Search Results (2)

Background/Objectives: Follicular helper T-cell (TFH)-type lymphomas, including angioimmunoblastic T-cell lymphoma (AITL) and TFH lymphoma, not otherwise specified (TFH-NOS), are characterized by marked immune dysregulation in the tumor microenvironment. We investigated whether TFH-type lymphomas are enriched in immunosuppressive cells and explored immunologic changes associated with denileukin diftitox (DD) treatment. Methods: FOXP3-positive mononuclear cells were quantified by immunohistochemistry in lymph node specimens from 10 patients with TFH-type lymphoma and six with non-TFH-type T-cell lymphoma. Paired skin biopsy specimens obtained before and after DD treatment from two patients with AITL were evaluated for CD4, CD8, CD68, CD163, and FOXP3 expression. Longitudinal flow cytometric T-cell receptor Vβ repertoire analysis of CD8-positive T-cell subsets was performed in three patients with AITL treated with DD. Clinical responses were retrospectively assessed in seven patients with relapsed or refractory TFH-type lymphoma treated with DD. Results: TFH-type lymphomas showed significantly higher intra-tumoral FOXP3-positive cell densities than non-TFH-type lymphomas (p = 0.0024). In paired skin biopsies, DD treatment was associated with reductions in CD68- and CD163-positive macrophage-rich infiltrates and a suggested decrease in FOXP3-positive cells. Among seven patients treated with DD, the overall response rate was 86%, including one complete response and five partial responses. Responders showed selective Vβ over-representation patterns in effector and/or memory CD8-positive T-cell subsets, whereas such findings were not convincing in the non-responder. Conclusions: TFH-type lymphomas were associated with higher FOXP3-positive cell density than selected non-TFH-type comparators. DD treatment may be associated with changes in tissue immune infiltrates and peripheral CD8/TCR Vβ skewing in responding cases, although these findings remain exploratory and do not establish causality. Full article

Background/Objectives: Regulatory T cells (Treg) suppress immunity in the tumor microenvironment, are linked to poor prognosis across breast cancer subtypes, and suppress the cytolytic function of cytotoxic CD8+ T cells. Denileukin diftitox, a diphtheria toxin (DT)/IL-2 fusion protein, targets and depletes Tregs. This Phase II study aimed to assess the safety of denileukin diftitox and its effect on Tregs and tumor growth in patients with advanced breast cancer. Methods: This single-arm Phase II study of denileukin diftitox enrolled patients with refractory stage IV breast cancer. Patients received denileukin diftitox 18 mcg/kg/day IV for Days 1–5 every 21 days for up to six cycles. Toxicity was assessed using CTCAE v3.0 and tumor response was evaluated per RECIST criteria. Blood samples were collected to analyze Tregs by flow cytometry and anti-DT antibodies by ELISA. Results: Fifteen patients with stage IV breast cancer were enrolled. Four patients completed all planned denileukin diftitox infusions and achieved stable disease (27%, 95% CI [0.08, 0.55]). Two patients (13%) discontinued due to toxicity, and nine patients (60%) discontinued due to progressive disease. Eleven patients experienced at least one grade 3 or 4 adverse event. Although there was a general reduction in peripheral blood Tregs, the difference in CD4+CD25+FOXP3+ Tregs levels post-treatment was not statistically significant (p = 0.10). Six patients (40%) achieved $\ge$25% reductions in Tregs. A significant increase in anti-DT IgG antibodies was observed post-treatment (p < 0.005). Conclusions: Denileukin diftitox demonstrated moderate toxicity in this advanced breast cancer cohort. Denileukin diftitox modulated regulatory T cells. However, the majority of patients experienced disease progression in the study. Full article