CAR T cells for diffuse intrinsic pontine gliomas - a phase 1 trial

A Seattle team published a paper on a phase 1 trial of intraventricularly administered Chimeric Antigen Receptor T cells (CAR T Cells) targeting B7-H4 protein in patients with diffuse intrinsic pontine gliomas (DIPG) in Nature Medicine on January 25, 2025 (1).

The principal purpose of Phase I trials is to assess the safety, dosage, and pharmacokinetics of drugs or agents for treating a specific disease. B7-H4 is a checkpoint protein. Checkpoint proteins can modulate the immune system to prevent the immune system from attacking normal tissue. However, tumours could also use checkpoint proteins to evade the immune system. The checkpoint protein B7-H4 is found in DIPG.

Chimeric Antigen Receptor T cells (CAR T cells) are the patient’s T cells harvested from the patient’s blood. In this study, the harvested (apheresis) CD4+ and CD8+ T-cells were engineered (transduced) by lentivirus to express receptors (chimeric antigen receptors) for B7-H4. Then, these cells were allowed to proliferate before they were administered intraventricularly in those patients in this study. These CAR T cells would directly recognise tumour cells carrying B7-H4 proteins.

The maximum dose they could administer was 100 million CAR T cells/dose. In the study, 21 patients received CAR T cells. One patient had an intratumoral haemorrhage. Headache was noted in 81%, nausea and vomiting in 81%, fatigue in 62% and fever in 57% of the patients.

The study was not powered to investigate the efficacy of this immunotherapy. However, the authors report that the median survival was 19.8 months, in contrast to historical outcomes for DIPGs of 11.2 months. The authors qualify the better prognosis in this study by pointing out the difficulty of comparing historical outcomes.

The authors also examined the subset of patients who had entered the trial after the progression following radiotherapy. These patients had a median survival of 9.4 months after CART T cell therapy. Historically, patients with disease progression survive for less than 3 months.

This study is the first on CAR T cells for DIPGs only, where the CAR T cells were exclusively administered intraventricularly. The paper on this impressively sophisticated study had been published as an open-access paper. Naturally, the authors need to be congratulated on their groundbreaking work. The authors are now planning for a Phase II trial (efficacy).

Vitanza NA, Ronsley R, Choe M, Seidel K, Huang W, Rawlings-Rhea SD, Beam M, Steinmetzer L, Wilson AL, Brown C, Beebe A, Lindgren C, Gustafson JA, Wein A, Holtzclaw S, Hoeppner C, Goldstein HE, Browd SR, Hauptman JS, Lee A, Ojemann JG, Crotty EE, Leary SES, Perez FA, Wright JN, Alonso MM, Dun MD, Foster JB, Hurst D, Kong A, Thomsen A, Orentas RJ, Albert CM, Pinto N, Annesley C, Gardner RA, Ho O, Pattabhi S, Gust J, Wendler JP, Park JR, Jensen MC. Intracerebroventricular B7-H3-targeting CAR T cells for diffuse intrinsic pontine glioma: a phase 1 trial. Nat Med. 2025 Mar;31(3):861-868. doi: 10.1038/s41591-024-03451-3. Epub 2025 Jan 7. PMID: 39775044; PMCID: PMC11922736. [Download]

Painful cervical radicular pain: surgery vs medical management

Taso et al., from Oslo published a randomised controlled trial on the surgical versus medical management of disablingly painful cervical radiculopathy in the NEJM Evidence on March 25, 2025.

They undertook two randomised controlled studies. The first trial assessed the two treatment methods for painful radiculopathy due to disc disease, and the second trial assessed painful radiculopathy due to spondylosis. The disc disease and spondylosis were diagnosed from the patient's MRI imaging.

The surgical treatment was anterior cervical discectomy and fusion (ACDF); the medical treatment consisted of three appointments with rehabilitation/physical therapy physicians and an additional three sessions with physiotherapists.

The primary outcome measure was the Neck Disability Index (NDI; the score ranged from 0 to 100) at a one-year follow-up. The authors state that the minimum score difference for a clinically significant difference is 15.

Figure 1. Patient allocation and the number of patients for whom outcome data was available at 1-year follow-up.

In the trial with radiculopathy due to disc disease, the results favoured surgical management. The NDI difference between the two groups (surgery vs medical management) was 7.4 (P-value = 0.01; 95% CI: 1.6 - 13.3). While this is a statistically significant result, the difference less than 15, the minimum threshold for it to be a clinically significant difference.

In the trial on patients with spondylosis, the NDI difference was 2.3. This was neither statistically nor clinically significant.

When interpreting this study, it is important to note this study was on a subpopulation of patients with cervical radiculopathy, i.e. those with disabling pain.

While there was a statistically but not clinically significant improvement in patients with disc disease who had undergone surgery, it is worth exploring the risk factors for favourable outcomes in each group and then devising a more specific patient selection for ACDF or medical management in such patients.

While there was no statistical or clinical difference between patients with spondylosis undergoing surgical or medical management, it is worth noting that in this trial, almost one-in-three (31%) patients assigned to medical management switched to surgical management. Higher cross-over rates reduce the power of an intention-to-treat analysis, i.e. when there is no statistical difference between the outcomes of control and test groups, there is higher risk of this being a false-negative finding (2).

The Power of the study was also affected by reduced recruitment of patients because of the COVID pandemic; the number of patients included in the studies was slightly lower than required for the per-protocol 80% power. Considering the the focus of the studies were disabling pain from cervical radiculopathy, the study could have been powered for Numeric rating Scale (NRS) for arm pain as well, which would have increased the relevance of the study.

The authors should be congratulated on this very relevant trial. However, it is worth discussing whether this small study has indeed answered the question of which is the better management for patients with disabling cervical radiculopathy.

References

1. Taso M, Sommernes JH, Sundseth J, Pripp AH, Bjorland S, Engebretsen KB, Kolstad F, Zwart JA, Brox JI. Surgical versus Nonsurgical Treatment for Cervical Radiculopathy. NEJM Evid. 2025 Apr;4(4):EVIDoa2400404. doi: 10.1056/EVIDoa2400404. Epub 2025 Mar 25. PMID: 40130970. [PubMed]

2. Weinstein GS, Levin B. Effect of crossover on the statistical power of randomized studies. Ann Thorac Surg. 1989 Oct;48(4):490-5. doi: 10.1016/s0003-4975(10)66846-4. PMID: 2802849. [PubMed]

Last updated: March 11, 2025 | GMT 09:11
Version: 7