OS05.6.A Modification of the tumor microenvironment in patients with glioblastoma using autologous, genetically modified, hematopoietic stem cell-based therapy: the TEM-GBM STUDY (NCT03866109)

Autor: G Finocchiaro, M Eoli, B Gentner, M Bruzzone, F Di Meco, P Mortini, A Olivi, L Naldini, C Russo, F Ciceri
Rok vydání: 2022
Předmět:
Zdroj: Neuro-Oncology. 24:ii13-ii14
ISSN: 1523-5866
1522-8517
Popis: Background Bone marrow-derived macrophages account for substantial GBM tumor volume and contribute to the local inflammatory tumor microenvironment, disease progression and treatment response. Material and Methods We have developed a genetically modified, autologous hematopoietic stem cell-based platform designed to deliver Interferon-alpha (IFNa), thanks to a transcriptional and post-transcriptional control mechanism mediated by miRNA target sequences, specifically into the tumor microenvironment via Tie-2 expressing monocytes (Temferon). Results As of Feb 2022, 3 escalating doses of Temferon (from 0.5 to 2.0x106/kg) were tested across 15 patients with newly diagnosed, unmethylated MGMT glioblastoma (GBM) assigned to 5 cohorts. The duration of follow-up from surgery is 6 - 28 mo (2 - 25 mo after Temferon). To date, no dose limiting toxicities have been identified. As expected, one month after the administration of the highest tested dose, the hematopoietic system of Temferon-treated patients was composed of up to 30% of CD14+ genetically modified cells, as determined by the presence of vector genomes in the DNA in peripheral blood and bone marrow cells. Temferon-derived progeny persisted, albeit at lower levels, up to 18 months (longest time of analysis). Despite the substantial proportion of engineered cells, very low median concentrations of IFNα were detected in the plasma (D+30, 5.9; D+90, 8.8pg/mL) and in the CSF (D+30, 1.5; D+90, 2.4pg/mL), indicating tight regulation of transgene 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 15 mo from surgery (range 6.1-28.4 mo; 10.8 mo post Temferon). Of the 15 pts treated so far, 4 pts belonging to low dose cohorts underwent 2nd surgery. Homing of transduced cells from BM to the tumor site was demonstrated by the presence of gene-marked cells in the specimens collected from 3 of the 4 analyzed pts. Single-cell RNA seq performed on CD45+ cells purified from the TME of Temferon-treated pts compared to recurrent tumors belonging to GBM pts treated as per the current standard of care, highlighted a Temferon signature defined by the induction of markers of IFNa responses and macrophage repolarization. Potential long-term benefit with Temferon was identified in a patient from cohort 3, who had disease progression at D+120 with two distant enhancing lesions, and increased tumor necrosis. One year following Temferon, with no 2nd line therapy added, there was approximately 40% reduction in enhancing tumor volume compared to D+180 with a stable clinical and imaging picture thereafter. Conclusion The results provide initial evidence of Temferon’s potential to modulate the TME of GBM patients, and anecdotal evidence for long lasting effects of Temferon in prevention of disease progression.
Databáze: OpenAIRE
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