GD2 CAR T Cells for Brain and Spinal Cord Gliomas

Recruiting in Palo Alto (17 mi)

Overseen by Michelle Monje

Age: < 65

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Recruiting

Sponsor: Crystal Mackall, MD

Must not be taking: Corticosteroids, Alternative therapies

Disqualifiers: Bulky tumor, Swallowing dysfunction, Infections, others

No Placebo Group

Trial Summary

What is the purpose of this trial?

The primary purpose of this study is to test whether GD2-CAR T cells can be successfully made from immune cells collected from children and young adults with H3K27M-mutant diffuse intrinsic pontine glioma (DIPG) or spinal H3K27M-mutant diffuse midline glioma (DMG). H3K27Mmutant testing will occur as part of standard of care prior to enrollment.

Will I have to stop taking my current medications?

The trial does not specify if you must stop taking your current medications, but ongoing use of dietary supplements, alternative therapies, extreme diets, or any medication not approved by the investigators is not allowed. It's best to discuss your current medications with the trial team.

What data supports the effectiveness of the GD2 CAR T cell treatment for brain and spinal cord gliomas?

Research shows that GD2 CAR T cells have shown promise in treating aggressive brain cancers like H3K27M-mutated gliomas, with three out of four patients experiencing clinical and radiographic improvement. Additionally, preclinical studies demonstrated that GD2 CAR T cells effectively targeted and killed glioma cells, suggesting potential benefits for patients with these types of tumors. ^{1 2 3 4 5}

Is GD2 CAR T cell therapy safe for humans?

GD2 CAR T cell therapy has been generally well tolerated in clinical trials, but there have been instances of serious side effects like neuroinflammation and fatal neurotoxicity in preclinical models. Careful monitoring and management are necessary to ensure safety in humans. ^{1 4 6 7 8}

How is the GD2 CAR T cell treatment different from other treatments for brain and spinal cord gliomas?

GD2 CAR T cell treatment is unique because it uses specially modified immune cells (CAR T cells) to target and attack cancer cells that express a specific marker called GD2, which is highly present in certain aggressive brain tumors. This approach is different from traditional treatments as it involves either intravenous or direct brain injections, and it has shown promise in improving survival without significant side effects in early studies. ^{1 3 4 5 6}

Research Team

Michelle Monje

Principal Investigator

Stanford University

Eligibility Criteria

This trial is for children and young adults aged 2 to 50 with H3K27M-mutant brainstem glioma (DIPG) or spinal cord glioma (DMG), post-radiation therapy, and without recent systemic treatments. US residents who can consent, practice birth control, have a negative pregnancy test if applicable, and have normal organ/marrow function are eligible. Exclusions include uncontrolled infections, certain tumor locations, ongoing corticosteroid use, significant medical conditions that could affect the study's outcome.

Inclusion Criteria

Pregnancy Test: Females of childbearing potential must have a negative serum or urine pregnancy test, Contraception: Subjects of child bearing or child fathering potential must be willing to practice birth control from the time of enrollment on this study and for four (4) months after receiving the preparative lymphodepletion regimen or for as long as GD2-CAR T cells are detectable in peripheral blood or cerebrospinal fluid (CSF)

My cancer is a specific type that affects the brainstem or spinal cord and has a certain genetic mutation.

I can understand and agree to participate, or if under 18, I can verbally agree if over 7 years old.

Exclusion Criteria

I have received GD2-antibody therapy before.

I have HIV or hepatitis B/C, or a history of hepatitis with no detectable viral load.

You have a significant problem swallowing or other issues with the nerves in your brainstem.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive GD2-CAR T cells after lymphodepletion chemotherapy with cyclophosphamide and fludarabine, followed by dose escalation of GD2-CAR T cells

4 weeks

Multiple visits for chemotherapy and T cell infusion

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessment of dose limiting toxicities and radiographic response

24 months

Regular visits at Day 28, 3 months, 6 months, 9 months, 12 months, and 24 months post-infusion

Long-term Follow-up

Participants are monitored for overall survival and progression-free survival

24 months

Treatment Details

Interventions

• Cyclophosphamide (Alkylating agents)
• Fludarabine (Anti-metabolites)
• GD2 CAR T cells (CAR T-cell Therapy)

Trial Overview The trial tests GD2-CAR T cells made from patients' immune cells against DIPG/DMG tumors in the brainstem or spinal cord. It checks if these CAR T cells can be created successfully and includes preparatory chemotherapy with Fludarabine and Cyclophosphamide before introducing the GD2-CAR T cells.

