Glioblastoma immunotherapy in the context of the aging immune system: a systematic review and meta-analysis

Immunotherapy has yet to meaningfully translate to more complex solid tumors, such as Glioblastoma (GBM), which is a disease of old age with a median diagnosis age of 64. Despite this clear age bias, very little research has been conducted on the interplay between the aging immune system and its impact on the efficacy of immunotherapy. A literature search and meta-analysis was performed to quantify the role of the aged immune system during immunotherapy treatments in GBM. Registered clinical trials conducted from Jan 2000-April 2025 were analyzed and risk ratio of death at 1 year post treatment was calculated using patient level data for participants aged 65 and older and 64 and under. Across 30 total studies and 556 patients’ data revealed a significantly higher risk of death (RR: 1.29: (1.09-1.53), p = 0.0040) at or before 1 year post immunotherapy treatment in the aged population compared to the young population. This risk was even larger in newly diagnosed GBM (RR: 2.24: (1.39-3.61), p = 0.0026). Finally, when examining the ages of patients enrolled in GBM immunotherapy clinical trials we found a significant bias towards enrolling younger patients. This bias was not present among lung cancer, also a disease of older adults, immunotherapy clinical trials. These data highlight that the aging of the immune system may play a role in the response to immunotherapy and trial designs with better tracking and reporting of this variable will allow for a more careful examination of this effect and overall successful immunotherapy development.