Abstract CT127: A macrophages-based immunotherapy of solid tumors microenvironment: Preliminary results of the TEM-GBM_01 study
Authors: Farina Francesca , Gentner Bernhard , Finocchiaro Gaetano , Eoli Marica , Capotondo Alessia , Anghileri Elena , Barcella Matteo , Brambilla Valentina , Carrabba Matteo , Cuccarini Valeria , D'alessandris Quintino Giorgio , DiMeco Francesco , Ferla Valeria , Ferroli Paolo , Gagliardi Filippo , Legnani Federico , Mazzoleni Stefania , Olivi Alessandro , Pallini Roberto , Saini Marco , Naldini Luigi , Russo Carlo , Ciceri Fabio 
Published: April 2024

Abstract
Glioblastoma multiforme (GBM) is an incurable tumor affecting the central nervous system. The reported median survival in the unfavorable patients′ subgroup with unmethylated MGMT promoter is 12.7 months with less than the 15% of patient surviving up to 2–years. Despite immunotherapies being able to slow or eradicate numerous tumors, none so far have extended survival in GBM. Using genetically modified autologous CD34+ HSPCs, we developed an advance medicinal product, (Temferon) designed to deliver interferon–α2 within the TME by Tie–2 expressing macrophages (TEMs). Temferon is currently in the clinic in a Phase 1/2a dose-escalation non-randomized open label study in newly diagnosed GBM with unmethylated MGMT. The study aims to evaluate the short– (up to 90 days) and long– (up to 2 years) term tolerability and safety of 5 escalating doses in up to 27 GBM patients. Following a sub–myeloablative conditioning regimen (Thiotepa + BCNU or Thiotepa + Busulfan or Busulfan alone), up to 3 million Temferon cells/kg are administered with a fixed dose of non–manipulated CD34+ supporter cells As of 27th July 2023, 21 GBM patients in 7 cohorts received incremental Temferon doses and 5 patients were still alive with a 17 months median OS and a 8.3 months median PFS (95% CI) post surgery. To date, no DLTs have been identified. In all patients, rapid engraftment and fast hematological recovery have been observed within 2 weeks from the transplantation. Grade 4 or 5 serious adverse events (n=7 patients), were mostly attributed to the conditioning chemotherapy, but steroid usage or disease progression were also listed. 1 SUSAR (persistent GGT elevation) occurred. The higher transduced cells proportion in the BM was observed 30 days after Temferon with a chimerism for the highest dose tested up to 40%, still detectable in the long–term. Very low IFNα concentrations were detected in the plasma, indicating a tight vector expression regulation. 7 patients underwent second surgery and genetically engineered cells were detected (in 85%) within the bulk tumor lesion (&gt;3% in 3 patients). IFN–responsive genes (IGS) were up–regulated, suggesting a local IFNα release by TEMs. In 1 patient, a stable lesion, compared to a synchronous, progressing lesion, had a higher proportion of T cells & TEMs, an increased IGS e and myeloid re–programming. TCR blood and tumor sample sequencing showed a post–treatment increase of peripherally expanded clones frequency in the tumor samples, as evidence of a crosstalk between peripheral and tumor T cell repertoires . These data corroborate the initial evidence on safety and tolerability of Temferon and suggest that Temferon has potential to counteract disease progression in patients affected by unmethylated MGMT GBM. Clinical Trial Registry (if applicable): NCT03866109
Citation Format: Francesca Farina, Bernhard Gentner, Gaetano Finocchiaro, Marica Eoli, Alessia Capotondo, Elena Anghileri, Matteo Barcella, Valentina Brambilla, Matteo Carrabba, Valeria Cuccarini, Quintino Giorgio D'alessandris, Francesco DiMeco, Valeria Ferla, Paolo Ferroli, Filippo Gagliardi, Federico Legnani, Stefania Mazzoleni, Alessandro Olivi, Roberto Pallini, Marco Saini, Luigi Naldini, Carlo Russo, Fabio Ciceri. A macrophages-based immunotherapy of solid tumors microenvironment: Preliminary results of the TEM-GBM_01 study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT127.