379TiP - TEM-GBM: A phase I-IIa clinical study of genetically modified Tie-2-expressing monocytes in patients with glioblastoma multiforme

Background

We developed a cell-based treatment, Temferon, relying on ex-vivo transduction of autologous HSPCs to express IFNa within the tumor microenvironment by Tie-2-expressing macrophages (TEMs). As of 8^th April 2021, 18 patients have been enrolled; 12 received Temferon (D+0) with follow-up of 42 – 640 days. There was rapid engraftment and hematological recovery after the conditioning regimen. Median neutrophil & platelet engraftment occurred at D+13 and D+12, respectively. Temferon-derived differentiated cells, as determined by the presence of vector genomes in the DNA of peripheral blood and bone marrow cells, were found within 14 days post treatment and persisted albeit at lower levels up to 18 months. We also detected very low concentrations of IFNa in the plasma & in the CSF, suggesting tight regulation of transgene expression. 3 deaths occurred: 2 at D+340 & +402 after Temferon administration due to disease progression, 1 at D+60 due to complications following the conditioning regimen. Eight patients had progressive disease (PD; range D-11 to +239) as expected for this tumor type. SAEs include infections, venous thromboembolism, brain abscess, hemiparesis, GGT elevation & poor performance status compatible with ASCT, concomitant medications & PD. Four patients underwent second surgery. These recurrent tumors had gene-marked cells present and increased expression of IFN-responsive gene signatures compared to diagnosis, indicative of local IFNa release by TEMs. In one patient, a stable lesion (as defined by MRI) had a higher proportion of T cells and TEMs within the myeloid infiltrate and an increased ISG than in a progressing lesion. The T-cell immune repertoire changed with evidence for expansion of tumor-associated clones. Our interim results show that Temferon is well tolerated by patients, with no dose limiting toxicities identified to date. The results provide initial evidence of Temferon potential to activate the immune TME of GBM patients, as predicted by preclinical studies.

Trial design

TEM-GBM is an open-label, phase I/IIa dose-escalation study evaluating safety and efficacy of Temferon in up to 21 newly diagnosed patients with glioblastoma and unmethylated MGMT promoter.

Clinical trial identification

NCT03866109.

Editorial acknowledgement

Legal entity responsible for the study

Genenta Science.

Funding

Genenta Science.

Disclosure

B. Gentner: Financial Interests, Personal, Funding: Genenta Science; Financial Interests, Personal, Stocks/Shares: Genenta Science; Financial Interests, Personal, Advisory Board: Genenta Science. S. Mazzoleni: Financial Interests, Personal, Full or part-time Employment: Genenta Science; Financial Interests, Personal, Stocks/Shares: Genenta Science. C. Russo: Financial Interests, Personal, Stocks/Shares: Genenta Science; Financial Interests, Personal, Full or part-time Employment: Genenta Science. L. Naldini: Financial Interests, Personal, Advisory Board: Genenta Science; Financial Interests, Personal, Stocks/Shares: Genenta Science; Financial Interests, Personal, Funding: Genenta Science. All other authors have declared no conflicts of interest.