Oncolytic therapy using modified herpesvirus shows promise for pediatric high-grade glioma
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Use of a modified herpesvirus with and without radiation showed promising efficacy and safety for the treatment of children with recurrent or progressive high-grade glioma, according to results of a phase 1 trial.
The oncolytic herpes simplex virus type 1 (HSV-1), known as G207, led to median 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, presented at the virtual American Association for Cancer Research Annual Meeting and simultaneously published in The New England Journal of Medicine.
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 tumor cells.
“This was a first-in-children trial to test the safety of an immunotherapy using an altered cold-sore virus (herpes virus or HSV-1), G207, infused directly via catheters into progressive or recurrent malignant brain tumors,” Gregory Friedman, MD, professor of pediatrics at The University of Alabama at Birmingham (UAB), research scientist at UAB O’Neal Comprehensive Cancer Center, and director of developmental therapeutics for Alabama Center for Childhood Cancer and Blood Disorders at UAB and Children’s of Alabama, said in a statement provided to Healio. “Due to modifications in G207, the virus does not harm normal cells but can infect and directly kill tumor cells while also stimulating the patient’s own immune system to attack the tumor.”
Survival rates for pediatric high-grade glioma haven’t improved in 30 years, with 3-year EFS for newly diagnosed patients treated with radiation and chemotherapy of only 11% to 22%, according to study background.
“The research is important because outcomes are very poor for children with progressive malignant brain tumors, and the toxicities caused by current standard therapies are unacceptably high,” Friedman said. “Therefore, we greatly need effective and less-toxic targeted therapies for children.”
Friedman and colleagues used a 3+3 study design to evaluate G207 among 12 patients (female, n = 6) aged 7 years to 18 years with high-grade glioma. Ten of the patients had tumors 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 tumor volume within 24 hours of receiving G207.
Identifying the safety and adverse event profile of G207 served as the study’s primary objective. 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 noted they placed the catheters throughout the cerebrum safely without causing neurologic sequelae.
Further, 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 hemorrhage, diarrhea, chills, anorexia and dizziness.
“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.
Eleven patients responded to treatment. Researchers reported median OS of 12.2 months (95% CI, 8-16.4), with four of 11 patients (36%) alive 18 months after treatment.
Compared with historical median OS of 5.6 months, this survival rate represents a 120% increase, Friedman said.
Three patients with baseline HSV-1 IgG antibodies had shorter median OS, at 5.1 months (95% CI, 3-7.2), than three patients who had seroconversion after G207, at 18.3 months (95% CI, 9.2-27.3), 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+ tumor-infiltrating lymphocytes in tumor tissue 2 to 9 months after treatment, indicating G207 turned these “cold” tumors “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 tumors are unresponsive to immunotherapies because tumor-infiltrating lymphocytes are necessary for an immune attack on the tumor.
“This change from ‘cold’ to ‘hot’ represents a critical step in the development of an effective immunotherapy for pediatric high-grade glioma,” he added.
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 pediatric medulloblastoma, which may be more sensitive to the therapy.
References:
- Friedman GK, et al. Abstract CT018. Presented at: American Association for Cancer Research Annual Meeting (virtual meeting); April 10-15, 2021.
- Friedman GK, et al. N Engl J Med. 2021;doi:10.1056/NEJMoa2024947.
Perspective
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Ajay Gupta, MD, MS
Friedman and colleagues’ promising findings highlight both a safe, well-tolerated emerging therapeutic avenue (immunologic conversion of the tumor microenvironment) and modality (oncolytic herpesviruses plus or minus radiation). The trial had a very impressive safety signal for the slow infusion of oncolytic virus and placement of multiple catheters (three or four) directly into the cerebrum of young patients.
It is currently unknown whether post-treatment expansion of tumor-infiltrating lymphocytes produced T cells specific to the infused virus or to the tumor itself, but it may not be salient if such T cells can still induce tumor death, whether directly or indirectly.
Given the limited size of the initial cohort (12 treated patients), but the outstanding improvement in median survival times, an expanded phase 2 clinical trial to validate safety and more broadly demonstrate efficacy is enthusiastically warranted. Future directions potentially could include this therapy in combination with chemotherapy or targeted therapy, as it has been well-established in other settings that oncolytic herpesvirus combination therapy is both feasible and synergistic.
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Friedman GK, et al. Abstract CT018. Presented at: American Association for Cancer Research Annual Meeting (virtual meeting); April 10-15, 2021.
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