Refer to 5.1.2 and 5.1.3 for tissue collection for Correlatives. 3.4 RADIATION THERAPY (RT) All eligible patients will be treated with standard RT to approximately 60 Gy (180 cGy (1.8 Gy) x 33 fractions or 200 cGy (2.0 Gy) x 30 fractions). 3.5 DRUG A DMINISTRATION 3.5.1 (RT+TMZ+Pembro) TMZ will be administered orally on day 1 of radiation therapy (RT) 1-2 hours before each session of radiotherapy or 1 night before RT (within 24 hours before Day 1); and it should be administered the same time throughout the course of RT. TMZ should continue throughout RT at the dose of 75 mg/m2/day. During weekends without radiotherapy (Saturday and Sunday), the drug will be taken at the same time as on radiotherapy days. Pembrolizumab at 200 mg will be administered on day 1 as a 30 minute IV infusion (+/- 24 hours day of RT) every 3 weeks during RT Phase on days 1, 22 and 43 (+/- 24 hours for each timepoint). Sites should make every effort to target infusion timing to be as close to 30 minutes as possible. However, given the variability of infusion pumps from site to site, a window of -10 minutes and +10 minutes is permitted (i.e., infusion time is 30 minutes: -10 min/+10 min). Observation for one hour after the infusion of the first dose of Pembrolizumab is recommended. 3.5.2 HSPPC-96 Vaccine or Placebo HSPPC-96 vaccine will be produced prior to the end of RT. If > 4 doses can be made, the patient will then be randomized 1:1 to the treatment with TMZ + Pembrolizumab with HSPPC- 96 vaccine or placebo. 39 Abbreviated Title: GBM Pembro HSPPC Version Date: 03/26/2024 3.6 POST RT TREATMENT REGIMEN 3.6.1 For patients not randomized (ancillary arm 2) Four weeks post end of RT, an MRI will be performed and then patients will start TMZ (days 1- 5 and 29-33) + Pembrolizumab (days 1, 22 and 43 of each cycle +/- 24 hours for each timepoint). 1 cycle = 9 weeks.