Participant Groups

Group I: GD2-CAR T Experimental Treatment 3 Interventions

Rolling-6 dose escalation design will test GD2-CAR T cells in subjects with H3K27M-mutant DIPG. GD2CART will be administered in escalating doses on Day 0 in hospitalized subjects with either DIPG or spinal DMG Intravenously * Dose Level -1: 3x10\^5 transduced T cells/kg(± 20%) * Dose Level 1: 1x10\^6 transduced T cells/kg (± 20%) * Dose Level 2: 3x10\^6 transduced T cells/kg (± 20%) Intracerebroventricularly, without conditioning lymphodepletion chemotherapy * Dose Level -1: 10x10\^6 transduced T cells (±20%) * Dose Level 1: 30x10\^6 transduced T cells (±20%) * Dose Level 2: 50x10\^6 transduced T cells (±20%) * Dose Level 3: 100x10\^6 transduced T cells (±20%) Intracerebroventricularly after administration of conditioning lymphodepletion chemotherapy regimen with cyclophosphamide and fludarabine * Dose Level -1: 10x10\^6 transduced T cells (±20%) * Dose Level 1: 30x10\^6 transduced T cells (±20%) * Dose Level 2: 50x10\^6 transduced T cells (±20%)

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

National Institutes of Health (NIH)

Collaborator

Trials

2,896

Recruited

8,053,000+

Dr. Jeanne Marrazzo

National Institutes of Health (NIH)

Chief Medical Officer

MD from University of California, Los Angeles

Dr. Jay Bhattacharya

National Institutes of Health (NIH)

Chief Executive Officer

MD, PhD from Stanford University

CureSearch

Collaborator

Trials

3

Recruited

130+

Findings from Research

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]

Chimeric antigen receptor (CAR) T cells show promise in treating glioblastoma (GBM) by targeting tumor-associated antigens, offering a different mechanism of action compared to traditional therapies.

While initial clinical trials of CAR T-cell therapies for GBM showed limited benefits, further genetic modifications have significantly enhanced their anti-tumor activity in preclinical models, suggesting potential for improved outcomes in future clinical testing.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CAR T-cell therapy for glioblastoma: ready for the next round of clinical testing? Prinzing, BL., Gottschalk, SM., Krenciute, G.[2019]

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]

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]

In a first-in-human phase I trial involving four patients with H3K27M-mutated DIPG or spinal cord DMG, GD2-directed CAR T cells showed promising clinical and radiographic improvements in three out of four patients, indicating potential efficacy of this treatment.

The treatment was associated with manageable toxicity primarily related to the tumor's location, and no on-target, off-tumor toxicity was observed, suggesting a favorable safety profile for GD2-CAR T cell therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

GD2-CAR T cell therapy for H3K27M-mutated diffuse midline gliomas. Majzner, RG., Ramakrishna, S., Yeom, KW., et al.[2023]

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]

CAR T cells targeting the GD2 ganglioside show promising antitumor activity against neuroblastoma, but modifications to enhance their efficacy can lead to severe central nervous system (CNS) toxicity, including neuronal destruction.

The observed CNS toxicity highlights the risks of targeting antigens like GD2 that are also present in critical normal tissues, indicating a need for strategies to manage CAR T-cell activity in the brain to ensure patient safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

High-Affinity GD2-Specific CAR T Cells Induce Fatal Encephalitis in a Preclinical Neuroblastoma Model. Richman, SA., Nunez-Cruz, S., Moghimi, B., et al.[2021]

References

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

Potent antitumor efficacy of anti-GD2 CAR T cells in H3-K27M+ diffuse midline gliomas. [2022]

2. England pubmed.ncbi.nlm.nih.gov

CAR T-cell therapy for glioblastoma: ready for the next round of clinical testing? [2019]

3. England pubmed.ncbi.nlm.nih.gov

GD2 CAR T cells against human glioblastoma. [2021]

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

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

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

GD2-CAR T cell therapy for H3K27M-mutated diffuse midline gliomas. [2023]

6. England pubmed.ncbi.nlm.nih.gov

Safety and antitumor activity of GD2-Specific 4SCAR-T cells in patients with glioblastoma. [2023]

7. England pubmed.ncbi.nlm.nih.gov

Preclinical assessment of the efficacy and specificity of GD2-B7H3 SynNotch CAR-T in metastatic neuroblastoma. [2021]

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

High-Affinity GD2-Specific CAR T Cells Induce Fatal Encephalitis in a Preclinical Neuroblastoma Model. [2021]