CAR T Cell Therapy Shows Tumour Regression and Neurological Improvement in H3K27M-mutated diffuse midline gliomas (DMGs). | The Medical Education Network

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Clinical Summary | Oncology | Neurology | Paediatrics & Neonatology

CAR T Cell Therapy Shows Tumour Regression and Neurological Improvement in H3K27M-mutated diffuse midline gliomas

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Time to listen: 14:33 minutes

Published on MedED: 17 November 2024
Originally Published: 13 November 2024
Source: Nature
Type of article: Clinical Research Summary
MedED Catalogue Reference: MPCSS0014
Category: Oncology
Cross-reference: Paediatrics & Neonatology, Neurology
Keywords: glioblastoma, neurology, CAR-T therapy, immunotherapy, genetics

Originally Published in Nature,13 November 2024, reproduced here under Creative Commons Attribution 4.0 International License. This is a summary of the clinical study and in no way represents the original research. Unless otherwise indicated, all work contained here is implicitly referenced to the original author and trial. Links to all original material can be found at the end of this summary.

Key Take Aways

1. High-grade glioma (HGG) is the most common cause of cancer death in children

2. The H3K27M mutation is responsible for up to 80% of paediatric midline gliomas, with poor survival rates and reduced therapy responses

3. This Phase 1 study demonstrated that when GD2-CART cell therapy is administered intravenously and followed by sequential ICV infusions, there were significant tumour regressions and, in some cases, sustained antitumour effects in patients with both diffuse intrinsic glioma and spinal diffuse midline gliomas.

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Study Context

High-grade glioma (HGG) is the leading cause of cancer-related death in children and the most common primary central nervous system tumour in adults.¹

However, unlike adult HGG, paediatric HGG is now known to have distinct molecular characteristics.1 A key shared mutation in both groups is the histone H3K27M mutation.²

This mutation occurs in up to 80% of paediatric diffuse midline gliomas (DMGs) and up to 60% of adult diffuse gliomas and is associated with poorer overall survival and reduced therapy response compared to H3 wild-type mutations^..¹,²

For patients with diffuse intrinsic pontine glioma (DIPG), a subtype of DMG, the prognosis is particularly bleak. The median overall survival is just 11 months, and the 5-year survival rate is less than 1%. Patients with DMGs outside the brainstem, including those in the spinal cord, have a slightly better median survival of around 13 months.¹

Understanding the distinct molecular features of H3K27M-mutated tumours is critical for developing targeted treatments for this aggressive cancer.

Despite initial optimism around targeted therapies and immuno-oncology approaches, outcomes remain poor, with standard treatments like radiotherapy providing only palliative benefits.

To explore new options, researchers at Stanford Medicine conducted a Phase 1 study investigating the potential of GD2-targeted CAR T-cell therapy (GD2-CART) for treating DMG tumours.

CAR T-cell therapy is a personalized immunotherapy that involves collecting a patient's T cells and genetically modifying them to express chimeric antigen receptors (CARs) that recognize specific antigens on cancer cells. These engineered T cells are then expanded in the lab and infused back into the patient, where they can multiply, recognize, and destroy tumour cells expressing the target antigen.³

While CAR T-cell therapies have been successful in treating certain blood cancers, their effectiveness against solid and brain tumours, including H3K27M-mutated DMGs, has been limited.

Recent research identified GD2, a disialoganglioside, as a highly and uniformly expressed antigen on H3K27M+ DMG cells.

Although gangliosides are common in normal tissues, the subtype GD2 is rarely found in healthy tissue but is overexpressed in several tumours, making it an ideal candidate for targeted cancer therapy.³

In 2018, Stanford researchers discovered that DIPG and other diffuse midline gliomas express high levels of GD2. This finding led to the development of GD2-targeting CAR T cells, previously used for other cancers. In preclinical models, these CAR T cells effectively eradicated DIPG tumours. ⁶

These promising results formed the basis for Phase 1 clinical trial (NCT04196413)⁵ evaluating the safety and efficacy of GD2-CART therapy in children with DIPG and spinal DMG (sDMG).

This study details the final clinical results following the completion of patient enrolment in arm A.

Study Purpose

According to the study filing in clinicaltrials.gov, the primary purpose of this study was 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)” ⁵

Study Design

Study Participants

Eligible trial participants were aged 2–30 years and had biopsy-confirmed H3K27M-mutated diffuse intrinsic pontine glioma (DIPG) or spinal diffuse midline glioma (SMG).

They had completed standard frontline radiotherapy at least 4 weeks before enrolment, were off corticosteroid therapy, and had a performance status score of 60 or above (Lansky or Karnofsky).

Exclusion criteria included bulky tumours in the thalamus or cerebellum due to a higher risk of GD2-CAR T cell therapy toxicity observed in these locations. Patients with clinically significant dysphagia, indicating potential medullary dysfunction, were also excluded.

