Key Inclusion Criteria:
1. Signed and dated approved informed consent form (ICF) before any protocol-directed screening procedures are performed.
2. Participants must have histopathologically confirmed recurrent supratentorial glioblastoma.
3. Participants must have progressed after at least 1 line but no more than 2 lines of therapy.
4. Evidence of progression by RANO criteria based on MRI scan.
5. Residual lesion must be ≥ 1.0 cm and \< 5.5 cm contrast-enhancing in diameter as determined by MRI.
6. Age ≥ 18 years.
7. Karnofsky Performance Score (KPS) ≥ 70.
8. Life expectancy \> 12 weeks.
9. Participants must have normal organ and marrow function.
10. Participants must commit to the use of a reliable method of birth control.
11. Resolution of all AEs due to previous therapies to ≤ Grade 1 or baseline.
12. Capable of understanding and complying with protocol requirements.
Key Exclusion Criteria:
1. Inability to undergo MRI examination for any reason.
2. A contrast-enhancing brain tumor that does not meet protocol criteria.
3. Prior history of encephalitis, multiple sclerosis, or other CNS infection.
4. Clinical diagnosis of Li-Fraumeni Syndrome or with a known germ line deficit in the retinoblastoma gene or its related pathways.
5. Required steroid increase within 2 weeks prior to date of C5252 administration.
6. Systemic therapy with immunosuppressive agents within 28 days prior to date of C5252 administration.
7. Uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or any other medical condition that precludes surgery. Also, psychiatric illness/social situations that would limit compliance with study requirements.
8. Bleeding diathesis, or requirement for anticoagulants, or antiplatelet agents, including NSAIDs that cannot be stopped for surgery or biopsy.
9. Current diagnosis of other cancer except in situ cervical cancer, basal or squamous cell carcinoma of the skin.
10. Requires continued concurrent therapy with any drug active against HSV (acyclovir, valaciclovir, penciclovir, famciclovir, ganciclovir, foscarnet, cidofovir).
11. Pregnant or lactating.
12. Prior organ transplantation.
13. Active hepatitis B virus, hepatitis C virus, or a positive serological test at Screening.
14. Active oral herpes lesion at Screening.
15. Congestive heart failure (\> New York Heart Association Class II), active coronary artery disease, unevaluated new onset angina within 3 months or unstable angina (angina symptoms at rest), or clinically significant cardiac arrhythmias.
16. History of allergic reactions attributed to compounds of similar biological composition to HSV-1, IL-12, or anti-PD-1 monoclonal antibody.
17. Active infection with SARS-CoV-2 virus.
18. Other systemic conditions or organ abnormalities that, in the opinion of the Investigator, may interfere with the conduct and/or interpretation of the current study.
