Prognostically significant cytotoxic T cell clones are stimulated after thalidomide therapy in patients with multiple myeloma

Abstract

The expanded T cell clones are associated with a prolonged survival in patients with multiple myeloma. We sought to confirm this prognostic significance in a multicenter patient cohort and investigate the effect of thalidomide on clones and T regulatory cells (T(regs)). Blood was collected from 120 patients enrolled in a Phase III trial of maintenance therapy +/- thalidomide after autologous stem cell transplantation. TCR Vbeta repertoire analysis identified T cell expansions in 48% of patients pre-transplant and 68% after 8-month maintenance. T cell expansions, previously shown to be clonal, were predominantly CD8+ (93%) and all 24 TCR Vbeta families tested were represented. Thalidomide therapy was associated with a significant increase in the incidence of patients with multiple expansions (49% vs. 23%; chi2 = 6.8; p = 0.01). The presence of expansions regardless of therapy was associated with a significantly longer median progression free survival (PFS) (32.1 vs. 17.6 months; chi2 = 5.6; p = 0.02) and overall survival (OS) (chi2 = 3.9; p < 0.05). Median PFS in the thalidomide arm was 50.9 months for patients with expansions and 28.3 months for patients without expansions (chi2 = 19.4; p = 0.0002). Thalidomide did not appear to modulate T(reg) numbers. Expanded T cell clones are prognostically significant and have an impact on progression after thalidomide therapy in a proportion of patients.

Clonal expansions of cytotoxic T cells exist in the blood of patients with Waldenström macroglobulinemia but exhibit anergic properties and are eliminated by nucleoside analogue therapy

“…16 As similar clonal expansions in patients with multiple myeloma [6][7][8][9][10][11][12][13][14][15] and CML 3 have prognostic significance, it is likely that these cells have an immunoregulatory function toward the tumor cells, although their specificity has yet to be confirmed. The presence of expanded cytotoxic lymphocytes in CML patients after dasatinib therapy was associated with excellent responses.…”

“…We have previously reported an incidence of 48% in patients with multiple myeloma (n ϭ 120) before autologous transplantation using the same criteria. 16 Five of the 6 patients without TCRV␤ expansions had previously received nucleoside analog therapy, and 1 later transformed to non-Hodgkin lymphoma, whereas only 1 of the 14 patients with significant T-cell expansions had received nucleoside analog therapy (Table 1). Thus, previous nucleoside analog therapy had a significant influence on the presence of TCRV␤ expansions ( 2 ϭ 11.6; P Ͻ .001).…”

“…[6][7][8][9][10][11][12][13][14][15] We previously reported that 48% of 120 patients with multiple myeloma have peripheral blood T-cell expansions that show the phenotype of CD3 ϩ CD8 ϩ T-cell receptor V␤-positive (TCRV␤ ϩ ) CD57 ϩ , and we confirmed the clonal nature of these expanded T cells by determining TCRV␤ CDR3 size distribution and direct sequencing. 10,11,16 Although the specificity of these T-cell clones has not yet been determined, several patient cohorts have shown that they persist for long periods and are associated with a good prognosis, suggesting that they may arise after chronic stimulation by a tumor-associated antigen. 5,9,11 Thus, these cells are likely to be tumor-specific cytotoxic lymphocytes with tumor-induced dysfunction.…”

Long-term survival in multiple myeloma is associated with a distinct immunological profile, which includes proliferative cytotoxic T-cell clones and a favourable Treg/Th17 balance

“…There is also indirect evidence of host anti-tumour immune activity through the identification of premalignancy-specific effector T cells in patients with monoclonal gammopathy, 7 the phenomenon of ‘plateau phase' where despite a significant residual tumour burden the disease does not progress 8 and the association between the presence of expanded T-cell clones and an improved survival. 9, 10, 11 We hypothesised that patients with myeloma who are long-term survivors (LTS-MM) have greater immunocompetence and that a study of immune biomarkers in these LTS-MM patients might provide a novel approach to understanding the mechanisms of immune dysfunction in MM.…”

The failure of immune checkpoint blockade in multiple myeloma with PD-1 inhibitors in a phase 1 study

“…4 The presence of these T cells in~50% of the patients with myeloma conveys a good prognosis and they are stimulated by thalidomide maintenance therapy. 5 Long-term survivors of myeloma invariably show the presence of such cells. 6 These T cells, however, do not show the exhausted phenotype essential for the reversal of PD-1 blockade.…”