Physiological Imaging Methods for Evaluating Response to Immunotherapies in Glioblastomas

Abstract

Glioblastoma (GBM) is the most malignant brain tumor in adults, with a dismal prognosis despite aggressive multi-modal therapy. Immunotherapy is currently being evaluated as an alternate treatment modality for recurrent GBMs in clinical trials. These immunotherapeutic approaches harness the patient’s immune response to fight and eliminate tumor cells. Standard MR imaging is not adequate for response assessment to immunotherapy in GBM patients even after using refined response assessment criteria secondary to amplified immune response. Thus, there is an urgent need for the development of effective and alternative neuroimaging techniques for accurate response assessment. To this end, some groups have reported the potential of diffusion and perfusion MR imaging and amino acid-based positron emission tomography techniques in evaluating treatment response to different immunotherapeutic regimens in GBMs. The main goal of these techniques is to provide definitive metrics of treatment response at earlier time points for making informed decisions on future therapeutic interventions. This review provides an overview of available immunotherapeutic approaches used to treat GBMs. It discusses the limitations of conventional imaging and potential utilities of physiologic imaging techniques in the response assessment to immunotherapies. It also describes challenges associated with these imaging methods and potential solutions to avoid them.

Multiparametric MRI assessment of response to convection-enhanced intratumoral delivery of MDNA55, an interleukin-4 receptor targeted immunotherapy, for recurrent glioblastoma

“…[ 1 , 2 , 6 , 10 , 13 , 19 , 22 , 28 - 30 , 32 , 33 ] On DTI, successful treatment is exhibited by increase in MD, and decrease in FA values reflecting destruction of tumor cells and reduction of barriers to proton motion. [ 5 , 20 , 21 , 32 ] From our case, we observed large % decreases (33–37%) in FA at follow-up periods relative to baseline indicating favorable treatment response. These results are in conformity with the previous studies reporting that reduced FA is associated with positive treatment outcomes.…”

“…[ 12 ] In recent times, dynamic contrast enhanced (DCE) MRI-derived parameters, such as volume transfer constant (K trans ) and volume fraction of plasma space in tissue (v p ) that are known to be less prone to susceptibility artifacts, have also been used in assessing the treatment response in GBMs. [ 4 , 5 , 15 ] Unfortunately, we did not have the availability of DCE-MRI data at all time points in our case due to time constraints. Nevertheless, we did not find any evidence of microhemorrhages within the tumor beds and we believe that CBV maps were reliable enough in assessing the effects of immunotherapy on tumor vasculature in our case.…”

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

“…Currently, pseudoprogression is still distinguished from true progression through sequential follow-up examinations for at least 3 months, potentially wasting precious time and resources. This situation may become even more challenging for the novel immunotherapy approaches, for which robust non-invasive biomarkers of early response are still missing [ 19 , 20 ]. In summary, conventional MRI alone cannot provide early and confident biomarkers for predicting the response to therapy in GB cases, at least when analyzed in the standard way.…”

“…This will be fine, provided that the information accrued is sufficient to produce the required translational answer. Most probably, MR and PET explorations will complement each other (see also Chawla et al, 2021 [ 20 ]). It seems sensible to expect multi-timepoint explorations in days to be MR-based, while confirmatory single timepoint explorations, asking single questions, should be based on PET scans.…”

“…On the other hand, all three cellular parameters can be relatively quantitated non-invasively by PET [ 23 , 24 , 25 , 26 , 114 ]. Thus, PET could confirm GB patients’ response status proposed by MRI/MRSI (see also [ 20 ]), allowing evidence-based decisions by the clinical review team as to whether the patient should stay in the initial therapy or discontinue it and switch to a second line, much faster in comparison with currently established follow-up protocols.…”