Tumor cells from patients with cutaneous T-cell lymphoma (CTCL) lost the mogamulizumab-kpkc (Poteligeo) target CCR4 and upregulated the anti-apoptotic BCL-2 protein at the point of resistance, according to translational data from a multicenter cohort of patients with mycosis fungoides (MF) and Sézary syndrome (SS), which were presented at the
Across serial blood samples collected before, during, and after mogamulizumab treatment, the proportion of CCR4-positive, CD4-positive T cells declined significantly regardless of patient response, whereas the levels of CD4-positive, CD26-negative Sézary cells remained stable or rose in patients who did not respond. Non-responding patients also experienced rising levels of interleukin-10 (IL-10) and IL-22, and single-cell RNA sequencing identified loss of CCR4-positive T cells alongside increased BCL-2 expression at the time of resistance.
“In the non-responder[s], we see that the CCR4 [levels are] continuously increasing, as expected, because there is no response, but we see that BCL-2 is still underregulated, so that we might have a third mechanism of secondary resistance: the upregulation of the anti-apoptotic protein BCL-2. That can be, of course, therapeutically targeted, which we plan to do in the next steps,” said Jan P. Nicolay, MD, PhD, a cutaneous lymphoma physician-scientist at University Medical Center Mannheim and the German Cancer Research Center (DKFZ), in Germany. “I presented...3 possible mechanisms that are involved in secondary mogamulizumab resistance: the downregulation of CCR4, the high levels of IL-22, and the upregulation of BCL-2.”
The analysis drew on a multicenter German cohort that enrolled across 5 dermatology centers in the ADO lymphoma network. Among patients profiled, 13 had MF, and 11 had SS. Among patients with MF, the mean age was 65 years (SD, 9), 76.9% were male, and most had stage IIB disease (61.5%); among patients with SS, the mean age was 70 years (SD, 9), 36.4% were male, and disease stages spanned IVA1 (54.5%) and IVA2 (45.5%). Resistance to mogamulizumab was recorded in 61.5% of patients with MF and 81.8% of patients with SS.
Investigators collected peripheral blood mononuclear cells and formalin-fixed, paraffin-embedded skin samples before mogamulizumab initiation, during therapy, at disease progression, and at the onset of mogamulizumab-associated rash. Samples were profiled with flow cytometry of T-helper cell subsets, bead-based immunoassays of plasma cytokines and chemokines, intracellular staining of CTCL-associated signaling pathways, and single-cell RNA sequencing paired with T-cell receptor clonotyping. The study was supported by Kyowa Kirin.
Mogamulizumab significantly reduced the frequency of CCR4-positive, CD4-positive T cells during therapy, a change observed independent of therapy response. A modest decrease in CD4-positive, FoxP3-positive regulatory T cells also occurred during treatment, but this did not reach statistical significance in the presented analysis. In contrast, CD4-positive, CD26-negative Sézary cell levels tracked with response, remaining stable or increasing in patients who did not respond.
Phospho-flow analysis of CD4-positive T cells showed downregulation of the PI3K/Akt/mTOR pathway during therapy, including reduced phosphorylated Akt, whereas JAK/STAT, NF-κB, and MAPK readouts varied across patients. Profiling of the cytokine and chemokine milieu revealed increasing levels of IL-10 and IL-22 in non-responding patients, consistent with prior reports implicating IL-22 in the CTCL microenvironment.
Integrated single-cell RNA sequencing of CD4-positive T cells tracked how the malignant compartment evolved on mogamulizumab. In patients who initially responded, the dominant CTCL clone contracted over successive time points, accompanied by the re-emergence of conventional effector and central memory T-cell populations. In a patient who did not respond, the malignant clone instead expanded across treatment.
Within the tumor compartment, CCR4 expression on CTCL cells fell at the time of resistance, reinforcing the flow cytometry signal that loss of the antibody’s target accompanies progression. Expression of the anti-apoptotic protein BCL-2 rose in tumor cells at resistance, supporting the hypothesis that survival-pathway rewiring contributes to mogamulizumab resistance. Earlier
The investigators framed these readouts as a step toward biomarkers that could guide mogamulizumab use and toward rational combinations, such as with venetoclax (Venclexta).
