Immunocompetent Mouse Models in the Search for Effective Immunotherapy in Glioblastoma

Abstract

Glioblastoma (GBM) is the most aggressive intrinsic brain tumor in adults. Despite maximal therapy consisting of surgery and radio/chemotherapy, GBM remains largely incurable with a median survival of less than 15 months. GBM has a strong immunosuppressive nature with a multitude of tumor and microenvironment (TME) derived factors that prohibit an effective immune response. To date, all clinical trials failed to provide lasting clinical efficacy, despite the relatively high success rates of preclinical studies to show effectivity of immunotherapy. Various factors may explain this discrepancy, including the inability of a single mouse model to fully recapitulate the complexity and heterogeneity of GBM. It is therefore critical to understand the features and limitations of each model, which should probably be combined to grab the full spectrum of the disease. In this review, we summarize the available knowledge concerning immune composition, stem cell characteristics and response to standard-of-care and immunotherapeutics for the most commonly available immunocompetent mouse models of GBM.

Towards more accurate preclinical glioblastoma modelling: reverse translation of clinical standard of care in a glioblastoma mouse model

“…These failures underscore the important translational gap currently present between the preclinical research and the clinical setting [13]. As shown in a review published by our group, a strong research investment directed to the development of new and more accurate tumor models could be noted, in the attempt to generate murine HGGs that would be as close as possible to their human counterpart [14]. However, this represents only part of the problem and another important discrepancy must be pointed out.…”

Immunotherapy for glioblastoma: the promise of combination strategies

“…Additionally, luciferase-expressing GL261 cells display even more immunogenic features than GL261, with a prolonged median survival time and an elevated inflammatory cytokines production [ 174 ]. Transitioning to other models that are less immunogenic and closer to human GBM is highly encouraged [ 175 ]. To that purpose, the recently developed SB28 and 005 GSC models are interesting alternatives and are among the best syngeneic models to represent human GBM TME [ 147 , 171 , 176 – 178 ].…”

“…However, the perfect model imitating exactly all characteristics of human GBM (e.g., intratumoral heterogeneity, invasive properties, low immunogenicity, resistance to radio- and chemotherapy) doesn’t exist [ 172 , 175 ]. It is therefore crucial to design the experiment and select the models according to their unique characteristics.…”

“…It is therefore crucial to design the experiment and select the models according to their unique characteristics. In addition, studies on different models will help to develop a more general therapy against GBM by (i) covering multiple aspects of GBM immunology and (ii) addressing GBM heterogeneity (intratumoral and interpatient) [ 175 ].…”

Establishing Imaging Biomarkers of Host Immune System Efficacy during Glioblastoma Therapy Response: Challenges, Obstacles and Future Perspectives

“…The following supporting information can be downloaded at: , Figure S1: Summary of steps performed for the nosological images calculation mentioned in this work; Figure S2: Hypothetical scheme for the rationale behind changes in the nosological images coding for response in MRSI of IMS-TMZ treated GB GL261 bearing mice; Table S1: Main similarities/differences between GL261 tumors and human GB tumors; Table S2: Metabolites (ppm and tentative assignment) associated with the main changes observed in the metabolomics profile of control and TMZ-treated GL261 GB. References [ 144 , 145 , 146 , 147 , 148 , 149 , 150 , 151 , 152 , 153 , 154 , 155 , 156 , 157 , 158 , 159 , 160 , 161 , 162 , 163 , 164 , 165 , 166 , 167 , 168 , 169 ] are cited in Supplementary Materials.…”