CC-122 immunomodulatory effects in refractory patients with diffuse large B-cell lymphoma

Abstract

In the three patients included in a phase I clinical trial (NCT01421524), we report the immunomodulatory effects and efficacy of CC-122, a novel pleiotropic pathway modifier compound originally developed for broad diffuse large B-cell lymphoma (DLBCL). The chemical structure of CC-122 includes the glutarimide moiety that is known to modulate the immune response. The immunomodulatory agents including lenalidomide represent a promising therapeutic strategy targeting tumors in B-cell lymphoid malignancies. We observed that CC-122 might regulate the NK phenotype and its activity due to the reduced accumulation of myeloid-derived suppressor cell and eventually decrease the Tregs subsets. Finally, the activation of T cells through co-stimulatory molecule (CD28) was detected as a delayed CC-122 effect. In this context, CC-122 arises as an alternative option for DLBCL patients refractory to the traditional chemotherapeutic agents.

Keywords: CC-122 treatment; DLBCL patients; immune response.

Figures

Figure 1.

Cytotoxic subsets features PBMCs were isolated from five healthy volunteers (black dots) and three patients with DLBC (white square: patient 1; black triangle: patient 2; and white triangle: patient 3) at baseline (T = 0), 4 h (T = 4 h), 7 d (T = 7 d), and 30 d (T = 30 d) after initiation treatment and analyzed by flow cytometry. (A) Percentage distribution of CD3−CD56+ on total NK cells (left) and CD3−CD56+CD16+ (middle) and CD3−CD562+CD16− (right) on total gated NK cells are shown. (B) Cytotoxic activity by europium–TDA-release assay after 2 h of incubation with K562 as target cells. Percentages of lysis are shown at different NK:K562 ratios. (C) NKG2D Mean of Intensity Fluorescence of gated CD3−CD56+ total NK cells. (D) Expression of GrB on CD3−CD56+CD16+ (left) and CD3−CD56+CD16− (right) of gated total NK cells. Percentage of GrB+ cells are shown in the both panels. *p < 0.05, **p < 0.001, ***p < 0.0001, by two-tailed unpaired Student's t test compared with HV.

Figure 2.

Immunosuppresive cells and immune adaptive activation PBMCs were isolated from five healthy volunteers (black dots) and three patients with DLBC (white square: patient 1; black triangle: patient 2; and white triangle: patient 3) at baseline (T = 0), 4 h (T = 4 h), 7 d (T = 7 d), and 30 d (T = 30 d) after initiation treatment and analyzed by flow cytometry. (A) Percentage distribution of CD14+DR−/low on total CD14+ is shown. (B) TGFβ expression analysis of adherent PBMCs (CD14+) by qPCR. (C) Tregs percentage of total CD4+ lymphocytes. (D) CD8+CD28+ cell percentages of gated CD8+ (E) γδ+CD28+ cell percentages of gated γδ+ and (F) CD3+CD56+ cell percentages of total lymphocytes. *p < 0.05, **p < 0.001, ***p < 0.0001, by two-tailed unpaired Student's t test compared with HV.