GD2 CAR T Cells for Brain and Spinal Cord Gliomas
Recruiting in Palo Alto (17 mi)
Overseen byMichelle 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.
12345Is 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.
14678How 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.
13456Eligibility 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.
+5 more
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.
+9 more
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
Participant Groups
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.
1Treatment groups
Experimental Treatment
Group I: GD2-CAR TExperimental Treatment3 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%)
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Lucile Packard Children's Hospital (LPCH)Stanford, CA
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Who Is Running the Clinical Trial?
Crystal Mackall, MDLead Sponsor
California Institute for Regenerative Medicine (CIRM)Collaborator
National Institutes of Health (NIH)Collaborator
CureSearchCollaborator
References
Potent antitumor efficacy of anti-GD2 CAR T cells in H3-K27M+ diffuse midline gliomas. [2022]Diffuse intrinsic pontine glioma (DIPG) and other diffuse midline gliomas (DMGs) with mutated histone H3 K27M (H3-K27M)1-5 are aggressive and universally fatal pediatric brain cancers 6 . Chimeric antigen receptor (CAR)-expressing T cells have mediated impressive clinical activity in B cell malignancies7-10, and recent results suggest benefit in central nervous system malignancies11-13. Here, we report that patient-derived H3-K27M-mutant glioma cell cultures exhibit uniform, high expression of the disialoganglioside GD2. Anti-GD2 CAR T cells incorporating a 4-1BBz costimulatory domain 14 demonstrated robust antigen-dependent cytokine generation and killing of DMG cells in vitro. In five independent patient-derived H3-K27M+ DMG orthotopic xenograft models, systemic administration of GD2-targeted CAR T cells cleared engrafted tumors except for a small number of residual GD2lo glioma cells. To date, GD2-targeted CAR T cells have been well tolerated in clinical trials15-17. Although GD2-targeted CAR T cell administration was tolerated in the majority of mice bearing orthotopic xenografts, peritumoral neuroinflammation during the acute phase of antitumor activity resulted in hydrocephalus that was lethal in a fraction of animals. Given the precarious neuroanatomical location of midline gliomas, careful monitoring and aggressive neurointensive care management will be required for human translation. With a cautious multidisciplinary clinical approach, GD2-targeted CAR T cell therapy for H3-K27M+ diffuse gliomas of pons, thalamus and spinal cord could prove transformative for these lethal childhood cancers.
CAR T-cell therapy for glioblastoma: ready for the next round of clinical testing? [2019]The outcome for patients with glioblastoma (GBM) remains poor, and there is an urgent need to develop novel therapeutic approaches. T cells genetically modified with chimeric antigen receptors (CARs) hold the promise to improve outcomes since they recognize and kill cells through different mechanisms than conventional therapeutics. Areas covered: This article reviews CAR design, tumor associated antigens expressed by GBMs that can be targeted with CAR T cells, preclinical and clinical studies conducted with CAR T cells, and genetic approaches to enhance their effector function. Expert commentary: While preclinical studies have highlighted the potent anti-GBM activity of CAR T cells, the initial foray of CAR T-cell therapies into the clinic resulted only in limited benefits for GBM patients. Additional genetic modification of CAR T cells has resulted in a significant increase in their anti-GBM activity in preclinical models. We are optimistic that clinical testing of these enhanced CAR T cells will be safe and result in improved anti-glioma activity in GBM patients.
GD2 CAR T cells against human glioblastoma. [2021]Glioblastoma is the most malignant primary brain tumor and is still in need of effective medical treatment. We isolated patient-derived glioblastoma cells showing high GD2 antigen expression representing a potential target for CAR T strategy. Data highlighted a robust GD2 CAR antitumor potential in 2D and 3D glioblastoma models associated with a significant and CAR T-restricted increase of selected cytokines. Interestingly, immunosuppressant TGF β1, expressed in all co-cultures, did not influence antitumor activity. The orthotopic NOD/SCID models using primary glioblastoma cells reproduced human histopathological features. Considering still-conflicting data on the delivery route for targeting brain tumors, we compared intracerebral versus intravenous CAR T injections. We report that the intracerebral route significantly increased the length of survival time in a dose-dependent manner, without any side effects. Collectively, the proposed anti-GD2 CAR can counteract human glioblastoma potentially opening a new therapeutic option for a still incurable cancer.
GD2-Targeting CAR T Cells Show Promise in H3K27M-Mutated Gliomas. [2022]Three out of four patients treated with GD2-targeting CAR T cells showed radiographic and clinical improvement.
