Response assessment of GBM during immunotherapy by delayed contrast treatment response assessment maps

Valeria Cuccarini; Filippo Savoldi; Yael Mardor; David Last; Serena Pellegatta; Federica Mazzi; Maria Grazia Bruzzone; Elena Anghileri; Bianca Pollo; Luisa Maddaloni; Camilla Russo; Elisa Bocchi; Valentina Pinzi; Marica Eoli; Domenico Aquino

doi:10.3389/fneur.2024.1374737

Response assessment of GBM during immunotherapy by delayed contrast treatment response assessment maps

Front Neurol. 2024 Apr 8:15:1374737. doi: 10.3389/fneur.2024.1374737. eCollection 2024.

Authors

Affiliations

¹ Neuroradiology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.
² Advanced Technology Center, Sheba Medical Center, Ramat Gan, Israel.
³ Tel Aviv University, Tel Aviv, Israel.
⁴ Molecular Neuro-Oncology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.
⁵ Neuro-Pathology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.
⁶ Dipartimento di Ingegneria Elettrica e delle Tecnologie dell'Informazione (DIETI), Università Degli Studi di Napoli "Federico II", Naples, Italy.
⁷ Radiotherapy Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.

Abstract

Introduction: Assessing the treatment response of glioblastoma multiforme during immunotherapy (IT) is an open issue. Treatment response assessment maps (TRAMs) might help distinguish true tumor progression (TTP) and pseudoprogression (PsP) in this setting.

Methods: We recruited 16 naïve glioblastoma patients enrolled in a phase II trial consisting of the Stupp protocol (a standardized treatment for glioblastoma involving combined radiotherapy and chemotherapy with temozolomide, followed by adjuvant temozolomide) plus IT with dendritic cells. Patients were followed up till progression or death; seven underwent a second surgery for suspected progression. Clinical, immunological, and MRI data were collected from all patients and histology in case of second surgery. Patients were classified as responders (progression-free survival, PFS > 12 months), and non-responders (PFS ≤ 12), HIGH-NK (natural killer cells, i.e., immunological responders), and LOW-NK (immunological non-responders) based on immune cell counts in peripheral blood. TRAMs differentiate contrast-enhancing lesions with different washout dynamics into hypothesized tumoral (conventionally blue-colored) vs. treatment-related (red-colored).

Results: Using receiver operating characteristic (ROC) curves, a threshold of -0.066 in V_Blue/V_CE (volume of the blue portion of tumoral area/volume of contrast enhancement) variation between values obtained in the MRI performed before PsP/TTP and at TTP/PSP allowed to discriminate TTP from PsP with a sensitivity of 71.4% and a specificity of 100%. Among HIGH-NK patients, at month 6 there was a significant reduction compared to baseline and month 2 in median "blue" volumes.

Discussion: In conclusion, in our pilot study TRAMs support the discrimination between tumoral and treatment-related enhancing features in immunological responders vs. non-responders, the distinction between PsP and TTP, and might provide surrogate markers of immunological response.

Keywords: Stupp protocol; TRAMs; glioblastoma; immunological responders; immunotherapy; magnetic resonance imaging; natural killer cells; pseudoprogression.

Grants and funding

The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. This study is carried out as part of an oncology network (Rete Oncologica Lombarda) and funded referring to the deliberations of the regional council of Regione Lombardia No. VIII/010761 of 11 December 2009 and DGR IX/1485 of 30 March 2011; contribution of the Italian Ministry of Health (RF-2019-12371008).