The new kid on the block: suicide gene therapy to modulate cancer immunosurveillance for children with high-risk malignant brain tumors

See the article by Kieran et al. in this issue, pp. 537–546.

The prognosis for children with high-grade gliomas remains dismal, despite aggressive multimodal therapies, including surgery, chemotherapy, and radiation therapy. While recurrent genomic alterations have been identified in pediatric high-grade gliomas, no effective molecular targeted therapies exist for the vast majority of patients.¹ In this context, increasing efforts are focusing on immunotherapeutic strategies to improve the outcome for children with high-grade gliomas.

Suicide gene therapy is the introduction of viral or bacterial genes into tumor cells, which in turn convert a nontoxic prodrug to a toxic one.² Gene-mediated cytotoxic immunotherapy (GMCI) is one such approach wherein an adenoviral vector containing the herpes virus thymidine-kinase gene (AdV-tk) is injected locally into the infiltrating tumor site leading to local expression of herpes simplex virus (HSV-tk). This is followed by oral administration of valacyclovir, which serves as a substrate for HSV-tk and undergoes phosphorylation to generate a nucleotide analog which is toxic to dividing or DNA-repairing cells.³ DNA damaging agents, such as radiation and some chemotherapies, increase DNA repair activity and consequently increase susceptibility to AdV-tk/prodrug activity. Necrosis and apoptosis of tumor cells including neighboring cells occur via spread of activated prodrug through gap junctions and apoptotic vesicles (bystander effect).⁴ Release of “danger signals” leads to an influx of antigen presenting cells such as dendritic cells. Furthermore, vector expressed thymidine-kinase protein functions as a super-antigen creating a hyper-immunogenic microenvironment, production of proinflammatory cytokines (interleukin [IL]-2 and IL-12) with consequent antitumor T-cell stimulation and proliferation. GMCI induces polyvalent immunity to autologous tumor antigens, akin to a personalized vaccine approach, and minimizes the probability of immune evasion. The replication-deficient adenoviral vectors trigger a strong humoral and cellular immune response that limits its effectiveness to a period of 2–3 weeks.²

In this issue, Kieran et al describe the results of a first-in-child trial of GMCI.⁵ The study follows an adult phase I/II trial, which suggested an improvement in median overall survival compared with historical controls, particularly in patients who had a gross total resection.⁶ The pediatric phase I study enrolled patients 3–18 years of age with newly diagnosed malignant glioma or recurrent ependymoma who were eligible to undergo additional surgery and radiation therapy. Patients with surgically inaccessible tumors located in the brainstem or deep midbrain were ineligible. The study used a rolling 3 + 3 design to test 2 dose levels. AdV-tk was administered locally during surgery, followed by oral valacyclovir for 14 days. Standard radiation therapy started 3–8 days post surgery to maximize the potential synergistic effects of the combination treatment. Patients received temozolomide during radiation therapy, followed by adjuvant chemotherapy with or without bevacizumab according to physician choice. Both dose levels were well tolerated without dose limiting toxicity or treatment delays, demonstrating the feasibility and safety of this approach for pediatric brain tumor patients. Median overall survival was 8.9 months for dose level 1, and 25.3 months for dose level 2. Three patients treated at dose level 2 (two with glioblastoma, one with ependymoma) were alive greater than 2 years post diagnosis.

Among the 4 glioblastoma patients treated at dose level 2, the median overall survival was 24 months. Two of these patients had unexpectedly long survival following disease progression after treatment, suggesting pseudo-progression. Many of the patients also received chemotherapy post injection of AdV-tk, raising the possibility of synergistic effects. However, this adds to the difficulty in interpreting study outcomes. While the authors acknowledge the small cohort of highly selected patients as a study limitation, the survival outcome data nevertheless appear favorable compared with historical controls of pediatric high-grade glioma patients, where median overall survival is ~18–20 months. Any therapy that suggests a possibility of a sustained response in these rapidly fatal brain tumors should be considered of interest for further investigation.

The study also provides data on immune correlates, including baseline and posttreatment circulating myeloid-derived suppressor cells (defined as Lin-/Lo, HLA DR-, CD33+ CD11b+) from whole blood, highlighting the immunosuppressive milieu in pediatric high-grade glioma patients. The authors also noted increased expression in genes related to CD8 cytotoxic T-cell function. These blood-based biomarkers provide points of reference to guide future immunotherapy trials.

How do these data relate to other emerging immunotherapies for brain tumors, including immune checkpoint inhibitors (ICIs) and adoptive cellular therapy, such as chimeric antigen receptor (CAR) T-cell therapy? Multipronged approaches involving tumor antigen priming and overcoming extrinsic and tumor-intrinsic immunoresistance mechanisms could help optimize CD8 T cell–mediated antitumor immunity.⁷ Therefore, the combination of CARs/GMCI and ICI represents an attractive option, and such a trial was recently launched for newly diagnosed adult patients with malignant glioma (ClinicalTrials.gov NCT03576612). Based on the encouraging safety and preliminary efficacy data observed in the present study by Kieran et al, a phase II pediatric trial is being planned, and we suggest that consideration be given to assessing the combination of GMCI with ICI.

In conclusion, Kieran et al are to be commended for pursuing a novel immunotherapeutic approach in children with high-risk brain tumors, and demonstrating both safety and feasibility in this vulnerable population. Further careful clinical investigation of GMCI, including as part of combination therapy, appears warranted and holds promise for improving the outcome of these young patients currently facing a dismal prognosis.