Effect of cA2 Anti–Tumor Necrosis Factor-α Antibody Therapy on Hematopoiesis of Patients with Myelodysplastic Syndromes

Abstract

Purpose: Tumor necrosis factor a (TNF-a) plays a prominent role in the pathophysiology of myelodysplastic syndromes (MDS). The aim of this study was to explore the biological and immunoregulatory effect of the treatment with the anti^tumor necrosis factor-a monoclonal antibody cA2 on bone marrow (BM) progenitor/precursor and stromal cells and lymphocyte subsets, as well as the clinical response in MDS patients. Experimental Design: Ten low-intermediate risk MDS patients received i.v. cA2 (3 mg/kg) at weeks 0, 2, 6, and 12. The number, survival, and clonogenic potential of BM progenitor/precursor cells, the hematopoiesis-supporting capacity of BM stromal cells, and the lymphocyte activation status were investigated in the patients at baseline and following treatment using flow cytometry, clonogenic assays, and long-term BM cultures (LTBMC). Clinical response was evaluated according to standardized criteria. Results: cA2 administration reduced the proportion of apoptotic and Fas + cells in the CD34 + cell compartment (P = 0.0215 and P = 0.0344, respectively) and increased the clonogenic potential of BM mononuclear and CD34 + cells (P = 0.0399 and P = 0.0304, respectively) compared with baseline. The antibody reduced tumor necrosis factor-a levels in LTBMC supernatants (P = 0.0043) and significantly improved the hematopoiesis-supporting capacity of LTBMC adherent cells. The proportion of activated peripheral blood and BM T-lymphocytes decreased significantly after treatment, suggesting an immunomodulatory effect of cA2. Two patients displayed minor hematologic responses whereas the remaining patients displayed stable disease with no disease progression. Conclusions: The encouraging biological insights from cA2 administration may be useful in conducting further clinical trials using cA2 for selected MDS patients, particularly those with evidence of immune-mediated inhibition of hematopoiesis.

TNF-α Regulates the Effects of Irradiation in the Mouse Bone Marrow Microenvironment

“…Strategies to block TNF-α activity, seeking to neutralize its inflammatory role, have met some success in the treatment of epithelial cancers, and to a lesser extent also in subsets of patients with primary MDS, although with varying degrees of therapeutic benefit [15]–[17], [40]. The fact that TNF-α is a key regulator of BM cell apoptosis provided the rationale for the use of TNF-α blockers in primary MDS.…”

“…Bone marrow failure in MDS involves apoptosis induction, which may involve TNF-α [13]; persistent BM dysplasia following benzene exposure has also been associated with TNF-α polymorphisms [14]. Nevertheless, the therapeutic efficacy of anti-TNF-α approaches, tested in patients with de novo , or primary, MDS, has been relatively modest [15]–[17].…”

Myelodysplasia and autoimmunity

“…Moreover, although normal primitive haemopoietic cells express elementary amounts of FAS, cytokines such as interferon g (IFNg) and TNF have been shown to upregulate FAS expression on CD34þ MDS cells, priming them for FAS-induced apoptosis and immune destruction [26,27]. In accordance with these findings, treatment with anti-TNF agents like iMIDS and antiTNF-a antibodies resulted in a reduction of apoptosis and enhanced in-vitro haemopoietic clonal culture [28,29].…”

Loss of SIMPL compromises TNF-α-dependent survival of hematopoietic progenitors

“…MDS comprises a collection of TNFα linked diseases in which hematopoietic cells are functionally and morphologically aberrant. Bone marrow cellularity in these patients is either normal or elevated with peripheral pancytopenia (global loss of all peripheral blood cell types), a condition known as ineffective hematopoiesis [18, 41–44]. MDS is linked to impaired hematopoietic cell differentiation, and can progress from less severe Refractory Anemia (RA) to in the most severe cases acute myeloid leukemia (AML) [18, 41].…”

“…In MDS patients, cA2 anti-TNFα antibody treatment decreases activated CD4 + and CD8 + T-lymphocyte populations which contribute to the MDS and TNFα release [44], but also diminishes the elderly patients cell mediated immune response. Previous studies from our laboratory demonstrated that loss of SIMPL targets NF-κB activity induced specifically by TNFα [23, 24] enabling NF-κB activity controlled by other cytokines to proceed unencumbered.…”