Concomitant Administration of EGFRvIII-Targeted CAR T-Cell Therapy and Pembrolizumab in Adults With Glioblastoma

Are we at risk of throwing away the baby with the bathwater?

The phase I trial by Bagley et al published in Nature Cancer in 2024 is essentially a negative phase I trial.¹ Why is it still of interest to the community?

Well, obviously, glioblastoma (GBM) is a horrible type of cancer, as it lacks effective treatment options beyond the current standard-of-care approach, which has dismal outcomes. Therefore, any improvements, even the slightest, to the current treatment paradigm would be very welcome. Moreover, the therapy that was tested is very novel in the sense that, although previous studies have looked at CAR T-cell therapy for GBM, this CAR T-cell therapy is different. A number of differences to note are: 1) the antigen target: EGFR variant III; 2) the fact that the CAR T-cells were infused not once but repeatedly (a maximum of three times); and 3) CAR T-cell therapy was combined with a systemic infusion of anti–PD-1 (pembrolizumab).¹

The authors found that, despite translational research studies showing the biological activity of the therapy, there was no clinical benefit, with a median progression-free survival of 5.2 months and a median overall survival of 11.8 months.¹

However, have they chosen the correct study population of patients with GBM to test this combination therapy in? Are we at risk of throwing away the baby with the bathwater?

My dear colleague, Prof. Richard Scolyer, MBBS, MD, FRCPA, FRCPath, FAHMS, AO, was diagnosed with GBM in May 2023. Rather than undergoing the classical treatment paradigm of debulking surgery followed by radiotherapy and temozolomide according to the EORTC 22981/26981 study by Stupp et al² and waiting for the inevitable recurrence, he decided to try a different treatment approach.

His therapy consisted of an open biopsy to obtain untreated tissue to allow the development of a personalized vaccine, followed by neoadjuvant triplet immunotherapy with anti–CTLA-4, anti–PD-1, and anti–LAG-3. Subsequently, he has undergone debulking surgery and adjuvant radiotherapy and is currently receiving adjuvant immunotherapy plus a personalized vaccine. He recently had a follow-up scan and is now 8 months progression-free.

Moreover, translational studies have shown, among other things, that neoadjuvant immunotherapy has led to an influx in T cells and upregulation of PD-L1, and even anti–PD-1 could be found bound to the tumor that was resected after the single dose of neoadjuvant triplet immunotherapy.

Of course, N = 1 studies do not deliver the evidence to be able to change practice definitively; but, they can be considered hypothesis-generating to test feasibility and find a potential signal in terms of efficacy. Importantly, Prof. Scolyer has not undergone immunotherapy after radiotherapy and chemotherapy, especially, has neither depleted his host immune system nor deteriorated his performance score. This means that we might need to test immunotherapy at a different stage in GBM — as a first-line treatment and not after having failed the current standard-of-care approach by Stupp et al or when the disease has destroyed the host to an extent that nearly nothing will show efficacy anymore.

Therefore, despite this negative trial on CAR T-cells for GBM, we must be careful not to throw away the baby with the bathwater. And we might need to reset our existing dogmata to do so.

Prof. Scolyer and his long-term friend, co-medical director of the Melanoma Institute Australia and oncologist Prof Georgina Long, have been very vocal about this journey and have used the lessons they learned in melanoma to attempt to break the cycle in GBM.³ Of course, it is early days; but, the enormous track record they have in melanoma, as well as this latest work in GBM recently, has seen them being awarded the prestigious title of Australian of the Year.

References

1. Bagley SJ, Binder ZA, Lamrani L, et al. Repeated peripheral infusions of anti-EGFRvIII CAR T cells in combination with pembrolizumab show no efficacy in glioblastoma: a phase 1 trial. Nat Cancer. 2024 Jan 12. Doi: 10.1038/s43018-023-00709-6. Online ahead of print. https://www.nature.com/articles
2. Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352(10):987-96. https://www.nejm.org/doi/
3. BBC. Tiffanie Turnbull. Richard Scolyer: Melanoma doctor's high-stakes gamble to treat his brain cancer. February 2, 2024. Accessed February 7, 2024. https://www.bbc.com/news/world-australia-67870595