Abstract CT180: Changes in immunologic responses and in the tumor microenvironment in patients with glioblastoma multiforme treated with IFN-a immune cell and gene therapy (TEM-GBM_001 Study)

• Published in: Cancer research (Chicago, Ill.) Ill.), 2021-07, Vol.81 (13_Supplement), p.CT180-CT180
• Main Authors: Gentner, Bernhard, Finocchiaro, Gaetano, Farina, Francesca, Capotondo, Alessia, Eoli, Marica, Anghileri, Elena, Ganzetti, Maya, Carabba, Matteo, Cuccarini, Valeria, Meco, Francesco Di, Legnani, Federico, Pollo, Bianca, Bruzzone, Maria Grazia, Saini, Marco, Ferroli, Paolo, Pallini, Roberto, Olivi, Alessandro, Paterra, Rosina, Garramone, Mariagrazia, Mazzoleni, Stefania, Brambilla, Valentina, Magnani, Tiziana, Antonarelli, Gabriele, Naldini, Matteo, Barcella, Matteo, Russo, Carlo, Naldini, Luigi, Ciceri, Fabio
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2021-CT180

Genetically modified cell-based therapies are of increasing relevance in immuno-oncology due to their potential for tumor specificity, long term efficacy & limiting off-target effects. We have developed a genetically modified cell-based platform, with ex-vivo transduction of autologous hematopoietic stem & progenitor cells with a lentiviral vector expressing the IFN-α transgene (Temferon) & delivery by autologous stem cell transplantation (ASCT). Specific control mechanisms restrict transgene expression to Tie-2 expressing macrophages (TEMs) thanks to a specific Tie-2 promoter & a post-transcriptional regulation layer represented by miRNA target sequences. TEM-GBM is an ongoing open-label, Phase I/IIa dose-escalation study evaluating safety & efficacy of Temferon in newly diagnosed patients with glioblastoma & unmethylated MGMT promoter. Part A includes 15 patients to optimize the dose & conditioning regimen (completion expected end of Q2/21), & Part B includes 6 patients. By 10th Nov 2020, 13 patients had enrolled; 8 received Temferon with a median follow up of 298 days (53-491). One patient died from progressive disease (PD) at D+403. PD occurred in 6 patients after a median 123 days (83-229) from treatment, within expectations for this tumor type. 4 patients underwent second surgery. Temferon was well tolerated, with median neutrophil & platelet engraftment occurring at D+13 & D+12, respectively, post submyeloablative BCNU + Thiotepa conditioning, & without dose-limiting toxicities. SAEs attributed to ASCT, concomitant medications & GBM progression included febrile neutropenia & other infectious complications, venous thromboembolism, poor performance status, liver enzyme elevation, brain abscess & hemiparesis. Temferon-derived differentiated cells, as determined by the presence of vector genomes in peripheral blood & bone marrow, were evident within 14 days from treatment & persisted, albeit at lower levels, in the long term (up to 1 year). The built-in transgene expression control mechanism was effective as suggested by the very low concentrations of IFN-α detected in the plasma & cerebrospinal fluid. The T-cell immune repertoire changed after treatment, with evidence for expansion of tumor-associated clones in peripheral blood. Preliminary data on tumor specimens from second surgery confirmed the presence of TEMs & increased expression of IFN-responsive gene signatures compared to diagnosis indicative of local IFN-α release. Biopsies of a stable as co