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.
Highlights
The development of immunotherapy against glioblastoma (GBM) has gained considerable interest over the last decade
We reported clinical and immunological data of 24 patients affected by GBM and treated by Dendritic Cells (DC) immunotherapy, together with standard radio-chemotherapy, and we found that increased progression free (PFS) and overall survival (OS) were primarily associated with a significant, persistent activation of natural killer (NK) cells that was not detected in control patients from another parallel study conducted in our Institute that did not imply immunotherapy [7,8]
To evaluate the potential contribution of Advanced MRI (aMRI) to distinguish the inflammatory response (i.e., PsP) from true tumor progression (TTP), and to identify patients who obtained therapeutic benefit from immunotherapy, we examined aMRI diffusion-weighted imaging (DWI) and dynamic susceptibility-weighted imaging perfusion (DSC-magnetic resonance imaging (MRI)) findings of GBM at first diagnosis in patients treated with DC immunotherapy added to standard treatment (surgery, radiotherapy with concomitant chemotherapy with temozolomide (TMZ) followed by adjuvant TMZ) [10]
Summary
The development of immunotherapy against glioblastoma (GBM) has gained considerable interest over the last decade. We reported clinical and immunological data of 24 patients affected by GBM and treated by Dendritic Cells (DC) immunotherapy, together with standard radio-chemotherapy, and we found that increased progression free (PFS) and overall survival (OS) were primarily associated with a significant, persistent activation of natural killer (NK) cells that was not detected in control patients from another parallel study conducted in our Institute that did not imply immunotherapy [7,8]. These data may be sustained by other evidence supporting an important role of DC in NK priming based on IL-15 trans-presentation [9]. Since GBMs are very heterogeneous tumors and given the presence of immune cells infiltrating the tumor during immunotherapy, the histogram analysis of ADC maps (which could allow a better representation of such heterogeneity [11]) was added to the identification of the Region of Interest (ROI)
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