In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 12_Supplement ( 2022-06-15), p. 5213-5213
Abstract:
Increasing clinical use of immune checkpoint inhibitors testifies to the importance of modulating the immune TME to obtain meaningful anti-tumor immune responses. Acting only on T lymphocytes may, however, not be sufficient, e.g. in immunologically-cold tumors or due to de novo or acquired resistance. Moreover, immune-related AEs remain hurdles of T cell therapies. To overcome these limitations and to awaken the immune system in an agnostic way against the tumor, we have developed a genetically modified cell-based autologous hematopoietic stem cell platform (Temferon) delivering immunotherapeutic payloads into the TME through Tie-2 expressing monocytes (TEMs), a subset of tumor infiltrating macrophages. TEM-GBM is an ongoing open-label, Phase 1/2a dose-escalating study evaluating the safety & efficacy of Temferon in up to 21 newly diagnosed patients with glioblastoma & unmethylated MGMT promoter assigned to 7 different cohorts (3 pts each) differing by Temferon dose (0.5-4.0x106/kg) and conditioning regimen (BCNU+ or Busulfan+Thiotepa). By Oct 15th, 2021, 15 pts (cohort 1-5) had received escalating doses of Temferon with a median follow up of 267 days (range: 60-749). Rapid engraftment and hematological recovery from nonmyeloablative conditioning occurred in all pts. Temferon-derived differentiated cells, as determined by the presence of vector genomes in the DNA, were found at increasing proportions in PB and BM, reaching up to 30% at 1 month for the highest cohorts tested (2.0x106/kg) and persisting up to 18 months, albeit at lower levels. Despite the significant proportion of engineered cells, only very low median concentrations of IFNα were detected in the plasma (D+30, 5.9; D+90, 8.8pg/mL) and in the cerebrospinal fluid (D+30, 1.5; D+90, 2.4pg/mL), indicating tight regulation of vector expression. SAEs were mostly attributed to conditioning chemotherapy (e.g. infections) or disease progression (e.g. seizures). 1 SUSAR (persistent GGT elevation) has occurred. Median OS is 14 mth from surgery (11 mth post Temferon). Four pts from the low dose cohorts underwent 2nd surgery. These recurrent tumors contained gene-marked cells and expressed IFN-responsive genes, indicative of local IFNα release by TEMs. In 1 pt, a stable lesion (as defined by MRI) had a higher proportion of T cells & TEMs, an increased IFN-response signature and myeloid re-programming revealed by scRNAseq, as compared to a synchronous, progressing tumor. TCR sequencing of blood and tumor samples showed a post-treatment increase in the cumulative frequency of tumor-associated T cell clones identified in 1st and 2nd surgery specimens (up to 4 out of 9 subjects). These results provide initial evidence for on-target activity of Temferon in GBM, to be consolidated with longer follow up in the higher dose cohorts. Citation Format: Bernhard Gentner, Gaetano Finocchiaro, Francesca Farina, Marica Eoli, Alessia Capotondo, Elena Anghileri, Matteo Barcella, Maria Grazia Bruzzone, Matteo Giovanni Carrabba, Valeria Cuccarini, Giorgio D'Alessandris, Francesco Di Meco, Valeria Ferla, Paolo Ferroli, Filippo Gagliardi, Federico Legnani, Pietro Mortini, Matteo Maria Naldini, Alessandro Olivi, Roberto Pallini, Monica Patanè, Rosina Paterra, Bianca Pollo, Marco Saini, Silvia Snider, Valentina Brambilla, Stefania Mazzoleni, Andrew Zambanini, Carlo Russo, Luigi Naldini, Fabio Ciceri. Genetically modified Tie-2 expressing monocytes target IFN-α2 to the glioblastoma tumor microenvironment (TME): Preliminary data from the TEM-GBM Phase 1/2a study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5213.
Type of Medium:
Online Resource
ISSN:
1538-7445
DOI:
10.1158/1538-7445.AM2022-5213
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2022
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
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