Investigator

Stanford University

Are You a Good Fit for This Trial?

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 can care for myself but may need occasional help.

Exclusion Criteria

Pregnant or patients who are breastfeeding

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.

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

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

Participants receive locoregional administration of B7-H3CART with a 3+3 dose escalation design to determine the maximum tolerated dose

Varies per dose level

Multiple visits for dose administration and monitoring

Dose Expansion

Participants receive repeat administrations at the maximum tolerated dose to further explore safety and conduct a preliminary assessment of benefit

Varies

Multiple visits for repeat administrations and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

5 years

What Are the Treatments Tested in This Trial?

Interventions

• B7-H3CART

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.

How Is the Trial Designed?

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?

Stanford University

Lead Sponsor

Trials

2,527

Recruited

17,430,000+

Crystal Mackall, MD

Lead Sponsor

Trials

6

Recruited

240+

California Institute for Regenerative Medicine (CIRM)

Collaborator

Trials

70

Recruited

3,300+

Parker Institute for Cancer Immunotherapy

Collaborator

Trials

12

Recruited

460+

Published Research Related to This Trial

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]

B7-H3 CAR T cells have shown significant antitumor activity in various pediatric solid tumor models, including osteosarcoma and medulloblastoma, indicating their potential as a treatment option for relapsed pediatric malignancies.

The effectiveness of B7-H3 CAR T cells is linked to the density of the B7-H3 antigen on tumor cells, suggesting that this therapy could be selectively effective against tumors with high antigen expression while minimizing effects on normal tissues with lower expression.

NCBI (Pubmed)

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. Majzner, RG., Theruvath, JL., Nellan, A., 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]

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 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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6713854/

B7-H3 as a Novel CAR-T Therapeutic Target for ... Here, we aimed to explore whether B7-H3 could serve as a novel therapeutic target for GBM in chimeric antigen receptor (CAR) T cell therapy.

2. jitc.bmj.com jitc.bmj.com/content/13/1/e010083

Novel B7-H3 CAR T cells show potent antitumor effects in ... Our preclinical study demonstrates that these B7-H3-targeted CAR T cells effectively eliminated primary tumors and controlled rechallenge tumor ...

3. nature.com nature.com/articles/s41591-024-03451-3

Intracerebroventricular B7-H3-targeting CAR T cells for ... We show the safety of repetitive intracerebroventricularly (ICV) dosed B7-H3 CAR T cells up to 10 × 107 cells per dose to children with DIPG, ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11456075/

Antitumor effects of intracranial injection of B7-H3-targeted ... 2B). Tumor burden was significantly reduced in mice treated with B7-H3 CAR-T cells compared with that in mice treated with control CAR-T cells ( ...

5. translational-medicine.biomedcentral.com translational-medicine.biomedcentral.com/articles/10.1186/s12967-023-04514-8

B7H3-targeting chimeric antigen receptor modification ... The study investigates the efficacy of genetically engineered Vγ9Vδ2 T cells expressing Car-B7H3 in targeting diverse GBM specimens.

6. clinicaltrials.gov clinicaltrials.gov/study/NCT05366179

NCT05366179 | Autologous CAR-T Cells Targeting B7-H3 ... The purpose of this study is to test the safety of using T lymphocyte chimeric antigen receptor cells against the B7-H3 antigen (CAR.B7-H3T cells) in ...

7. sciencedirect.com sciencedirect.com/science/article/pii/S2352396419305523

B7-H3-redirected chimeric antigen receptor T cells target ... We demonstrated in this report that B7-H3 is an attractive target for CAR-T cells in GBM because it is highly expressed in 76% of GBM specimens.

8. 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 ...