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R-CHOP preceded by blood-brain barrier permeabilization with engineered tumor necrosis factor-α in primary CNS lymphoma

Andrés J. M. Ferreri, Teresa Calimeri, Gian Marco Conte, Dario Cattaneo, Federico Fallanca, Maurilio Ponzoni, Eloise Scarano, Flavio Curnis, Alessandro Nonis, Paolo Lopedote, Giovanni Citterio, Letterio Politi, Marco Foppoli, Stefania Girlanda, Marianna Sassone, Salvatore Perrone, Caterina Cecchetti, Fabio Ciceri, Claudio Bordignon, Angelo Corti and Nicoletta Anzalone

Key Points

  • TNF-α coupled with NGR peptide targets CD13+ tumor vessels and increases vascular permeability selectively in tumor/peritumoral areas of PCNSL.

  • R-CHOP preceded by low-dose NGR-hTNF was not associated with unexpected toxicity, and resulted in tumor regression in 9 of 12 PCNSL patients.

Abstract

Patients with primary CNS lymphoma (PCNSL) are treated with high-dose-methotrexate-based chemotherapy, which requires hospitalization and extensive expertise to manage related toxicity. The use of R-CHOP could overcome these difficulties, but blood-brain barrier (BBB) penetration of related drugs is poor. Tumor Necrosis Factor-a coupled with NGR (NGR-hTNF), a peptide targeting CD13+ vessels, induces endothelial permeabilization and improves tumor access of cytostatics. We tested the hypothesis that NGR-hTNF can break the BBB, thereby improving penetration and activity of R-CHOP in patients with relapsed/refractory PCNSL (NCT03536039). Patients received six R-CHOP21 courses, alone at the first course and preceded by NGR-hTNF (0.8 μg/m²) afterwards. This trial included two phases: an "explorative phase" addressing the effect of NGR-hTNF on drugs pharmacokinetics and on vessel permeability, assessed by DCE-MRI and 99mTc-DTPA-SPECT, and the expression of CD13 on tumor tissue; and an "expansion phase" with ORR as primary endpoint, where the two-stage Simon Minimax design was used. At the first stage, if {greater than or equal to}4 responses were observed among 12 patients, the study accrual would have continued (sample size: 28). Herein, we report results of the explorative phase and the first-stage analysis (n=12). CD13 was expressed in tumor vessels of all cases. NGR-hTNF selectively increased vascular permeability in tumoral/peritumoral areas, without interfering with drug plasma/CSF concentrations. NGR-hTNF/R-CHOP combination was well tolerated: there were only two SAEs and grade-4 toxicity was almost exclusively hematological, which were resolved without dose reductions or interruptions. NGR-hTNF/R-CHOP was active, with nine confirmed responses (75%; 95%CI=51-99%), eight of which were complete. In conclusion, NGR-hTNF/R-CHOP was safe in these heavily-pretreated patients. NGR-hTNF enhanced vascular permeability specifically in tumoral/peritumoral areas, which resulted in fast and sustained responses.

  • Submitted December 21, 2018.
  • Revision received April 29, 2019.
  • Accepted April 25, 2019.