In modern practice a trimodality treatment has emerged as standard of care for histologically confirmed glioblastoma.

We hypothesize that the additional vaccination against herpes zoster, after surgical resection followed by irradiation therapy and chemotherapy of patients with glioblastoma will lead to a superior local control, overall and progression free survival. In an additional experimental setting based on patient preference the immunological effectiveness of the adoptive transfer of autologous polyclonal cytomegalovirus (CMV) specific T cells will be examined.

This multicenter study investigates novel immunomodulatory strategies in patients with histologically confirmed glioblastoma undergoing microsurgical resection at initial diagnosis.

In the randomized intervention arm, patients receive an EMA-approved, inactivated herpes zoster vaccine postoperatively, followed by standard radiotherapy or radiochemotherapy according to ESTRO/EANO guidelines. In a patient-preference experimental arm, the same regimen is combined with autologous CMV-specific T-cell adoptive transfer.

The control group undergoes neurosurgical resection and standard-of-care radiotherapy, with or without temozolomide, without additional herpes zoster vaccination or CMV-specific T-cell therapy.

Primary endpoint is overall survival (OS), while secondary endpoints include progression-free survival (PFS) and local tumor control, immunological response, safety, and tolerability. Exploratory endpoints incorporate patient-reported outcome measures (PROMs), assessing quality of life, cognitive function, and treatment-related symptoms. Interventions are delivered from surgical resection through completion of radiochemotherapy. We hypothesize that herpes zoster vaccination will improve survival and local tumor control, while adoptive CMV-specific T-cell therapy will provide additional immunotherapeutic benefit in this refractory glioblastoma population.

Inclusion Criteria:

Subjects must meet all of the following inclusion criteria to be eligible for enrolment into the trial:

• At least 18 years of age
• Written informed consent of the subject
• Life expectancy at least 3 months
• Participants of child-bearing age must use effective contraception
• Indication for definitive radiotherapy of glioblastoma or adjuvant radiation therapy of glioblastoma resection cavity according to interdisciplinary tumor board consensus and after radiation oncologists evaluation
• Histopathologically proven glioblastoma
• Incorporation of pre-neurochirurgical /-treatment PET/CT or/ and PET/MRI findings into the radiation therapy plan if patient undergoes PET/CT or/ and PET/MRI

Exclusion Criteria:

Subjects will not be included in the study if any of the following criteria apply. General Exclusion Criteria:

• Subjects not able to give consent
• Subject without legal capacity who is unable to understand the nature, scope, significance, and con- sequences of this clinical trial
• Simultaneously participation in another clinical trial or participation in any clinical trial involving ad- ministration of an investigational medicinal product within 30 days prior to clinical trial beginning
• Subjects with a physical or psychiatric condition which at the investigator's discretion may put the subject at risk may confound the trial results or may interfere with the subject's participation in this clinical trial
• Known or persistent abuse of medication, drugs or alcohol
• Contraindications for radiotherapy (including active inflammatory disease)
• Known hypersensitivity against vaccine contra herpes zoster, or its constituents
• Gliomatosis cerebri at time of enrollment on any imaging or proved by histopathology
• Synchronous secondary malignancy

Exclusion criteria regarding special restrictions for females as the treatment procedures require the highest degree of safety for the child:

• Current or planned pregnancy or nursing women
• Females of child-bearing potential, who are not using and not willing to use medically reliable methods of contraception for the entire study duration (such as oral, injectable, or implantable contracep- tives, or intrauterine contraceptive devices) unless they are surgically sterilized / hysterectomized or there are any other criteria considered sufficiently reliable by the investigator in individual cases

Indication-specific exclusion criteria in order to guarantee the highest degree of safety of all treatment procedures from a medical point of view:

• Primary infra-tentorial located glioblastoma (justification: specific subgroup of patients with different prognosis)

• Significant comorbidities at baseline, which would prevent possible chemotherapy, including:

  i. Platelet count < 100/nl ii. Absolute neutrophil count (ANC) < 1.5/nl iii. AST or ALT > 3 times the upper limit of normal iv. Total bilirubin above the normal range v. Serum creatinine > 1.7 mg/dl

• Patients with clinically significant liver-, renal- or blood disorder

• Patients with known additional significant neurological disease (e.g. primary seizure disorder*, de-mentia, progressive degenerative neurological disease, meningitis or encephalitis, hydrocephalus with increased intracranial pressure)

• Patients with brain tumor-related epilepsy, seizure-free under antiepileptic therapy are eligible

• Active implanted medical device (e.g. deep brain stimulators, spinal cord stimulators, vagus nerve stimulators, pacemakers, defibrillators and programmable shunts) or documented clinically signifi- cant arrhythmias

• History of HIV infection