285MO - The combination of lomustine and antibody-based targeted TNF (L19TNF) as a promising treatment for recurrent glioblastoma

Background

Glioblastoma is a poorly immunogenic cancer and treatment options for recurrent glioblastoma are limited. Therefore, there is an urgent need for effective treatment strategies against recurrent glioblastoma. Here, we investigated a new treatment combination based on the tumor-stroma targeting antibody-cytokine fusion protein L19TNF and the alkylating chemotherapy lomustine in preclinical glioma models and patients with recurrent glioblastoma.

Methods

Orthotopic immunocompetent mouse glioma models were used to study the anti-glioma activity of L19TNF in combination with anti-PD1, bevacizumab or lomustine. Tumor-infiltrating immune cells were characterized by microscopy and flow cytometry and the MHC immunopeptidome was analyzed by MHC immunoaffinity purification and subsequent mass spectrometry. Subsequently, we translated the most efficient treatment combination to patients with recurrent glioblastoma within a phase I/II clinical trial (NCT04573192).

Results

The combination of L19TNF and lomustine demonstrated strong synergistic anti-tumor activity in two immunocompetent orthotopic glioma models curing the majority of tumor-bearing mice, whereas the other mono- or combination therapies had only limited anti-glioma activity. The combination of L19TNF and lomustine led to the strongest increase in tumor-infiltrating lymphoid cells as demonstrated by flow cytometry and microscopy and to the highest number of peptides presented in the context of MHC-I. The anti-tumor activity was also abrogated in immune-deficient mouse models. Furthermore, the treatment was well tolerated in the first patients treated within a phase I/II clinical trial and we observed partial tumor responses and long-lasting disease stabilizations even in patients with an unfavorable unmethylated MGMT promoter.

Conclusions

The combination of L19TNF and lomustine demonstrated promising anti-glioma activity. Patients are currently recruited within a phase I/II clinical trial for patients with recurrent glioblastoma.

Clinical trial identification

NCT04573192.

Editorial acknowledgement

Legal entity responsible for the study

Philogen S.p.A.

Funding

Philogen S.p.A.

Disclosure

T. Weiss: Financial Interests, Personal and Institutional, Principal Investigator: Philogen S.p.A.; Financial Interests, Personal and Institutional, Advisory Role: Philogen S.p.A. E. Puca, T. Hemmerle, R. Stucchi: Financial Interests, Personal, Full or part-time Employment: Philogen S.p.A. R. De Luca: Financial Interests, Institutional, Full or part-time Employment: Philochem AG. D. Neri: Financial Interests, Personal, Full or part-time Employment: Philogen S.p.A.; Financial Interests, Personal, Ownership Interest: Philogen S.p.A. M. Weller: Financial Interests, Personal and Institutional, Advisory Role: Philogen S.p.A. All other authors have declared no conflicts of interest.