This protocol design minimizes the risk of bias and enhances the impartial bias analysis of the study vaccine versus placebo effect. However, it is important to note that in case this information is required for safety purposes (affects care or medically needed), it will be provided in an expedited manner. In this double blind study, neither the study personnel (including pharmacists) nor the subject will have knowledge of the vaccine assignment being administered. Data analysis personnel and the Central Registration Office will have access to vaccine assignment. Blinded vaccine (HSPPC-96 or placebo) will be prepared by Agenus and shipped directly to sites. HSPPC-96 or placebo will be dispensed in identical appearing single-use vial as a clear, colorless solution. Each vial of vaccine or placebo is labeled with the subject/patient number, subject/patient initials, and subject/patient date of birth (DOB). Unblinding may occur at the discretion of the principal investigator and only where knowledge of treatment affects patient care. Site would need to submit the document found in Appendix 16.11 to request unblinding. Unblinding will only be done upon approval by the lead PI as documented in Appendix 16.12. NOTE: Based on the DSMB’s May 2021 decision for early termination, unblinding treatment assignments for participants receiving HSPPC-96 vaccine or placebo will be provided to the Lead NCI PI by the NCI Central Registration Office (CRO) in consultation with and confirmed by Agenus, the vaccine manufacturer. The Lead NCI PI or designee at the BTTC Coordinating 37 Abbreviated Title: GBM Pembro HSPPC Version Date: 03/26/2024 Center will be responsible for notifying site PIs (at the participating BTTC site) of the unblinded treatment assignments for participants receiving HSPPC-96 vaccine or placebo. Participants receiving pembrolizumab, temozolomide and/or HSPPC-96 vaccine will continue to receive those study treatments per Study Calendar (See Section 3.11). Participants who are on placebo will stop receiving placebo but may continue to receive pembrolizumab and/or temozolomide per Section 3.10. Participants who decide to discontinue treatment will continue to be followed for overall survival, and the procedures for removal from protocol therapy will be followed (see Section 3.14). Off-Study Procedures will be followed per protocol for patients who decide to withdraw from the study (see Section 3.14). 3.2.1.1 Rationale for Double Blinding This study has been designed to be double blinded despite having an objectively ascertained primary endpoint for the following reasons: (1) This limits study defection due to randomization disappointment (so subjects randomized to placebo will not quit the study), (2) there will be no difference in the interpretation of biomarkers or lab tests due to knowing the intervention being delivered. (3) Adverse event reporting will not be impacted with the knowledge of the treatment arm.