Pilot Study of Anti-Th2 Immunotherapy for the Treatment of Breast Cancer-Related Upper Extremity Lymphedema

Abstract

Recent studies suggest that Th2 cells play a key role in the pathology of secondary lymphedema by elaborating cytokines such as IL4 and IL13. The aim of this study was to test the efficacy of QBX258, a monoclonal IL4/IL13 neutralizing antibody, in women with breast cancer–related lymphedema (BCRL). We enrolled nine women with unilateral stage I/II BCRL and treated them once monthly with intravenous infusions of QBX258 for 4 months. We measured limb volumes, bioimpedance, and skin tonometry, and analyzed the quality of life (QOL) using a validated lymphedema questionnaire (Upper Limb Lymphedema 27, ULL-27) before treatment, immediately after treatment, and 4 months following treatment withdrawal. We also obtained 5 mm skin biopsies from the normal and lymphedematous limbs before and after treatment. Treatment was well-tolerated; however, one patient with a history of cellulitis developed cellulitis during the trial and was excluded from further analysis. We found no differences in limb volumes or bioimpedance measurements after drug treatment. However, QBX258 treatment improved skin stiffness (p < 0.001) and improved QOL measurements (Physical p < 0.05, Social p = 0.01). These improvements returned to baseline after treatment withdrawal. Histologically, treatment decreased epidermal thickness, the number of proliferating keratinocytes, type III collagen deposition, infiltration of mast cells, and the expression of Th2-inducing cytokines in the lymphedematous skin. Our limited study suggests that immunotherapy against Th2 cytokines may improve skin changes and QOL of women with BCRL. This treatment appears to be less effective for decreasing limb volumes; however, additional studies are needed.

Current Mechanistic Understandings of Lymphedema and Lipedema: Tales of Fluid, Fat, and Fibrosis

“…Lymphatic vessels not only transport fluid, but also immune cells, and thus, prolonged lymph stasis induces an inflammatory response [ 48 ]. Not all patients with lymphatic disruption demonstrate lymphedema, however, such that the biochemical and biomechanical perturbations of infection or inflammation in the tissue may serve as a periodic driver of clinical lymphedema [ 49 ].…”

Pharmacological Treatment of Secondary Lymphedema

“…Our observations that inhibition of TH2 differentiation improved lymphedema outcomes in preclinical models led to a clinical trial to study the efficacy of IL4/IL13 neutralizing antibodies for the treatment of unilateral BCRL (NCT02494206). (Mehrara et al, 2021) Neutralizing antibodies are now commonly used to treat many chronic inflammatory diseases due to the decreased toxicity of these targeted treatments compared with traditional treatments. (Hansel et al, 2010) We recruited 9 women with stage I/II BCRL to a phase I, open-label trial utilizing QBX258, an experimental drug consisting of two humanized monoclonal antibodies that inhibit IL4 (VAK296) and IL13 (QAX576).…”

“…(Hansel et al, 2010) We recruited 9 women with stage I/II BCRL to a phase I, open-label trial utilizing QBX258, an experimental drug consisting of two humanized monoclonal antibodies that inhibit IL4 (VAK296) and IL13 (QAX576). (Mehrara et al, 2021) Patients that met the inclusion criteria were treated with once-monthly intravenous infusions of QBX258 for 4 months. (Mehrara et al, 2021) Outcomes were analyzed immediately after and 4 months following cessation of treatment.…”

“…(Mehrara et al, 2021) Patients that met the inclusion criteria were treated with once-monthly intravenous infusions of QBX258 for 4 months. (Mehrara et al, 2021) Outcomes were analyzed immediately after and 4 months following cessation of treatment. QBX258 treatment was safe, and most adverse events were minor and self-limited.…”

Hypoxia and Hypoxia-Inducible Factors in Lymphedema

“…Anti-inflammatory therapies, including ketoprofen (NSAID) and Th2 cell inhibition, improve skin pathology but are ineffective in reducing limb volume and fat deposition ( Rockson et al, 2018 ; Mehrara et al, 2021 ). Findings from these pilot clinical trials suggest that anti-inflammatory therapy alone may not be sufficient to reverse lymphedema.…”