The primary objective was to determine the feasibility of manufacturing, assessment of safety and tolerability and identification of a maximally tolerated and/or recommended Phase 2 dose of IV GD2-CART following lymphodepleting chemotherapy in this population.

Secondary objectives included evaluating the preliminary benefits of GD2-CAR T cell therapy based on radiographic response using MRI and improvements in neurological function, while also monitoring dose-limiting toxicities (DLTs).

Additional Objectives: Six months after the trial commenced, a protocol amendment added a new objective which was to assess the safety and clinical benefit of sequential intravenous (IV) followed by intracerebroventricular (ICV) GD2-CAR T cell administration.

Patients who demonstrated complete, partial, minor, or stable disease response on MRI or clinical improvement could receive additional IV or ICV infusions.

Eligibility for subsequent infusions required a minimum of 28 days after the initial infusion, with resolved toxicity and low circulating CAR T cell levels.

Patients received standard supportive care for seizure prophylaxis, immunosuppression associated with lymphodepleting chemotherapy, cytokine release syndrome (CRS) and immune effector cell acute neurotoxicity syndrome (ICANS).

Neurotoxicity that was distinct from ICANS and attributable to local tumour inflammation was designated tumour inflammation-associated neurotoxicity (TIAN) and graded using NCI Common Terminology Criteria for Adverse Events

Intervention

Arm A of Phase I trial administered one intravenous (IV) dose of autologous GD2-CART to patients with H3K27M-mutant pontine (DIPG) or spinal DMG (sDMG) at two dose levels: DL1, 1 × 10⁶ kg⁻¹orDL2, 3 × 10⁶ kg⁻¹ .

Patients with clinical or imaging benefits were eligible for subsequent intracerebroventricular (ICV) intracranial infusions (10–30 × 10⁶ GD2-CART).

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Findings

In this Phase 1 study, 13 patients were enrolled (median age 15 years, range 4-30), with 53.8% being female.

Ten of these patients had diffuse intrinsic pontine glioma (DIPG), and three had spinal diffuse midline glioma (SMG).

All tumours tested positive for the H3K27M mutation via immunohistochemistry or DNA sequencing.

The median time from diagnosis to enrolment was 5.0 months (range 3.9–11.6 months). At enrolment, eight patients showed disease progression or pseudo-progression on MRI, while 5 had no documented progression.

Two patients were withdrawn before receiving treatment due to rapid tumour progression and declining performance status.

Of the 11 remaining patients:

A total of 20 GD2-CART products were successfully manufactured for the study, including seven re-manufactured for multiple repeated intracerebroventricular (ICV) infusions.

The average manufacturing time was 7 days.

The median interval from enrolment to intravenous (IV) GD2-CART infusion was 22.9 days (range 15–38 days). One patient's product was not characterized because the patient experienced rapid tumor progression and died before receiving the CAR T-cell infusion.

Of the 11 patients who received an initial intravenous (IV) GD2-CART infusion, 9 showed clinical or imaging benefits on MRI, or both.

These patients subsequently received additional intracerebroventricular (ICV) infusions over a period ranging from 1.0 to 29.4 months at the time of data cut-off.

All patients experienced Cytokine Release Sydrome(CRS):

One of three patients on Dose Level 1 Protocol (DL1) experienced grade 2 CRS

Six of eight patients on Dose Level 2 Protocol (DL2) experienced a grade 2 or higher CRS, and three patients on DL2 experienced Dose Limiting Toxicities attributed to grade 4 CRS

Immune effector cell acute neurotoxicity syndrome (ICANS) developed in one of three patients at DL1 (grade 2) and in four of eight patients at DL2.

These patients subsequently received additional intracerebroventricular (ICV) infusions over a period ranging from 1.0 to 29.4 months at the time of data cut-off.

Among 62 ICV infusions, no DLTs occurred

Forty-one ICV infusions (66%) were associated with no CRS.

Among 19 ICV infusions associated with CRS, most were low-grade

No ICANS was observed following ICV infusions

Tumour Inflammation Associated Neuropathy (TIAN) was observed in 91% of patients following IV infusion and in 100% of patients following the first ICV infusion.

The TIAN grade typically diminished with subsequent infusions and reversed in all patients following treatment.

No patients experienced a DLT due to TIAN.

In one patient with sDMG, high-grade communicating hydrocephalus was observed during peak tumour inflammation

Tumour Reduction

Four patients had their tumours decrease by at least 50% (52%, 54%, 91%, 100%).

Three others had smaller tumour reductions

One patient demonstrated a continuing reduction in tumour volume to the point of complete response within months following the first GD2-CAR T cell infusion.

