The goal of this clinical research study is to learn about the safety and effects of G207 combined with radiation therapy in patients with recurrent or progressive high-grade glioma (HGG).

Primary Objective:

To assess the efficacy of G207 administered intratumorally followed by 5 Gy radiation within 24hours in patients with recurrent or progressive high-grade glioma (HGG) as measured by postprogression overall survival (pp-OS), focused on patients with one progression following their priorsurgery and radiotherapy, compared to matched historical controls.

Secondary Objectives:

To describe the pp-OS survival in patients treated with G207 + 5 Gy with more than one progression following their prior surgery and radiotherapy

To establish safety and characterize toxicity of G207 + 5 Gy radiation

To survey for virologic shedding following G207

To evaluate immunologic response(s) to G207

To assess radiographic changes from baseline by RANO 2.0 criteria and by tumor volume, cerebral blood volume, and apparent diffusion coefficient.

To describe the efficacy of G207 + 5 Gy radiation as measured by response rate and progressionfree survival (PFS)

Exploratory Objectives:

To assess performance status score changes over time after treatment with G207 + 5 Gy radiation

To evaluate pre- and post-treatment tissue for immune cell populations and checkpoint proteins in patients who are amendable to and meet criteria for resection/biopsy while on study

To assess OS in subgroups of patients based on therapies received after G207 + 5 Gy radiation (surgery versus no surgery; reirradiation versus no reirradiation, immunotherapy versus no immunotherapy)

Inclusion Criteria:

Exclusion Criteria:

Pregnancy

Pregnant women are excluded from this study. Female patients of childbearing potential must have a negative serum or urine pregnancy test. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.

Pregnant women are excluded from this study because G207 is an agent with the potential for teratogenic or abortifacient effects.

Lactation Status

Lactating females are not eligible unless they have agreed not to breastfeed their infants

Because there is an unknown potential risk for adverse events in nursing infants secondary to treatment of the mother with G207, breastfeeding should be discontinued if the mother is treated with G207.

Disease-Related Exclusion Criteria

Patients with a prior or concurrent malignancy whose natural history or treatment has the potential to interfere with the safety or efficacy assessment of the investigational regimen for this trial.

Patients with primary tumor involving the cerebellum, brainstem or spinal cord, or that would require surgical access through a ventricle to deliver the prescribed protocol treatment.

Metastatic disease or diffuse, widespread, abnormal tumor pattern involving 3 or more lobes of the brain.

Tumor with evidence of clinically significant uncal herniation or midline shift, or evidence of ventricular obstruction from tumor or tonsillar herniation.

Concurrent Illness

Patients with any clinically significant unrelated systemic illness (serious infections or significant cardiac, pulmonary, hepatic or other organ dysfunction), that in the opinion of the investigator would compromise the patient's ability to undergo surgery and/or tolerate protocol therapy, put them at additional risk for toxicity or would interfere with the study procedures or results.

Known HIV seropositivity.

Diagnosis of encephalitis or CNS infection < 12 weeks prior, or receiving ongoing treatment for encephalitis, CNS infection or multiple sclerosis.

Concurrent Medications

Patients who are receiving any other anti-cancer or investigational drug therapy are ineligible.

Patients who are receiving ≥ 2 mg of dexamethasone (or ≥ 10 mg of prednisone) daily

• Patient requires an escalation in ongoing systemic corticosteroid therapy within 7 days prior to G207 inoculation
• For this study, 'systemic corticosteroids' include oral, intravenous, or intramuscular formulations. A single, non-consecutive dose does not constitute exclusion. Physiologic corticosteroid replacement therapy (e.g., hydrocortisone for adrenal insufficiency), intermittent use of bronchodilators and topical steroids, is not considered immunosuppressive and does not constitute exclusion.

Concurrent therapy with any drug active against HSV (acyclovir, valacyclovir, penciclovir, famciclovir, ganciclovir, foscarnet, cidofovir).

Inability to Participate

Patients who in the opinion of the investigator are unwilling or unable to return for required followup visits or obtain follow-up studies required to assess toxicity to therapy or to adhere to the drug administration plan, other study procedures, and study restrictions.