CAR T Cell Therapy for Brain Cancer

Overseen By Jasia Mahdi, MD

Age: < 65

Sex: Any

Trial Phase: Phase 1

Sponsor: Baylor College of Medicine

Must not be taking: Immunotherapy, Colony-stimulating factors

Disqualifiers: Pregnancy, Breastfeeding, Other risk factors, others

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

Compensation: Varies

Number of Visits: 7

37 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to test a new treatment for certain types of brain cancer using a special kind of immune cell called T cells. Researchers have designed these T cells, known as (C7R)-GD2.CART cells, to attack cancer cells more effectively by helping them live longer in the body. The trial will explore the safest dose of these T cells when administered in different ways, both through the bloodstream and directly into the brain. The study seeks patients with specific brain cancers, such as high-grade gliomas or medulloblastomas, that express a protein called GD2. Participants with these types of brain tumors who have had stable symptoms after treatment might be a good fit for this trial. 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 to join the trial?

The trial requires you to stop any concurrent anti-cancer therapy at least three half-lives before treatment. You also cannot have received any other forms of immunotherapy within 42 days before the investigational agent or colony-stimulating factors within 14 days prior to lymphodepletion. The protocol does not specify about other medications, so please consult with the trial team for more details.

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

Research has shown that C7R-GD2.CAR T cells have potential in early studies. These specialized T cells are designed to locate and attack cancer cells. In past studies, most patients tolerated them well, experiencing no severe side effects. Some patients even experienced temporary improvements.

The addition of the C7R gene helps these T cells survive longer in the body, potentially enhancing their ability to fight tumors. Before receiving the T cells, patients undergo chemotherapy to improve the T cells' effectiveness. This step, known as lymphodepletion, prepares the body to accept and support the new cells.

These studies remain in the early stages, so researchers are primarily focused on ensuring the treatment's safety. More research is needed to fully understand the possible side effects. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatment?

Researchers are excited about C7R-GD2.CAR T cell therapy for brain cancer because it represents a novel approach that modifies a patient's own immune cells to specifically target cancer cells. Unlike traditional treatments like surgery, radiation, and chemotherapy that attack both healthy and cancerous cells, this therapy uses CAR T cells engineered to recognize and attack only the cancer cells, potentially reducing side effects. Additionally, the therapy's ability to be administered directly into the cerebrospinal fluid via an ommaya reservoir or programmable VP shunt allows for more precise delivery to the brain, which could improve effectiveness and outcomes. This targeted approach offers hope for more effective and less toxic treatment options for brain cancer patients.

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

Research has shown that CAR T cell therapy, which uses specially altered T cells to fight cancer, may help treat brain cancers. In earlier studies with children who had neuroblastoma, GD2-CAR T cells successfully found and attacked cancer cells, but these T cells did not persist long in the body. To address this, researchers added a gene called C7R to help the T cells survive longer by providing a steady supply of cytokines. Early results suggest this could enhance the T cells' ability to fight brain tumors. In this trial, participants in Cohort 1 will receive C7R-GD2.CAR T cells administered intracerebroventricularly (ICV) and intravenously, while those in Cohort 2 will receive the cells intravenously. Additionally, administering chemotherapy before the T cell therapy has been shown to help the T cells remain in the body longer, enhancing their ability to combat cancer cells. ^{1 3 6 7 8}

Who Is on the Research Team?

Jasia Mahdi, MD

Principal Investigator

Baylor College of Medicine

Bilal Omer, MD

Principal Investigator

Baylor College of Medicine

Are You a Good Fit for This Trial?

This trial is for children and young adults aged 1 to 21 with specific brain cancers that have a protein called GD2 on their surface. These include newly diagnosed or recurrent tumors like diffuse midline glioma, high-grade glioma, medulloblastoma, and others. Participants need measurable disease on MRI and a functional score indicating they can perform daily activities at least half the time.

Inclusion Criteria

My tumor is smaller than 5 cm.

Procurement

My tumor was between 5 and 5.5 cm but was surgically reduced in size.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Lymphodepletion Chemotherapy

Patients receive cyclophosphamide and fludarabine (or clofarabine) to prepare for T cell infusion

3 days

1 visit (in-person)

T Cell Infusion and Monitoring

Patients receive GD2-C7R T cells via IV and/or ICV infusion and are monitored for side effects

4 weeks

Hospital stay for up to 5 days post-infusion, with monitoring in Houston for up to 4 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

15 years

Visits at weeks 1, 2, 3, 4, 6, 8, then at months 3, 6, 9, 12, and biannually for 4 years, then annually

What Are the Treatments Tested in This Trial?

