(4) Subject/patient responses in the MDASI will not be impacted with the knowledge of the treatment arm. 3.3 SURGERY & TISSUE C OLLECTION FOR VACCINE ADMINISTRATION 3.3.1 Surgery Patients with presumed GBM based on MRI or if they require a more definitive surgery may be consented for the trial. At the time of surgery, tissue will be collected for vaccine production (≥ 7 grams is required) and processed per Appendix 16.2 Tumor must be confirmed to be MGMT promoter unmethylated and IDH wildtype prior to starting treatment. GBM patients whose tumor is MGMT promoter methylated and is not IDH wildtype are not eligible for treatment on this protocol and will be removed from the protocol. Those patients with < 80% of contrast enhanced tumor resected or < 7 grams of tissue will be no longer eligible for treatment with SOC (RT + TMZ) + Pembrolizumab. Tumor will be measured per RANO criteria. The determination of ≥ 80% resection will be based on the pre-operative and post operative cross sectional measurements, the residual tumor, if any, should be < 20% or original cross sectional measurements. Post tumor resection, all patients must have a post-operative MRI done no more than 72 hours after surgery. This MRI can be used as baseline prior to treatment. 3.3.2 Tissue Collection for Vaccine Production at NCI Tumor sample will be collected at time of surgery by the Laboratory of Pathology NCI. Tissue sections will be obtained and will be labeled with the Study Subject ID number. The relationship between the Study Subject ID number and the patient clinical information will be stored in a secure database that is maintained and regularly backed up by the Laboratory of Pathology NCI. The Laboratory of Pathology NCI will submit tumor tissue for vaccine manufacture according to Appendix 16.2. 38 Abbreviated Title: GBM Pembro HSPPC Version Date: 03/26/2024 Tumor tissue that does not qualify either because of incorrect diagnosis, MGMT status, or presence of IDH mutation will remain at or be returned to the site of origin. Tissue will also be collected at NCI for Correlatives. Refer to 5.1.2, 5.1.3, and 5.1.4 for tissue collection for Correlatives. Tumor tissue that does not qualify either because of incorrect diagnosis, MGMT status, or presence of IDH mutation will remain at or be returned to the site of origin. 3.3.3 Tissue Collection for Vaccine Production at Participating BTTC Sites Tumor sample will be collected at time of surgery at the participating sites. Tissue sections will be obtained and will be labeled with the Study Subject ID number. The participating BTTC site will submit tumor tissue for vaccine manufacture according to Appendix 16.2. Tumor tissue that does not qualify either because of incorrect diagnosis, MGMT status, or presence of IDH mutation will remain at or be returned to the site of origin. Tissue will also be collected at the participating BTTC sites for Correlatives.