Reframing Radical Chemoradiation for High-Grade Glioma: The Iatrogenic Immunosuppression Bottleneck and the Case for a Lymphocyte-Sparing, Molecularly Stratified Backbone

Abstract

Newly diagnosed high grade glioma has been treated with radical radiotherapy with concomitant and adjuvant temozolomide (the Stupp regimen) since 2005, but median overall survival has only had a marginal improvement over the last 20 years, and recurrence is close to universal [1, 3]. Meanwhile, immune checkpoint blockade has now revolutionized treatment in melanoma and lung cancer, but has not had any positive effect in any large randomized trials in glioblastoma [15,16,17]. The two facts are typically broken down as two distinct points. We believe that they are related. We propose that the standard chemoradiation backbone itself is a powerful and durable immunosuppressive intervention, and that the treatment-related lymphopenia is an iatrogenic immunosuppression bottleneck – once the effector lymphocytes that any immunotherapy requires to mobilize are depleted, it may undermine the efficacy of both itself and any agents added to it. The principal causes of lymphopenia (radiation doses to circulating blood and to lymphocyte-rich structures, size of the target volume, temozolomide alkylation, and corticosteroids) can all be modified and therefore lymphopenia should not be considered as an inevitable side effect, but rather a quantifiable, partially avoidable side effect associated with the treatment of the organ-at-risk. We combine the 2021 WHO molecular reclassification of grade 4 gliomas [4] and the radiobiology of treatment-related lymphopenia to establish a backbone of lymphocyte-sparing molecularly stratified chemoradiation, and to define a biomarker-stratified randomized trial with preserved absolute lymphocyte count as a co-primary endpoint with survival. If it's accurate, the framework is a 20-year-old standard that's no longer a platform on which drugs are simply dropped on, but one that can be adjusted so that the drugs can perform better.