Interventions

• (C7R)-GD2.CART cells

Trial Overview The study tests genetically modified T cells (a type of immune cell) designed to last longer in the body by adding a gene called C7R. This helps them fight cancer more effectively. The trial involves two methods of infusing these cells: directly into the brain (ICV) and into the vein (IV), after chemotherapy to improve their survival.

How Is the Trial Designed?

Group I: C7R-GD2.CAR T cells (Cohort 2) Experimental Treatment 1 Intervention

The dose level for autologous cell C7R-GD2.CAR T cell immunotherapy administered via intravenous (IV) infusion was determined in the initial phase of the protocol. The standard IV dosing is 10 million cells/m2 with lymphodepletion chemotherapy.

Group II: C7R-GD2.CAR T cells (Cohort 1) Experimental Treatment 1 Intervention

The dose level for autologous cell C7R-GD2.CAR T cells administered via intravenous (IV) infusion was determined in the initial phase of the protocol. The standard IV dose is 10 million cells/m2 with lymphodepletion chemotherapy. In this subsequent phase of the study, the safe dosing levels for autologous cell C7R-GD2.CAR T cell immunotherapy administered intracerebroventricularly (ICV) via ommaya reservoir or programmable VP shunt in combination with subsequent IV doses will be determined.

Who Is Running the Clinical Trial?

Baylor College of Medicine

Lead Sponsor

Trials

1,044

Recruited

6,031,000+

Faris Foundation

Collaborator

Trials

1

Recruited

40+

Center for Cell and Gene Therapy, Baylor College of Medicine

Collaborator

Trials

114

Recruited

2,900+

Violet Foundation for Pediatric Brain Cancer

Collaborator

Trials

1

Recruited

40+

The Faris Foundation

Collaborator

Trials

1

Recruited

40+

ChadTough Defeat DIPG Foundation

Collaborator

Trials

1

Recruited

40+

Published Research Related to This Trial

GD2-targeted CAR T cells have shown promising efficacy in preclinical models of H3-K27M-mutant diffuse midline gliomas, effectively clearing tumors in five patient-derived xenograft models.

While the treatment was generally well tolerated, there were instances of neuroinflammation leading to hydrocephalus in some models, highlighting the need for careful monitoring and management in potential human trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Potent antitumor efficacy of anti-GD2 CAR T cells in H3-K27M+ diffuse midline gliomas. Mount, CW., Majzner, RG., Sundaresh, S., et al.[2022]

Infusion of GD2-specific fourth-generation safety-designed chimeric antigen receptor (4SCAR)-T cells in eight patients with GD2-positive glioblastoma (GBM) was found to be safe and well tolerated, with no severe adverse events reported.

Of the eight patients, four experienced a partial response lasting between 3 to 24 months, indicating that 4SCAR-T cells can exert anti-GBM activity, with a median overall survival of 10 months post-infusion.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and antitumor activity of GD2-Specific 4SCAR-T cells in patients with glioblastoma. Liu, Z., Zhou, J., Yang, X., et al.[2023]

Murine GD2 CAR-T cells can cause severe neurotoxicity, which is influenced by the costimulatory domain used, highlighting the need for careful evaluation of CAR designs in preclinical models.

The newly developed SynNotch gated CAR-T, GD2-B7H3, shows improved efficacy and specificity against neuroblastoma in mouse models, benefiting from enhanced metabolic fitness and reduced exhaustion compared to traditional CAR-T cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preclinical assessment of the efficacy and specificity of GD2-B7H3 SynNotch CAR-T in metastatic neuroblastoma. Moghimi, B., Muthugounder, S., Jambon, S., et al.[2021]

Immunotherapy, particularly CAR T-cell therapy, is a promising approach for treating glioblastoma multiforme (GBM), a highly aggressive brain tumor, by using genetically engineered cells from the patient to target tumor-specific proteins.

Current CAR T clinical trials are exploring various generations of this therapy to improve efficacy against GBM, addressing the challenges faced in treating this difficult-to-manage cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chimeric Antigen Receptor T-Cell Therapy: Updates in Glioblastoma Treatment. Feldman, L., Brown, C., Badie, B.[2022]

CAR-T cell therapy shows promise as a treatment for glioblastoma (GBM), with early trials indicating good safety and tolerability, as well as some initial signs of antitumor activity.

Ongoing trials are exploring new strategies, such as targeting novel antigens and combining CAR-T therapy with other treatments, to improve patient outcomes in GBM.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CAR T Cells. Tudor, T., Binder, ZA., O'Rourke, DM.[2021]

In a study involving patients treated with GD2-targeting CAR T cells, 75% experienced both radiographic and clinical improvements, indicating a strong efficacy of this treatment approach.

