Brain tumor treatment is hampered by the blood-brain barrier (BBB). This barrier prevents drugs carried in the bloodstream from getting into the brain. If the BBB can be opened, making it temporarily more permeable, drugs may able to better reach the brain tumor. In this trial we will implant a novel device with 9 ultrasound emitters, allowing temporary and reversible opening of the BBB to maximize brain penetration of drugs that modulate the immune system. The device will be implanted after radiation is completed. Immune modulating drugs will be given every 3 weeks in conjunction with activation of the device to open the BBB.

The objectives of this trial are to establish whether it is safe and feasible to administer immune modulating drugs in this manner, and identify whether the treatment is effective in treating glioblastoma.

Eligible patients will undergo implant of the Soncloud-9 device within 1-5 weeks of completion of radiotherapy. About 1-3 weeks after surgery, patients will undergo sonication and intravenous administration of balstilimab, botensilimab and liposomal doxorubicin. Brain MRI will be done to quantify extent of blood brain barrier opening. The dose for balstilimab is 450 mg every 3 weeks. The dose for botensilimab is 1mg/kg every 6 weeks. The dose for liposomal doxorubicin is 30 mg every 3 weeks. Sonication and administration of study agents will continue every 3 weeks (21 days= 1 cycle) for a total of 9 cycles (approx. 6 months). Additional cycles may be considered if deemed beneficial and in the patient's best interest. Blood samples for circulating tumor DNA will also be collected before and after each sonication. The first 6 patients will comprise a safety run-in cohort with intensified safety monitoring through the end of the second cycle.

Inclusion Criteria:

• Have newly diagnosed pathologically proven glioblastoma, isocitric dehydrogenase-1/2 wild-type
• Tumor with methyl guanine methyl transferase (MGMT) gene promoter unmethylated
• Available paraffin embedded tumor tissue for the study
• Have completed standard radiotherapy with or without temozolomide
• 18 years of age or older
• Able to undergo contrast-enhanced MRI
• Have an Eastern Cooperative Oncology Group/World Health Organization performance status ≤ 2
• Size and location of the residual tumor and/or resection cavity must allow to be able to be covered by the sonication field
• Have not received any prior treatment with immunotherapeutic agents treatments for glioblastoma or other indications
• Have the ability to understand and willingness to sign a written informed consent prior to registration on study.
• Be willing and able to comply with the protocol.
• Have adequate organ and bone marrow function
• Agree to use adequate contraception if appropriate

Exclusion Criteria: Patients will be ineligible if they have:

• Multifocal tumor (unless all localized in a 50-mm diameter area accessible to ultrasound field) or tumor located in the posterior fossa.
• Uncontrolled epilepsy.
• Received other investigational agents within 2 weeks of registration
• Received prior therapy with or have history of allergic reactions attributed to compounds of similar chemical or biologic composition to agents used in this study.
• Contraindication to checkpoint inhibitor therapy (e.g., history of autoimmune disease)
• Uncontrolled illness
• History of active malignancy other than the brain tumor within 12 months prior to registration.
• Are pregnant or breastfeeding.