Anti-CD94 monoclonal antibody DR-01 induced response in a refractory primary CNS T-cell lymphoma

Abstract Primary central nervous system (CNS) lymphoma is an extranodal non-Hodgkin lymphoma affecting the brain, spine, cerebrospinal fluid (CSF), or vitreoretinal space and only 2 - 8.5% are primary CNS T-cell lymphomas. No standard of care has been established. We report the first case of refractory primary CNS T-cell lymphoma responding to the anti-CD94 IgG1 monoclonal antibody DR-01. A 23-year-old female developed intermittent speech and fluency alterations in 11/2022 which worsened to dysarthria and right-sided facial asymmetry in 3/2023. Brain imaging revealed multiple superficial patchy enhancing lesions. Ultimately a biopsy was performed identifying a peripheral T-cell lymphoma on immunohistochemistry (CD3+, CD8+, TCR-alpha+, Granzyme B+) and flow cytometry without PET-avid systemic involvement. The patient received methotrexate-based chemotherapy with a complete response and associated improved deficits followed by high dose chemotherapy with autologous stem cell rescue consolidation in 12/2023. In 3/2024, new deficits including aphasia and confusion, and imaging findings prompted a biopsy and confirmed recurrent disease. The patient was re-challenged with methotrexate chemotherapy but was no-longer chemo-sensitive. Tumor tissue was positive for CD94 expression and in 5/2024, was started on the anti-CD94 monoclonal antibody DR-01 which demonstrated promising preliminary efficacy in a phase I/II (Iyer 2025), as part of a single patient use protocol approved by the institutional IRB. DR-01 monotherapy was dosed during an induction period (cycle 1) at 10 mg flat on day 1, 40 mg flat on day 8, and then 6 mg/kg on day 15 followed by a maintenance period with 6 mg/kg every 4 weeks. After initiation of treatment, her confusion resolved within the first month of treatment and aphasia continuously improved over The neoplastic T-cells were positive for CD94 expression by immunohistochemistry the last 6 months, and imaging findings improved with a near complete response. Treatment is ongoing without significant adverse events or recurrence 15 months after treatment initiation. Our patient demonstrates for the first time, clinical activity of DR-01 in a patient with CNS involvement.