Polatuzumab vedotin in CNS lymphoma: proof-of-concept study for blood-brain barrier penetration Open Access

• Polatuzumab vedotin exhibits significant pre-clinical activity against primary and secondary CNS lymphoma xenografts.

• Polatuzumab vedotin partially penetrates the BBB in CNS lymphoma patients with CSF drug concentrations reaching 0.56% - 1.31% plasma levels.

Polatuzumab vedotin (pola) is a CD79B-targeting antibody-drug conjugate with significant clinical activity in systemic diffuse large B-cell lymphoma. However, the ability of pola to penetrate the blood-brain barrier (BBB) and induce responses in central nervous system lymphoma (CNSL) is unknown. Since other antibody-based therapies can partially penetrate the BBB to induce clinical responses in CNSL and other CNS malignancies, we hypothesized that pola would also partially penetrate the BBB, which could support its evaluation in future CNSL clinical trials. To test this hypothesis, we first evaluated the pre-clinical efficacy of pola in primary and secondary CNSL xenografts, where we observed pola significantly decreased CNS tumor burden and prolonged the survival of mice. To extend these findings, we compiled a clinical case series of 3 CNSL patients treated with pola-based treatment. Here, on-treatment cerebrospinal fluid (CSF) samples revealed pola CSF drug concentrations in excess of its established IC50 with CSF drug levels being 0.56% - 1.31% of that in the plasma. Interestingly, 2 of the 3 CNSL patients achieved a complete response to pola-based treatment. In summary, these data indicate pola is effective against pre-clinical CNSL models and can partially penetrate the BBB in CNSL patients, which together provide support for the evaluation of pola-based treatment in future clinical trials of primary and secondary CNSL.