The PuMP Trial: "A Multistage Phase 1 Open-Label Study to Evaluate the Safety, Tolerability and Efficacy of the Oncolytic HSV1 MVR-C5252 in Patients With Recurrent High-Grade Glioma"

Inclusion Criteria: 1. Age \>18 years of age 2. Disease recurrence of at least 1x1cm and a maximum of 3x3cm of enhancing tumor: Dose escalation portion: patients with recurrent high-grade glioma, IDH wt or IDH mutated, grade 3 or grade 4 based on imaging. Dose expansion portion: Recurrent, IDH wt, glioblastoma, WHO grade 4. Diagnosis has be made using the 2021 WHO Classification of Tumors of the CNS. 3. The neurosurgeon must confirm (a) the tumor location (\> 1 cm from eloquent brain), (b) that the placement of infusion catheter within or through the progressive enhancing tumor is feasible and is at a safe distance to eloquent brain function. These aspects will be determined prior catheter placement on the basis of prior (screening) MRI and then at the time of catheter placement on the basis of a CT scan prior to infusion. The tip of the catheter must be placed as follows: 1. Within the enhancing portion or in the vicinity of enhancement of target lesion (i.e., infiltrative disease) 2. ≥ 0.5 cm from ventricles 3. ≥ 1 cm deep into the brain 4. ≥ 0.5 cm from the corpus callosum 4. If a histological or pathological confirmation of recurrence (\< 6 weeks) is not available, a pre-infusion biopsy will be required to confirm recurrence. 5. Adequate pulmonary function, with a baseline pulse oximetry of at 90% on room air. 6. The subject must have received standard radiation therapy plus temozolomide and be refractory to radiation therapy plus temozolomide prior to enrollment. 7. Prior to administration of MVR-C5252, the presence of recurrent tumor must be confirmed by histopathological analysis. (Distinguishing between recurrent active tumor and radiation necrosis is important to avoid delivering MVR-C5252 when there is no active disease). Should participants have further surgical resection at any time following their participation in the study, patients will be invited to make any biospecimens available for correlative research. 8. Karnofsky Performance Status (KPS) ≥ 70% 9. Labs: 1. platelets ≥ 100,000 unsupported at initial screening, but ≥ 125,000 supported prior to biopsy/catheter insertion 2. hemoglobin ≥ 9 gm/dL, ANC ≥ 1000/µL 3. creatinine ≤ 1.5x upper limit of normal (ULN) 4. total bilirubin ≤ 1.5 x ULN, AST/ALT ≤ 2.5 x ULN (subjects with known or suspected Gilbert's syndrome are excluded if total bilirubin \> 3.0 x ULN or direct bilirubin \> 1.5 x ULN) 5. PT, aPTT ≤ 1.2 x ULN prior to biopsy (if patient is taking warfarin, INR should be obtained and be \< 2.0) 10. Able to undergo MRI brain with and without contrast 11. If the patient is a sexually active female of childbearing potential, whose partner is male, or if the patient is a sexually active male, whose partner is a female of child bearing potential, the patient must use appropriate contraceptive measures for the duration of the treatment and for 6 months afterwards. Female patients of childbearing potential must have a negative serum pregnancy test at the time of screening and within 48 hours of starting the MVR-C5252 infusion. 12. Signed informed consent approved by the Institutional Review Board Exclusion Criteria: 1. Prior, unrelated malignancy requiring current active treatment with the exception of cervical carcinoma in situ and adequately treated basal cell or squamous cell carcinoma of the skin 2. Patients who are pregnant or breastfeeding 3. Patients with contrast-enhancing tumor crossing the midline, multifocal tumor, infratentorial tumor, tumor in eloquent brain regions, extensive tumor dissemination (subependymal or leptomeningeal), or in unsafe brain regions per the opinion of the treating neurosurgeon 4. Unstable systemic disease in the opinion of the treating physician. 5. Active infection requiring systemic therapy or causing fever (temperature \> 38.1˚C) or subjects with unexplained fever (temperature \> 38.1˚C) within 7 days prior to the day of investigational product administration. 6. Patients on \>4 mg per day of dexamethasone within the 2 weeks prior to admission for MVR-C5252 infusion or systemic therapy with immunosuppressive agents within 28 days prior to admission for MVR-C5252 infusion 7. Patients who have not completed standard of care treatment prior to participation in this trial 8. Less than 12 weeks from radiation therapy, unless progressive disease outside of the radiation field or 2 progressive scans at least 4 weeks apart or histopathologic confirmation of recurrent tumor 9. Treated with immunotherapeutic agents prior to MVR-C5252 treatment, within 4 weeks, alkylating agents within 4 weeks, nitrosoureas within 6 weeks, or non-alkylating chemotherapy within 2 weeks before enrollment, unless the patient has recovered from the expected toxic effects of such therapy 10. Treated with antiangiogenic agents (i.e., bevacizumab) within 4 weeks before biopsy 11. Patients who require an attenuated or live vaccine within 28 days prior to the first trial drug administration and during the study treatment period 12. Prior treatment with any oncolytic virus, cell therapy or gene therapy. 13. Prior antitumor treatment with intracranial implants, such as Carmustine 14. Previous history of allergic reactions to similar biological components such as HSV-1, IL-12 or anti-PD-1 antibodies, or with known allergic reactions to any component of the MVR-C5252 prescription, including glycerol. 15. Systemic use (other than topical) of anti-HSV drugs (including, but not limited to, acyclovir, valaciclovir, penciclovir, famciclovir, ganciclovir, foscarnet, cidofovir, etc.) 16. Patients with cardiac risks including congestive heart failure (as defined by New York Heart Association Functional Classification III or IV), unstable angina, serious uncontrolled cardiac arrhythmia, a myocardial infarction within 6 months prior to study entry, or a history of myocarditis.