An NIH/IRB approved patient flyer is used to recruit patients. 2.2 SCREENING EVALUATION 2.2.1 Screening activities performed prior to obtaining informed consent Minimal risk activities that may be performed before the subject has signed a consent include the following: Email, written, in person or telephone communications with prospective subjects Review of existing medical records to include H&P, laboratory studies, etc. Review of existing MRI, x-ray, or CT images Review of existing photographs or videos Review of existing pathology specimens/reports from a specimen obtained for diagnostic purposes A waiver of consent for these activities has been requested in section 12.6.2. 2.2.2 Screening activities performed after a consent for screening has been signed The following activities will be performed only after the subject has signed the consent for this study for screening. Assessments performed at outside facilities or on another NIH protocol within the timeframes below may also be used to determine eligibility once a patient has signed the consent. The screening evaluation elements must be completed within (+/-) 14 days of signing consent unless otherwise noted: Outside lab/procedure results for standard of care studies or another protocol that are performed within this timeframe may be used to determine eligibility. Medical History Prior and Concomitant medication review Karnofsky performance status Physical and Neurological Exam Vital signs and Weight Tumor Imaging (by MRI unless contraindicated) showing tumor consistent with a GBM. Tumor Pathology (before Step 3) Pregnancy Test PT/INR or aPTT CBC with differential Na, K, CL, Bicarbonate, BUN/Cr, AST, ALT, ALP, T. Bili, Calcium, Albumin Urinalysis 31 Abbreviated Title: GBM Pembro HSPPC Version Date: 03/26/2024 2.3 PARTICIPANT REGISTRATION AND STATUS UPDATE PROCEDURES Patients who are candidates for the study will first be evaluated for eligibility by the local investigator. All patients must be registered both locally and centrally with BTTC prior to surgery (see Section 3.3.1, Surgery). BTTC patients will be registered with the BTTC Coordinating Center. All subjects must be registered through the BTTC NCI Central Registration Office (CRO). The CRO is open from 8:30 am to 5:00 pm EST Monday through Friday, excluding federal holidays. If any emails described in sections 2.3.2 through 2.3.6 contain protected health information (PHI), they must be encrypted. 2.3.1 Informed Consent/Authorization Prior to protocol enrollment and initiation of treatment, subjects must sign and date an Institutional Review Board (IRB) approved consent form. Registrations must be completed after the patient has signed the informed consent and has been determined to be eligible by the local investigator. At the time of registration, the following information will be requested by the BTTC Coordinating Center: oA copy of a completed and signed, protocol specific, Registration Form (eligibility checklist) oOne copy of the signed and dated Informed Consent/Authorization. oCopies of all source documents to support protocol specific eligibility. Please refer to the BTTC Operations Manual for specific source documents required. 2.3.2 Registration at the NCI Registration and status updates (e.g., when a participant is taken off protocol therapy and when a participant is taken off-study) will take place per CCR SOP ADCR-2, CCR Participant Registration & Status Updates found here. Registration will be a three part process as patients are screened on this protocol. Authorized staff must register an eligible candidate with NCI Central Registration Office (CRO) within 24 hours of signing consent. See Section 2.3.5 for Step 3 of Registration Form (Randomization at NCI). 2.3.3 Registration at Participating BTTC Sites Registration will be a three part process as patients are screened on this protocol. A protocol registration form and cover memo will be supplied by the Coordinating Center, NCI CCR and updates will be provided as needed. Registration will be completed within 2 business days of receipt of documents required for registration. Step 1: All patients must be registered both locally and centrally with BTTC prior to surgery. To initially register a subject, after the participant has signed the consent, site will complete and send Step 1 of the Registration Form, source documents, and consent form, indicating that the patient is being registered for screening and surgery, to the BTTC Coordinating Center via secure fax (240-541-4432) or send to the BTTC CC research nurse via Secure Email and File Transfer [SEFT] (preferred). Upon confirmation of consent and available slot, the BTTC CC 32 Abbreviated Title: GBM Pembro HSPPC Version Date: 03/26/2024 research nurse will send the Registration Form to NCI Central Registration Office ncicentralregistration-l@mail.nih.gov via encrypted email. Within 1 business day, NCI Central Registration Office will send the Verification of Registration with the assigned subject ID number to the BTTC CC research nurse via