Lenalidomide enhances antigen-specific activity and decreases CD45RA expression of T cells from patients with multiple myeloma.

The aim of this study was to investigate whether the specific T cell response against the multiple myeloma Ag HM1.24 is enhanced by the immunomodulatory drug lenalidomide (Revlimid). Ag-specific CD3(+)CD8(+) T cells against the HM1.24 Ag were expanded in vitro by dendritic cells in 29 healthy donors and 26 patients with plasma cell dyscrasias. Ag-specific activation was analyzed by IFN-γ, granzyme B, and perforin secretion using ELISA, ELISPOT assay, and intracellular staining, and generation of Ag-specific T cells was analyzed by tetramer staining. Expression of T cell maturation markers (CD45RA, CD45R0, CCR7, and CD28) was investigated by flow cytometry. We found that activation of HM1.24-specific T cells from healthy donors and patients with plasma cell dyscrasias was enhanced significantly by lenalidomide and furthermore that the impact of lenalidomide on T cells depends on the duration of the exposure. Notably, lenalidomide supports the downregulation of CD45RA on T cells upon activation, observed in healthy donors and in patients in vitro and also in patients during lenalidomide therapy in vivo. We showed for the first time, to our knowledge, that lenalidomide enhances the Ag-specific activation of T cells and the subsequent downregulation of CD45RA expression of T cells in vitro and in vivo.

Pentostatin, cyclophosphamide and rituximab is a safe and effective treatment in patients with Waldenström's macroglobulinemia.

Waldenström's macroglobulinemia (WM) is an indolent lym phomaand is responsive to therapy regimens containing alkylating agents, purine analogs and rituximab if treatment becomes necessary. We initiated a multicenter phase II trial to determine the safety and efficacy of a regimen containing pentostatin, cyclophosphamide and rituximab (PER) in patients with WM. Between May 2005 and December 2010, 25 patients with WM were included in the study. Twenty-one patients received PER as first-line therapy. In these patients, 2-year progression-free survival was 83.6% and 2-year overall survival was 100%. Thirteen patients (52%) received R maintenance therapy. In these patients, the 2-year progression-free survival was 91.67% and 2-year overall survival was 100%. We have provided evidence that PER is a safe and effective regimen for WM. Although R maintenance therapy after PER seemed to induce a better long-term outcome, this study was not powered to address this issue.

Thalidomide maintenance therapy maturates the T cell compartment and compromises antigen-specific antitumor immunity in patients with multiple myeloma.

Interferon (INF)-α was the maintenance treatment of choice after autologous stem cell transplantation in multiple myeloma in the past, but currently Thalidomide is commonly used. In this prospective study, the implications of the various types of maintenance therapy on the patients T cell pattern and activation status were assessed. T cells were analyzed for expression of surface molecules, cytokine secretion, the presence of regulatory T cells, and the specific activation against the multiple myeloma antigen HM1.24. T cells from 69 multiple myeloma patients were analyzed: 19 patients were treated with IFN-α; 26 were treated with Thalidomide; and 24 patients received no maintenance therapy. Specific T cell activation with an immunogenic HLA-A2(+)-restricted peptide from the myeloma-associated antigen HM1.24 was impaired in the Thalidomide group. In accordance with this observation, there was a trend toward a higher amount of regulatory T cells in the Thalidomide group. Furthermore, patients treated with IFN-α showed high rates of naive T cells, whereas a high rate of effector memory T cells was observed in the Thalidomide group. Importantly, after cessation of Thalidomide therapy, this effect was reversible in the CD8 compartment. In conclusion, Thalidomide maintenance therapy has profound implications on T cell pattern and activation status, which compromise antigen specific antitumor immunity.