The use of oncolytic virus therapy using a modified herpes simplex virus (HSV) may help improve the overall survival of children with recurrent or progressive high-grade glioma after therapy, according to a study presented at the American Association for Cancer Research Annual Meeting.
The oncolytic herpes simplex virus type 1 (HSV-1), known as G207, led to the median overall survival (OS) of 12.2 months, compared with 5.6 months historically among children treated with a variety of other therapies at initial progression, according to the results of the phase 1 study.
HSV-1 preferentially infects cells of the peripheral and central nervous system. Researchers created G207 to prevent HSV-1 replication in normal cells, thus leading the virus to replicate in and kill only tumour cells.
The research was a first-in-children trial to test the safety of immunotherapy using an altered cold-sore virus (herpes virus or HSV-1), G207, infused directly via catheters into progressive or recurrent malignant brain tumours, said Gregory Friedman, MD, professor of paediatrics at The University of Alabama at Birmingham (UAB) in a statement.
Due to modifications in G207, the virus does not harm normal cells but can infect and directly kill tumour cells while also stimulating the patient’s own immune system to attack the tumour.
Friedman and colleagues used a 3+3 study design to evaluate G207 among 12 patients involving females (6) aged 7 years to 18 years with high-grade glioma. Ten of the patients had tumours with a bi-perpendicular sum of 5.5 cm or larger, three had multifocal disease, eight had failed two or more prior treatment regimens and four had failed three or more prior regimens.
The patients underwent stereotactic placement of three to four intratumoral catheters and, on the next day, received a controlled-rate infusion of G207 over a period of 6 hours based on their assignment to one of four dose cohorts: 107 plaque-forming units (PFU), 108 PFU, 107 PFU with 5 Gy of radiation, and 108 PFU with 5 Gy of radiation.
Patients assigned to dose cohorts 3 and 4 received radiation to the gross tumour volume within 24 hours of receiving G207.
The primary objective of the study was to identify the safety and adverse event profile of G207. Secondary objectives included assessing for potential efficacy and biologic response to G207 and the presence of G207 viremia or shedding in blood, saliva and conjunctiva.
Researchers explained that they could place the catheters throughout the cerebrum safely without causing neurologic sequelae. The G207 appeared safe and tolerable among all patients including those who received radiation with no grade 3 or grade 4 adverse events or evidence of virus shedding.
Eleven patients experienced grade 1 events, which included fever, fatigue, vomiting, nausea, headache, seizure, postoperative haemorrhage, diarrhoea, chills, anorexia and dizziness. Eleven patients responded to treatment with four of 11 patients (36%) alive 18 months after treatment.
“This is important because children did not experience the degree of toxicities that occur with almost all other types of therapy and, therefore, their quality of life after treatment was not adversely impacted by the therapy,” Friedman said. Compared with historical median OS of 5.6 months, this survival rate represents a 120% increase, he said.
Three patients with baseline HSV-1 IgG antibodies had shorter median overall survival, at 5.1 months, than three patients who had seroconversion after G207, at 18.3 months, which only occurred among patients treated with 108 PFU.
Researchers also compared pre- and post-treatment biopsies of four patients and found marked increases in CD3+, CD4+ and CD8+ tumour-infiltrating lymphocytes in tumour tissue 2 to 9 months after treatment, indicating G207 turned these “cold” tumours “hot,” according to the researchers.
“Classically, pediatric high-grade gliomas are immunologically ‘cold’ or silent, which means they have very few infiltrating immune cells or lymphocytes,” Friedman said.
Cold tumours are unresponsive to immunotherapies because tumour-infiltrating lymphocytes are necessary for an immune attack on the tumour. The change from cold to hot represented a critical step in the development of an effective immunotherapy for paediatric high-grade glioma.
Researchers are planning a phase 2 trial to replicate these findings in a larger cohort, and they also plan to study G207 in newly diagnosed children with glioma, as well as in paediatric medulloblastoma, which may be more sensitive to the therapy.
The study is now published in The New England Journal of Medicine.