284MO - Targeting the tumor microenvironment of glioblastoma multiforme using a macrophage-based treatment for the local delivery of immune-therapeutic payload: The TEM-GBM study (NCT03866109)

Background

Bone marrow-derived macrophages account for a substantial Glioblastoma (GBM) tumor volume and contribute to the local inflammatory tumor microenvironment (TME), disease progression & treatment response.

Methods

We have developed a genetically modified, autologous hematopoietic stem cell-based platform designed to deliver IFNa, specifically into the TME via Tie-2 expressing monocytes (Temferon). TEM-GBM is an open-label, phase I/IIa dose-escalation study evaluating safety and efficacy of Temferon in up to 21 newly diagnosed, unmeth-MGMT GBM patients. The patients will be assigned to 7 cohorts and will receive a single increasing dose of Temferon.

Results

As of April 2022, 4 doses of Temferon (0.5-3.0x10⁶/kg) were tested across 16 patients assigned to 6 cohorts. Follow-up from surgery is 6–28mo (2–25mo after Temferon). To date, no DLTs have been identified. Temferon-derived progeny as defined by gene-marked cells were found within the hematopoietic system within 2-weeks of Temferon administration and persisted, albeit at lower levels, up to 18mo (longest time of analysis). Very low concentrations of IFNα were detected in plasma and CSF, indicating tight regulation of transgene expression. SAEs were mostly attributed to conditioning chemotherapy (infections) or disease progression (PD) (seizures). 1SUSAR (persistent GGT elevation) occurred. Median OS is 15mo from surgery. Transduced cells were detected in the 2^nd surgery specimens of 3 out 4 pts belonging to low dose cohorts. Single-cell RNA seq of the TME highlighted a Temferon signature associated with the induction IFNa responsive genes and macrophage repolarization. Potential long-term benefit with Temferon was identified in a patient from C3, who had PD at D+120 with 2-distant enhancing lesions, and increased tumor necrosis. 1y following Temferon, with no 2^nd-line therapy added, there was approximately 40% reduction in enhancing tumor volume compared to D+180 with a stable clinical and imaging picture thereafter.

Conclusions

The results provide initial evidence of Temferon’s potential to modulate GBM TME, and anecdotal evidence for long lasting effects of Temferon in prevention of PD.

Clinical trial identification

NCT03866109.

Editorial acknowledgement

Legal entity responsible for the study

Genenta Science.

Funding

Genenta Science.

Disclosure

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