Part 27 of our Bridging the Gap Series (Summary of the webinar session held in February 2026)
CAR-T therapy has already demonstrated what’s possible in certain blood cancers. However, solid tumors are proving much harder to treat.
This challenge was the focus of Azenta’s recent Bridging the Gap webinar. Moderated by Olga Bukatova, Associate Director of Business Development for CGT at Azenta Life Sciences, the panel brought together Professor Denis Migliorini, Head of the Neuro-Oncology Unit at Geneva University Hospital and Associate Professor at the University of Geneva; Albert Ribickas, Assistant Director of the Cell Therapy Facility at Moffitt Cancer Center; George Eastwood, Executive Director of the Emily Whitehead Foundation; and Tom Whitehead, Co-founder of the Emily Whitehead Foundation.
The discussion explored what makes solid tumors different, why glioblastoma remains difficult to treat, and how researchers are adapting their approaches.
Why Solid Tumors Are Harder to Treat
Unlike blood cancers, solid tumors create biological conditions that work against CAR-T cells. In glioblastoma, those issues become even more pronounced:
- The blood–brain barrier restricts immune cell access to the central nervous system.
- Tumor heterogeneity results in clusters of tumor cells expressing different markers, reducing the effectiveness of single-target approaches.
- A highly immunosuppressive microenvironment, where macrophages can represent 40–50% of the tumor mass.
- Diffuse invasion into surrounding brain tissue makes complete eradication difficult.
Another critical issue is distribution. Glioblastoma is a highly diffuse disease, and imaging often captures only a portion of the tumor burden.
As Professor Migliorini noted, clinicians may be seeing “only the tip of the iceberg,” with tumor cells extending far beyond what appears on MRI scans. Ensuring CAR-T cells reach these dispersed cells is therefore as important as designing the cells themselves.
Antigen Escape and and the Move Toward Multi-Target CAR-T
Antigen escape was a recurring theme during the discussion. In glioblastoma, targeting a single antigen can produce a partial response, but is often followed by recurrence as tumor cells adapt.
To address this, Professor Migliorini’s team is developing CAR-T cells designed to recognize four tumor-associated antigens simultaneously. The strategy is based on profiling data from newly diagnosed and recurrent tumors to reduce escape by covering multiple tumor populations.
Other approaches mentioned included:
- Intracerebroventricular delivery via the Ommaya reservoir to improve biodistribution
- Ultrasound-mediated blood–brain barrier opening
- Engineering CAR-T cells to resist immunosuppressive signals
- Combination strategies, including dendritic cell progenitors engineered to secrete IL-12
Early results suggest signs of activity, but making those responses last remains a challenge. Many researchers now believe that CAR-T therapy alone may not be sufficient for complex solid tumors. Combination approaches – pairing engineered T cells with immune-activating cells, vaccines, or other immunotherapies – are increasingly being explored to strengthen anti-tumor responses.
From Initial Activity to Durable Responses
CAR-T cells can generate responses in glioblastoma and other brain tumors, but maintaining those responses has been difficult.
In many patients, CAR-T cells are no longer detectable in cerebrospinal fluid after roughly 28 to 30 days. Planned Phase I studies will include repeat dosing to maintain immune pressure and better understand how persistence might be improved.
Encouragingly, early studies suggest CAR-T cells can produce measurable biological activity in brain tumors. The challenge is not whether they work at all, but whether that activity can be sustained long enough to control disease.
While repeat dosing adds logistical complexity, it also reflects how cancer treatment often works in practice. Sustained control typically requires multiple interventions rather than a single infusion. Longer-term efforts are focused on improving persistence through vector engineering and metabolic optimization.
Scaling these therapies will also require advances in manufacturing. As Professor Migliorini noted, reducing production costs and shortening the “vein-to-brain” interval could make repeat dosing strategies far more feasible in the future.
Connecting the Pieces: Bridging Lab and Clinic
Another theme that surfaced was coordination. Professor Migliorini described the physician-scientist as the bridge between surgery, tumor sample collection, manufacturing, laboratory testing, and clinical care. Timing across these steps can directly influence outcomes, from tumor retrieval in the operating room to manufacturing schedules and treatment delivery.
Cell and gene therapy development requires tight coordination across disciplines rather than isolated efforts. In practice, this coordination can involve everything from arranging tumor sample collection during neurosurgery to aligning manufacturing timelines and laboratory testing so that experiments and clinical insights inform one another in real time.
Monitoring Neurotoxicity in Brain Tumor CAR-T
Durability is only part of the challenge. The panelists also addressed neurotoxicity, including Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) and tumor inflammation-associated neurotoxicity (TIAN).
In brain tumor patients, some inflammatory response may signal CAR-T activity. The challenge is recognizing when inflammation becomes harmful and intervening early. Safety planning is built directly into trial design, particularly given the sensitivity of brain tissue. Binder selection, antigen specificity, and inflammatory monitoring are being refined to reduce off-target effects and edema.
The Reality for Patients
For patients with glioblastoma, median overall survival remains approximately 15 months. Researchers frequently hear from patients and families asking when new trials will open.
That urgency shapes how investigators think about progress. Advances may be incremental, but each study adds critical insight into how these therapies behave in the brain.
Professor Migliorini noted that patients and families frequently reach out asking when new trials will open – an urgency that underscores both the promise of these therapies and the pressure researchers feel to move carefully but quickly.
Key Takeaways
- Solid tumors present biological and anatomical barriers not seen in hematologic malignancies.
- Glioblastoma requires multi-antigen targeting strategies to address tumor heterogeneity.
- CAR-T persistence in the brain remains a challenge, with repeat dosing currently under investigation.
- Neurotoxicity management requires careful cytokine monitoring and rapid intervention.
- Physician-scientists play a role in coordinating laboratory, manufacturing, and clinical efforts.
- Collaboration across research, clinical care, and advocacy is essential to expanding access.
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About the Guest
Prof. Denis Migliorini
Head, Neuro Oncology Unit, HUG Assistant Professor, Department of Oncology, UNIGE
Professor Denis Migliorini completed his MD studies and internal medicine post graduate training at the Universities of Toulouse and Strasbourg. He then moved to the University Hospitals of Geneva (HUG) where he completed his postgraduate training in medical oncology under the mentorship of Professor Pierre-Yves Dietrich. From 2015 to 2016, he successfully completed his clinical fellowship in neuro-oncology. He holds a DAS in clinical trial management from the University of Geneva (UNIGE) and became principal investigator of several early phase trials testing various anti-tumor immunotherapy approaches, including peptide vaccines for the treatment of glioblastoma.
From 2017 to 2019, he performed a post-doctoral fellowship at the Center for Cellular Immunotherapies, University of Pennsylvania, in the laboratories of Professor Carl June and Professor Avery D. Posey. He trained in synthetic biology and T cell engineering, disciplines that enabled the development of CAR-T cell technology. In 2019, he was awarded the Swiss Bridge Foundation Prize in recognition of his work identifying neurotoxicity mechanisms of engineered cell therapies. Returning to Switzerland in 2020, he was appointed assistant professor at the Department of Medicine of the Faculty of Medicine of the UNIGE, and holds the ISREC Chair in Brain Tumour Immunology. At the HUG, he is an attending physician, head of the Neuro-Oncology Unit and clinical coordinator of the brain tumor biobank. Professor Migliorini is a member of the CRTOH steering committee.