Chimeric antigen receptor (CAR) T cell therapy has emerged as one of the most transformative advances in cancer immunotherapy over the past decade. By engineering a patient’s own T cells to express synthetic receptors targeting specific tumour-associated antigens, clinicians have achieved remarkable remissions in a variety of relapsed and refractory hematological malignancies, including certain leukemias and lymphomas. These successes have fueled immense excitement and optimism about extending the promise of CAR T cell therapy to solid tumours, which represent the vast majority of cancer cases. However, solid tumours present a unique set of obstacles that have so far limited the efficacy of CAR T cells, including issues with tumour heterogeneity, the immunosuppressive tumour microenvironment (TME), and poor trafficking and infiltration of engineered T cells into the tumour mass.
Among the solid tumours, central nervous system (CNS) malignancies present even greater challenges. CNS tumours are often associated with devastating prognoses and lack of effective therapies, particularly in paediatric populations. The presence of the blood–brain barrier (BBB) restricts the infiltration of therapeutic agents and immune cells into the CNS. Moreover, concerns over potential neurotoxicity raise complex questions about dosing and safety. Yet despite these formidable hurdles, a growing body of preclinical and clinical research suggests that CAR T cell therapy can provide meaningful clinical benefit for some patients with CNS tumours.
Recent clinical trials, conducted in both adult and paediatric cohorts with primary CNS malignancies such as glioblastoma multiforme (GBM) and diffuse intrinsic pontine glioma (DIPG), have demonstrated promising signals of efficacy. These trials have employed unique strategies to enhance CAR T cell delivery, persistence, and activity within the CNS microenvironment. For example, local delivery approaches including intraventricular or intracavitary administration circumvent the BBB and facilitate direct exposure of CAR T cells to tumour cells. These trials have highlighted not only therapeutic potential but also key safety considerations, underscoring the importance of balancing efficacy and minimizing neurotoxic side effects.
One fundamental obstacle to CAR T cell success in CNS tumours is their limited persistence and expansion following infusion. Unlike hematologic cancers that circulate in lymphatic tissues or blood, CNS tumours tend to be highly immunosuppressive, secreting cytokines such as transforming growth factor-beta (TGF-β) and promoting regulatory T cell subsets that dampen immune activity. Additionally, the dense extracellular matrix and abnormal vasculature within CNS tumours create physical barriers to T cell infiltration. Engineering strategies to enhance CAR T cell durability—including the incorporation of co-stimulatory domains that optimize T cell activation and survival—are therefore critical areas of ongoing research.
The immunosuppressive TME in CNS malignancies not only constrains CAR T cell function but also creates avenues for immune escape. Tumour cells can downregulate or alter antigen expression, effectively evading CAR recognition. Researchers are exploring multi-specific CAR constructs capable of targeting multiple antigens simultaneously to counteract antigen heterogeneity and loss. Furthermore, combining CAR T cells with checkpoint blockade therapies or agents that modulate the microenvironment holds promise to restore and sustain potent antitumour responses.
Another transformative area involves the modulation of CAR T cell trafficking to ensure robust homing to CNS tumours. Preclinical models demonstrate that the chemokine milieu within CNS tumours can be manipulated to attract CAR T cells expressing corresponding chemokine receptors. This approach may be further enhanced by transient modulation or disruption of the BBB to facilitate systemic administration. Investigations into nanotechnology and biomaterial scaffolds aim to provide controlled local delivery of CAR T cells while reducing systemic exposure and toxicity.
Neurotoxicity remains a significant clinical concern when deploying immune therapies in the CNS. Conditions such as neuroinflammation, edema, and cytokine release syndrome (CRS) can have catastrophic consequences. Emerging clinical data emphasize the importance of vigilant monitoring protocols and the development of “off-switch” mechanisms—such as suicide genes or pharmacologically controllable CAR constructs—that allow rapid abrogation of CAR T cell activity in the event of adverse effects.
Despite challenges, early-phase trials in pediatric and adult patients offer encouraging evidence. Target antigens like EGFR variant III (EGFRvIII), IL13 receptor alpha 2 (IL13Rα2), and HER2 have been leveraged in CAR designs, each with varying degrees of success in reducing tumour burden and prolonging survival. A handful of patients have achieved durable responses, exemplifying the potential of this modality to change the natural history of otherwise fatal CNS cancers.
The clinical application of CAR T cells in CNS malignancies also motivates exciting advancements in manufacturing processes. Autologous CAR T cell production requires time and resources, frequently delaying treatment initiation. Novel approaches to accelerate manufacturing, or to develop allogeneic “off-the-shelf” CAR T cells, could broaden access and reduce costs, an imperative for patients with rapidly progressing CNS disease.
An equally important direction lies in the integration of CAR T therapy within multimodal treatment regimens. Combining CAR T cells with radiation, chemotherapy, or targeted agents may synergize immune activation while debulking tumours and modulating the tumour microenvironment. Investigating optimal sequencing and combinations remains a priority to maximize therapeutic index and patient outcomes.
Looking to the future, ongoing and anticipated clinical trials are expanding the scope of CAR T cell therapy for CNS tumours. These include studies with next-generation CAR designs incorporating novel co-stimulatory molecules, synthetic biology approaches for enhanced target specificity, and gene-editing techniques to render CAR T cells resistant to immunosuppressive signals. The dynamic interplay between technological innovation and clinical need is driving a new era of personalized immunotherapy in neuro-oncology.
Ultimately, the development of CAR T cells for CNS malignancies epitomizes the complexity and promise of immunotherapy in solid tumours. The road ahead demands multidisciplinary collaboration across immunology, neurology, oncology, and bioengineering. Each incremental advancement not only deepens fundamental understanding but also offers hope for patients facing some of the most aggressive and lethal cancers.
As the field continues to evolve, transparency in reporting clinical outcomes, adverse events, and mechanistic insights will be paramount. Harnessing big data analytics, artificial intelligence, and integrative biomarker discovery can enable predictive models for patient selection and response monitoring. These tools will be crucial in realizing the full potential of CAR T cells to become transformative therapies extending beyond hematological malignancies to address the unmet needs in CNS cancer.
In conclusion, while substantial obstacles remain, the momentum generated by preclinical innovation and early clinical success supports a cautiously optimistic outlook for CAR T cell therapy in CNS tumours. Sustained investment in research, coupled with thoughtful trial design and patient-centered care, will dictate the pace at which this groundbreaking modality reshapes the therapeutic landscape for one of oncology’s most intractable challenges.
Subject of Research: Development and clinical application of chimeric antigen receptor (CAR) T cell therapy for central nervous system (CNS) malignancies.
Article Title: The development of CAR T cells for patients with CNS malignancies.
Article References:
Binder, Z.A., Bagley, S.J., Foster, J.B. et al. The development of CAR T cells for patients with CNS malignancies. Nat Rev Clin Oncol (2025). https://doi.org/10.1038/s41571-025-01102-1
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