Polyclonal expansion of functional tumor-reactive lymphocytes infiltrating glioblastoma for personalized cell therapy

Martina Maffezzini, Silvia Musio, Natalia Ianni, Agnese Rumolo, Monica Patanè, Andrea Galluzzo, Irene Sambruni, Arianna Berlendis, Domenico Aquino, Giacomo Baso, Manuela Zingarelli, Manuel Facciolla, Luisa Maddaloni, Rossella Valentino, Rosina Paterra, Fabio Agistri, Mariangela Farinotti, Luca Mattei, Paola Coluccia, Francesco Acerbi, Francesco DiMeco, Bianca Pollo, Antonio Silvani, Marica Eoli, Catia Traversari, Daniela Montagna and Serena Pellegatta ()
Additional contact information
Martina Maffezzini: Fondazione IRCCS Istituto Neurologico Carlo Besta
Silvia Musio: Fondazione IRCCS Istituto Neurologico Carlo Besta
Natalia Ianni: Fondazione IRCCS Istituto Neurologico Carlo Besta
Agnese Rumolo: Fondazione IRCCS Policlinico San Matteo
Monica Patanè: Fondazione IRCCS Istituto Neurologico Carlo Besta
Andrea Galluzzo: Fondazione IRCCS Istituto Neurologico Carlo Besta
Irene Sambruni: Fondazione IRCCS Istituto Neurologico Carlo Besta
Arianna Berlendis: Fondazione IRCCS Istituto Neurologico Carlo Besta
Domenico Aquino: Fondazione IRCCS Istituto Neurologico Carlo Besta
Giacomo Baso: Fondazione IRCCS Istituto Neurologico Carlo Besta
Manuela Zingarelli: Fondazione IRCCS Istituto Neurologico Carlo Besta
Manuel Facciolla: Fondazione IRCCS Istituto Neurologico Carlo Besta
Luisa Maddaloni: Fondazione IRCCS Istituto Neurologico Carlo Besta
Rossella Valentino: Fondazione IRCCS Istituto Neurologico Carlo Besta
Rosina Paterra: Fondazione IRCCS Istituto Neurologico Carlo Besta
Fabio Agistri: Fondazione IRCCS Istituto Neurologico Carlo Besta
Mariangela Farinotti: Fondazione IRCCS Istituto Neurologico Carlo Besta
Luca Mattei: Fondazione IRCCS Istituto Neurologico Carlo Besta
Paola Coluccia: Fondazione IRCCS Istituto Nazionale dei Tumori
Francesco Acerbi: University of Pisa
Francesco DiMeco: Fondazione IRCCS Istituto Neurologico Carlo Besta
Bianca Pollo: Fondazione IRCCS Istituto Neurologico Carlo Besta
Antonio Silvani: Fondazione IRCCS Istituto Neurologico Carlo Besta
Marica Eoli: Fondazione IRCCS Istituto Neurologico Carlo Besta
Catia Traversari: Unit of Cell Therapy Fondazione IRCCS Istituto Neurologico Carlo Besta
Daniela Montagna: Fondazione IRCCS Policlinico San Matteo
Serena Pellegatta: Fondazione IRCCS Istituto Neurologico Carlo Besta

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: Abstract Tumor-infiltrating lymphocyte (TIL)-therapy has received FDA approval for the treatment of advanced melanoma and shows potential for broader applications in solid tumors, including glioblastoma. In this study, tumor-reactive TILs (tr-TILs) are isolated and enriched for CD137 expression from cavitron ultrasonic aspirator (CUSA) emulsions of 161 adult patients diagnosed with diffuse gliomas. Tr-TILs are successfully expanded in 87 out of the 161 patients, reflecting an expansion rate of 54%. Notably, the presence of IDH1 mutation and the cumulative dose of steroids are identified as significant negative predictors of expansion efficacy. The expanded tr-TILs exhibit distinct phenotypic and molecular dysfunctional features yet show upregulated expression of progenitor/memory-like markers and polyclonal T-cell receptors. Importantly, these tr-TILs demonstrate specific antitumor reactivity against autologous tumor cells in both in vitro and in vivo xenograft models. These findings provide a compelling background for a personalized immunotherapeutic approach while tackling one of the most significant challenges in oncology.

Date: 2025
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DOI: 10.1038/s41467-025-62263-2

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