Advanced MRI Assessment during Dendritic Cell Immunotherapy Added to Standard Treatment Against Glioblastoma

Abstract

Evaluating changes induced by immunotherapies (IT) on conventional magnetic resonance imaging (MRI) is difficult because those treatments may produce inflammatory responses. To explore the potential contribution of advanced MRI to distinguish pseudoprogression (PsP) and true tumor progression (TTP), and to identify patients obtaining therapeutic benefit from IT, we examined aMRI findings in newly diagnosed glioblastoma treated with dendritic cell IT added to standard treatment. We analyzed longitudinal MRIs obtained in 22 patients enrolled in the EUDRACT N° 2008-005035-15 trial. According to RANO criteria, we observed 18 TTP and 8 PsP. Comparing MRI performed at the time of TTP/PsP with the previous exam performed two months before, a difference in cerebral blood volume ΔrCBVmax ≥ 0.47 distinguished TTP from PsP with a sensitivity of 67% and specificity of 75% (p = 0.004). A decrease in minimal apparent diffusion coefficient rADCmin (1.15 vs. 1.01, p = 0.003) was observed after four vaccinations only in patients with a persistent increase of natural killer cells (response effectors during IT) in peripheral blood. Basal rADCmin > 1 was independent predictor of longer progression free (16.1 vs. 9 months, p = 0.0001) and overall survival (32.8 vs. 17.5 months, p = 0.0005). In conclusion, rADC predicted response to immunotherapy and survival; Apparent Diffusion Coefficient (ADC) and Cerebral Blood Volume (CBV) modifications over time help differentiating PsP from TTP at onset.

Radiomic biomarkers of tumor immune biology and immunotherapy response

“…Changes in DWI parameters may also provide value in predicting immunotherapy response. Recently, Cuccarini et al found that up to 4 months after immunotherapy via dendritic cell vaccine, an increase in NK cell response was associated with a decrease in normalized minimum ADC (rADC min ) [54]. Interestingly, higher pre-vaccination rADC min , which is consistent with higher baseline permissiveness to immune cell infiltration, was associated with better PFS and OS [54].…”

“…Currently, few biomarkers exist to measure the temporal response of tumors to immunotherapy. Recent studies have demonstrated the importance of radiomic measurements before and after treatment in predicting response to immunotherapy, specifically for checkpoint inhibition and dendritic cell therapy [34,[42][43]54]. Changes to FDG uptake features, rADCmin, and perinodular Gabor were shown to be associated with response and prognosis, and ought to be validated in future studies.…”

“…1), we identified 54 studies in which imaging features were associated with tumor immune phenotypes (Table 1 and Supplemental Table 1) or response to immunotherapy (Table 2 and Supplemental Table 2). The following types of cancers were investigated: lung [3,[26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44] (20), brain [45][46][47][48][49][50][51][52][53][54] (10), breast [55][56][57][58][59][60][61][62][63] (9), liver [9,41,[64][65]…”

“…Recently, Cuccarini et al found that up to 4 months after immunotherapy via dendritic cell vaccine, an increase in NK cell response was associated with a decrease in normalized minimum ADC (rADC min ) [54]. Interestingly, higher pre-vaccination rADC min , which is consistent with higher baseline permissiveness to immune cell infiltration, was associated with better PFS and OS [54]. While increased baseline diffusion may be prognostic, DADC appears to be the relevant interval biomarker for predicting immunotherapy response.…”

Innovative and Promising Strategies to Enhance Effectiveness of Immunotherapy for CNS Tumors: Where Are We?

“…Several approaches aimed at overcoming this CNS tumor limitation have been described. Current evidence deriving from phase I and II trials suggests that DC vaccination may activate an immune response against CNS tumors (198)(199)(200)(201)(202). Although more than 500 GBM patients have been treated with DC vaccination and clinical results have been encouraging, there is not robust evidence of clinical efficacy, because of either the noncontrolled design of the studies or the low patient numbers.…”