encrypted email. The BTTC CC research nurse will email the Verification of Registration to the site and Agenus (redacted with subject ID number and patient initials). The subject ID number is unique to the patient and must be written on all data and correspondence for the patient and used to enter data into the NCI-designated eCRF database. Step 2: Study treatment may not begin until a subject is registered. After completion of screening and surgery, site will complete Step 2 of the Registration Form indicating that the patient has met all inclusion and no exclusion criteria. The Registration Form and source documents will be sent to the BTTC CC via secure fax (240-541-4432) or send to the BTTC CC research nurse via Secure Email and File Transfer [SEFT] (preferred). Upon confirmation of eligibility, the BTTC CC research nurse will sign the Registration Form (eligibility checklist) and send it via encrypted email to the CRO at NCI Central Registration Office ncicentralregistration-l@mail.nih.gov. The CRO will send the Verification of Registration to the BTTC CC research nurse via encrypted email. The BTTC CC research nurse will email the Verification of Registration to the site and Agenus (redacted with study ID number and patient initials). When a participant has a status change (e.g., subject screened on the study, does not meet eligibility criteria and is removed from the study, participant is taken off protocol therapy or off study, etc.), the Participant Status Update Form will be supplied by the BTTC Coordinating Center research nurse coordinator. Send the completed form to the BTTC Research Nursevia secure fax: 240-541-4432, or via Secure Email and File Transfer (SEFT).. See Section 2.3.6 for Step 3 of Registration Form (Randomization for Participating Sites). 2.3.4 Initiation of Therapy (Radiation Therapy, Temozolomide and Pembrolizumab) Treatment may not be initiated until the participating institution receives a faxed or emailed copy of the patient’s Registration Verification Letter from the Central Registration Office. Treatment must be initiated > 14 days and < 6 weeks from surgery. The BTTC Coordinating Center must be notified in writing of any exceptions to this policy. 2.3.5 Registration Step 3: Randomization for NCI Following vaccine manufacture and completion of quality testing, Agenus will send the Vaccine Production Notification form to NCI. This Form indicates whether manufacture of vaccine was successful. The site will send Step 3 of the Registration form and Vaccine Production Notification Form to BTTC CC research nurse via secure fax: 240-541-4432, hand-delivery, or encrypted email. BTTC CC will confirm verification and send via encrypted email to CRO and via Secure Email and File Transfer [SEFT] to Agenus. CRO will send the Verification of Registration with the assigned sequence number to the site and the BTTC CC research nurse via encrypted email. The BTTC CC research nurse will send the Verification of Registration with the assigned sequence number (vaccine assignment) to Agenus (redacted with subject ID number 33 Abbreviated Title: GBM Pembro HSPPC Version Date: 03/26/2024 and patient initials). Agenus will send the blinded vaccine or placebo directly to the site. In parallel, CRO will also notify the NCI Pharmacy to release blinded vaccine or placebo. 2.3.6 Registration Step 3: Randomization for Participating Sites Following vaccine manufacture and completion of quality testing, Agenus will send the Vaccine Production Notification form to the site. This Form indicates whether manufacture of vaccine was successful. The site will send Step 3 of the Registration form and Vaccine Production Notification Form to BTTC CC research nurse via secure fax: 240-541-4432 or via Secure Email and File Transfer [SEFT] (preferred). BTTC CC will confirm verification and send via encrypted email to CRO and via Secure Email and File Transfer [SEFT] to Agenus. CRO will send the Verification of Registration with the assigned sequence number to the BTTC CC research nurse. The BTTC CC research nurse will send the Verification of Registration with the assigned sequence number (vaccine assignment) to the site and Agenus (redacted with subject ID number and patient initials). Agenus will send the blinded vaccine or placebo directly to the site. 2.3.7 Study Status Updates for Participating Sites For participating BTTC Sites: The Participant Status Updates Form will be supplied by the BTTC Coordinating Center, NCI, CCR. Send the completed Participant Status Updates Form via secure fax: 240-541-4432, or via Secure Email and File Transfer (SEFT). 2.3.8 Screen Failures Screen failures are defined as participants who consent to participate in the clinical trial but are not subsequently assigned to the study intervention or entered in the study. A minimal set of screen failure information is required to ensure transparent reporting of screen failure participants, to meet the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to respond to queries from regulatory authorities.