GD2-CAR T cell therapy for H3K27M-mutated diffuse midline gliomas. [2023]Diffuse intrinsic pontine glioma (DIPG) and other H3K27M-mutated diffuse midline gliomas (DMGs) are universally lethal paediatric tumours of the central nervous system1. We have previously shown that the disialoganglioside GD2 is highly expressed on H3K27M-mutated glioma cells and have demonstrated promising preclinical efficacy of GD2-directed chimeric antigen receptor (CAR) T cells2, providing the rationale for a first-in-human phase I clinical trial (NCT04196413). Because CAR T cell-induced brainstem inflammation can result in obstructive hydrocephalus, increased intracranial pressure and dangerous tissue shifts, neurocritical care precautions were incorporated. Here we present the clinical experience from the first four patients with H3K27M-mutated DIPG or spinal cord DMG treated with GD2-CAR T cells at dose level 1 (1 × 106 GD2-CAR T cells per kg administered intravenously). Patients who exhibited clinical benefit were eligible for subsequent GD2-CAR T cell infusions administered intracerebroventricularly3. Toxicity was largely related to the location of the tumour and was reversible with intensive supportive care. On-target, off-tumour toxicity was not observed. Three of four patients exhibited clinical and radiographic improvement. Pro-inflammatory cytokine levels were increased in the plasma and cerebrospinal fluid. Transcriptomic analyses of 65,598 single cells from CAR T cell products and cerebrospinal fluid elucidate heterogeneity in response between participants and administration routes. These early results underscore the promise of this therapeutic approach for patients with H3K27M-mutated DIPG or spinal cord DMG.
Safety and antitumor activity of GD2-Specific 4SCAR-T cells in patients with glioblastoma. [2023]This study aimed to validate whether infusion of GD2-specific fourth-generation safety-designed chimeric antigen receptor (4SCAR)-T cells is safe and whether CAR-T cells exert anti-glioblastoma (GBM) activity.
Preclinical assessment of the efficacy and specificity of GD2-B7H3 SynNotch CAR-T in metastatic neuroblastoma. [2021]The ability to utilize preclinical models to predict the clinical toxicity of chimeric antigen receptor (CAR) T cells in solid tumors is tenuous, thereby necessitating the development and evaluation of gated systems. Here we found that murine GD2 CAR-T cells, specific for the tumor-associated antigen GD2, induce fatal neurotoxicity in a costimulatory domain-dependent manner. Meanwhile, human B7H3 CAR-T cells exhibit efficacy in preclinical models of neuroblastoma. Seeking a better CAR, we generated a SynNotch gated CAR-T, GD2-B7H3, recognizing GD2 as the gate and B7H3 as the target. GD2-B7H3 CAR-T cells control the growth of neuroblastoma in vitro and in metastatic xenograft mouse models, with high specificity and efficacy. These improvements come partly from the better metabolic fitness of GD2-B7H3 CAR-T cells, as evidenced by their naïve T-like post-cytotoxicity oxidative metabolism and lower exhaustion profile.
High-Affinity GD2-Specific CAR T Cells Induce Fatal Encephalitis in a Preclinical Neuroblastoma Model. [2021]The GD2 ganglioside, which is abundant on the surface of neuroblastoma cells, is targeted by an FDA-approved therapeutic monoclonal antibody and is an attractive tumor-associated antigen for cellular immunotherapy. Chimeric antigen receptor (CAR)-modified T cells can have potent antitumor activity in B-cell malignancies, and trials to harness this cytolytic activity toward GD2 in neuroblastoma are under way. In an effort to enhance the antitumor activity of CAR T cells that target GD2, we generated variant CAR constructs predicted to improve the stability and the affinity of the GD2-binding, 14G2a-based, single-chain variable fragment (scFv) of the CAR and compared their properties in vivo We included the E101K mutation of GD2 scFv (GD2-E101K) that has enhanced antitumor activity against a GD2+ human neuroblastoma xenograft in vivo However, this enhanced antitumor efficacy in vivo was concomitantly associated with lethal central nervous system (CNS) toxicity comprised of extensive CAR T-cell infiltration and proliferation within the brain and neuronal destruction. The encephalitis was localized to the cerebellum and basal regions of the brain that display low amounts of GD2. Our results highlight the challenges associated with target antigens that exhibit shared expression on critical normal tissues. Despite the success of GD2-specific antibody therapies in the treatment of neuroblastoma, the fatal neurotoxicity of GD2-specific CAR T-cell therapy observed in our studies suggests that GD2 may be a difficult target antigen for CAR T-cell therapy without additional strategies that can control CAR T-cell function within the CNS. Cancer Immunol Res; 6(1); 36-46. ©2017 AACR.