A KIR3DL2 Antibody Is Safe and Active in Cutaneous T-cell Lymphoma

Sézary syndrome is a particularly rare and aggressive subtype of cutaneous T-cell lymphoma with a median survival of only 2.5 to 4 years. KIR3DL2, a cell-surface protein, is often expressed in patients with T-cell lymphomas, including more than 85% of patients with Sézary syndrome. In a phase I clinical trial of IPH4102, a first-in-class monoclonal antibody to KIR3DL2, Bagot and colleagues showed that the drug is safe in T-cell lymphoma. IPH4102, which had previously been shown to be effective in mouse xenograft models and patient-derived NK and Sézary cells, is intended to target KIR3DL2-expressing cancer cells for antibody-dependent cytotoxicity and phagocytosis. The open-label trial enrolled 44 adult patients with relapsed or refractory primary cutaneous T-cell lymphoma who had undergone two or more previous systemic therapies. Of the patients, 35 (80%) had Sézary syndrome, 8 (18%) had mycosis fungoides, and 1 (2%) had primary cutaneous T-cell lymphoma. Based on preliminary dose-escalation experiments, which showed no dose-limiting toxicity, the maximum tested dose of 750 mg was used for cohort expansion. The most common side effects were peripheral edema and fatigue. The trial provided promising preliminary evidence of the drug's efficacy: 16 (36%) of patients had a global overall response, and responses were observed in 15 of the 35 (43%) patients with Sézary syndrome. At data cutoff, the median duration of response in patients with Sézary syndrome was 13.8 months and the progression-free survival was 11.7 months. IPH4102 treatment was associated with an early reduction in the concentration of aberrant Sézary cells and circulating KIR3DL2-expressing CD4+ T cells, and biopsies obtained before and after treatment suggested that a ≥50% reduction of KIR3DL2-expressing skin cells or minimal residual disease in the blood was associated with response. A phase II study to confirm the activity of IPH4102 in Sézary syndrome and investigate its activity in other KIR3DL2-expressing T-cell lymphomas is ongoing.

Bagot M, Porcu P, Marie-Cardine A, Battistella M, William BM, Vermeer M, et al. IPH4102, a first-in-class anti-KIR3DL2 monoclonal antibody, in patients with relapsed or refractory cutaneous T-cell lymphoma: an international, first-in-human, open-label, phase 1 trial. Lancet Oncol 2019 June 25 [Epub ahead of print].

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