The results suggest that GD2-targeting CAR T cell therapy could be a promising option for patients, potentially leading to significant positive outcomes in their cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

GD2-Targeting CAR T Cells Show Promise in H3K27M-Mutated Gliomas. [2022]

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 has shown great success in treating blood cancers but faces significant challenges when applied to solid tumors like brain tumors due to factors such as the immunosuppressive environment and the blood-brain barrier.

Despite these challenges, ongoing research and clinical trials are exploring the potential of CAR T therapy for brain tumors, with advancements being made to improve its efficacy in this difficult area of treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CAR T-cells to treat brain tumors. Guzman, G., Pellot, K., Reed, MR., 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]

Recent advancements in CAR T cell therapy are addressing the unique challenges posed by the central nervous system (CNS) environment, enhancing the efficacy and safety of treatment for malignant gliomas.

Innovative strategies, such as metabolic manipulation, cytokine delivery, and improved delivery techniques, are being developed to boost CAR T cell performance and specificity in targeting brain tumors, including the potential use of allogeneic T cells and natural killer (NK) cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Future development of chimeric antigen receptor T cell therapies for patients suffering from malignant glioma. Watchmaker, PB., Colton, M., Pineo-Cavanaugh, PL., et al.[2023]

Patient-derived glioblastoma cells expressing high levels of GD2 antigen can be effectively targeted by CAR T cell therapy, showing promising antitumor activity in both 2D and 3D models.

Intracerebral delivery of CAR T cells significantly improved survival times in orthotopic NOD/SCID models of glioblastoma, demonstrating a safe and effective route for treatment without side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

GD2 CAR T cells against human glioblastoma. Prapa, M., Chiavelli, C., Golinelli, G., et al.[2021]

The third-generation GD2-CAR T cells (CARTs) were found to be safe in a phase 1 study involving 11 patients with relapsed or refractory neuroblastoma, with no dose-limiting toxicities reported.

Using cyclophosphamide and fludarabine (Cy/Flu) before CART infusion significantly enhanced the expansion of CARTs, increasing their levels by up to 3 logs, although the overall antitumor responses observed at 6 weeks were modest.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CAR T Cells Administered in Combination with Lymphodepletion and PD-1 Inhibition to Patients with Neuroblastoma. Heczey, A., Louis, CU., Savoldo, B., et al.[2022]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT04099797

Study Details | NCT04099797 | C7R-GD2.CAR T Cells for ... Researchers have found from previous research that they can put a new antibody gene into T cells that will make them recognize cancer cells and kill them. GD2 ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11241811/

CAR-T Cells Therapy in Glioblastoma: A Systematic Review ... These GSCs play a crucial role in tumor recurrence and resistance due to their strong DNA repair capabilities, multi-drug resistance properties ...

3. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/38771986/

Phase I Trial of GD2.CART Cells Augmented With ... - PubMed Intravenous GD2.CARTs with and without C7R were well tolerated. Patients treated with C7R-GD2.CARTs exhibited transient improvement of ...

4. sciencedirect.com sciencedirect.com/science/article/pii/S2405803323001346

CAR T cell therapies for diffuse midline glioma Studies evaluating CAR T cells across almost all cancer types have demonstrated loss of effectiveness owing to antigen escape or treatment ...

5. academic.oup.com academic.oup.com/noa/article/7/Supplement_4/iv84/8249865

Cellular immunotherapies for central nervous system cancers Here, we review cancer cellular therapeutics for cancers of the brain and spinal cord, focusing on the preclinical and clinical studies that ...

6. ascopubs.org ascopubs.org/doi/10.1200/JCO.23.02019

Phase I Trial of GD2.CART Cells Augmented With ... We present our trial design, safety data, and clinical and tumor imaging response findings, offering insights into the feasibility and ...

7. mycancergenome.org mycancergenome.org/content/clinical_trials/NCT04099797/

Clinical Trial: NCT04099797 The purpose of this study is to find the largest safe dose of GD2-C7R T cells, and also to evaluate how long they can be detected in the blood ...

8. texaschildrens.org texaschildrens.org/departments/cancer-and-hematology-center/clinical-trials-and-novel-therapies/c7r-gd2car-t-cells-for

Cancer and Hematology Center C7R-GD2.CAR T Cells for ... In this study, the CAR T cells are enhanced with a gene called C7R, which helps them survive longer in the body and potentially fight tumors more effectively.