“Therapy itself can also cause swelling — radiation for example; radiation necrosis, swelling — and we use dexamethasone here, too,” said Dr Venur. “One big challenge is that all of these patients are on dexamethasone as an immunosuppressive agent,” who noted that this could affect the efficacy of the IL-12 therapy.

“I think it’s going to be a real problem to minimize steroids in these patients,” said Dr Peters, who also noted that the authors of a 2019 paper showing preliminary results acknowledged this after observing an overall survival (OS) of 6.4 months compared with 16.7 months in patients who received more than 20 mg of steroids and for those who got less than 20 mg, respectively, on days 0-14 of the treatment.4

“They showed a big, big difference in OS in that paper. Steroids are a ubiquitous drug in our population — we’ve only got so many tools in our toolbox. It’s a necessary evil at the moment, and they will have to contend with this issue moving forward,” added Dr Peters.

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“There is a huge drawback to steroids, as they handicap the immune response, but the need of this is being challenged. We are asking if patients really need all of these steroids. Many patients can go onto our clinical trial with low to negligible amounts of steroids,” said Dr Cooper, noting that Dr Chiocca, one of the lead clinical investigators of the trial, is conducting investigations on this specific topic.

The aforementioned phase 2 trial expects to recruit 30 to 40 patients with recurrent or progressive GBM. Patients will receive an intratumoral injection of the IL-12 gene therapy, daily oral veledimex, and the trial will use infusions of the PD-1 antibody cemiplimab-rwlc every 3 weeks.

“We expect to have data from these patients within this year and next,” said Dr Cooper. “With the monotherapy, we have a median OS of 16 months, so we already see improvement. In the phase 2 trial, we will ask the question of whether we can get past 16 months OS.”

The gene therapy is also being trialed in children with diffuse intrinsic pontine glioma (DIPG), which is almost universally fatal, and where there is a huge unmet need for new treatment approaches. A phase 1/2 trial (ClinicalTrials.org Identifier: NCT03330197) of the human IL-12 vector (transcriptionally regulated by the oral activator veledimex) as a monotherapy has begun, with the first patient recently treated at Lurie Children’s Hospital in Chicago. The trial hopes to recruit up to 12 patients in total to evaluate the safety and tolerability of the therapy in pediatric DIPG patients.

References

  1. Queirolo P, Spagnolo F, Ascierto PA, et al. Efficacy and safety of ipilimumab in patients with advanced melanoma and brain metastases. J Neurooncol. 2014; 118(1):109-116. doi:10.1007/s11060-014-1400-y
  2. Goldberg SA, Schalper KA, Gettinger SN, et al. Pembrolizumab for management of patients with NSCLC and brain metastases: long-term results and biomarker analysis from a non-randomised, open-label, phase 2 trial. Lancet Oncol. 2020;21(5):655-663. doi: 10.1016/S1470-2045(20)30111-X
  3. Chiocca EA, Lukas RV, Chen CC, et al. Evaluation of controlled IL-12 in combination with a PD-1 inhibitor in subjects with recurrent glioblastoma. J Clin Oncol. 2020;38(15_suppl):2510-2510. doi:10.1200/JCO.2019.37.15_suppl.2020
  4. Chiocca EA, Yu JS, Lukas RV, et al. Regulatable interleukin-12 gene therapy in patients with recurrent high-grade glioma: Results of a phase 1 trial. Sci Transl Med. 2019;11(505):eaaw5680. doi:10.1126/scitranslmed.aaw5680

Topics:

Brain Cancer Glioblastoma