One of the patients with sDMG, who was in clear clinical and radiographic tumour progression at the time of first treatment, demonstrated a 91% reduction in tumour volume by 7 months following the first GD2-CAR T cell infusion

In general, clinical improvement coincided with tumour response on MRI

Survival Rate

Median overall survival for patients treated on arm A was 20.6 months from diagnosis, with two patients with DIPG alive at 30 and 33 months, respectively.

One patient remains alive 4 years after his diagnosis.

Conclusion

Based on their findings, the researchers concluded that the study demonstrated the tolerability of 1 × 106 GD2-CART cells per kg administered intravenously (DL1) followed by sequential ICV infusions, tumour regressions and, in some cases, sustained antitumour effects in patients with DIPG and sDMG.

According to the trial’s lead author Michelle Monje, MD, PhD, the Milan Gambhir Professor in Paediatric Neuro-Oncology and professor of neurology at Stanford Medicine. “This is a universally lethal disease for which we’ve found a therapy that can cause meaningful tumour regressions and clinical improvements. While there is still a long way to go to figure out how to optimize this for every patient, it’s very exciting that one patient had a complete response. I’m hopeful he has been cured.” ⁶

The FDA granted this approach regenerative medicine advanced therapy designation in October. Researchers continue to enrol patients in the trial and are investigating whether ICV alone is effective.

This study was registered with Clinicaltrials.gov NCT04196413

Access the original research

Monje, M., Mahdi, J., Majzner, R., Yeom, K. W., Schultz, L. M., Richards, R. M., Barsan, V., Song, K., Kamens, J., Baggott, C., Kunicki, M., Rietberg, S. P., Lim, A. S., Reschke, A., Mavroukakis, S., Egeler, E., Moon, J., Patel, S., Chinnasamy, H., . . . Mackall, C. (2024). Intravenous and intracranial GD2-CAR T cells for H3K27M+ diffuse midline gliomas. Nature, 1-8. https://doi.org/10.1038/s41586-024-08171-9

Ethical Disclaimer

M.M., R.M., and C. Mackall are co-inventors on a patent for GD2-CAR T-cell use in H3K27M gliomas, managed through Stanford University. C. Mackall also holds patents for modulating CAR function with dasatinib and other molecules, and for various CAR T-cell therapies. She is involved with Link Cell Therapies and GBM Newco, which are developing CAR-based therapies, and consults for several biotech companies, receiving research funding from Lyell and Tune Therapeutics. R.M. co-founded Link Cell Therapies and CARGO Therapeutics, holds equity, and consults for multiple companies, including Lyell Immunopharma and NKarta. S.A.F. has several patents in cellular immunotherapy, while V.B. is an investor and Director at Umoja Biopharma and Arsenal Bio. S.P.R. holds equity in Lyell Immunopharma, and M.M. holds equity in MapLight Therapeutics and CARGO Therapeutics. The other authors report no competing interests.

References

1 .Saratsis AM, Knowles T, Petrovic A, Nazarian J. H3K27M mutant glioma: Disease definition and biological underpinnings. Neuro Oncol. 2024 May 3;26(Supplement_2):S92-S100. doi: 10.1093/neuonc/noad164. PMID: 37818718; PMCID: PMC11066930. https://pmc.ncbi.nlm.nih.gov/articles/PMC11066930

2. Monje, M., Mahdi, J., Majzner, R., Yeom, K. W., Schultz, L. M., Richards, R. M., Barsan, V., Song, K., Kamens, J., Baggott, C., Kunicki, M., Rietberg, S. P., Lim, A. S., Reschke, A., Mavroukakis, S., Egeler, E., Moon, J., Patel, S., Chinnasamy, H., . . . Mackall, C. (2024). Intravenous and intracranial GD2-CAR T cells for H3K27M+ diffuse midline gliomas. Nature, 1-8. https://doi.org/10.1038/s41586-024-08171-9

3. National Cancer Institute. (n.d.). CAR T cells: Engineering patients' immune cells to treat their cancers. National Institutes of Health. Retrieved November 17, 2024, from https://www.cancer.gov/about-cancer/treatment/research/car-t-cells

4. Nazha B, Inal C, Owonikoko TK. Disialoganglioside GD2 Expression in Solid Tumours and Role as a Target for Cancer Therapy. Front Oncol. 2020 Jul 7;10:1000. doi: 10.3389/fonc.2020.01000. PMID: 32733795; PMCID: PMC7358363.

5.ClinicalTrials.gov GD2 CAR T Cells in Diffuse Intrinsic Pontine Gliomas(DIPG) & Spinal Diffuse Midline Glioma(DMG). NCT04196413. Retrieved 17 November 2004 https://clinicaltrials.gov/study/NCT04196413

6. Stanford Medicine. (2024, November). CAR-T cell therapy shows promise against deadly childhood brain cancer. Stanford Medicine News. https://med.stanford.edu/news/all-news/2024/11/car-t-brain-cancer.html

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