Clinical and Immune Effects of Lenalidomide in Combination with Gemcitabine in Patients with Advanced Pancreatic Cancer

Abstract

Purpose: To assess the immunomodulatory and clinical effects of lenalidomide with standard treatment of gemcitabine in patients with advanced pancreatic cancer.

Patients and methods: Patients with advanced pancreatic cancer were treated in first line with lenalidomide orally for 21 days of a 28 days cycle and the standard regimen for gemcitabine. In Part I, which we previously have reported, the dose of lenalidomide was defined (n = 12). In Part II, every other consecutive patient was treated with either lenalidomide (Group A, n = 11) or gemcitabine (Group B, n = 10) during cycle 1. From cycle 2 on, all Part II patients received the combination.

Results: A significant decrease in the proliferative response of peripheral blood mononuclear cells and the frequency of DCs were noted in patients at baseline compared to healthy control donors while the frequencies of CD4+ and CD8+ T cells, NK-cells and MDSCs were significantly higher in patients compared to controls. In Group A, a significant increase in the absolute numbers of activated (HLA-DR+) CD4 and CD8 T cells and CD8 effector memory T cells (p<0.01) was noted during treatment. A statistical increment in the absolute numbers of Tregs were seen after cycle 1 (p<0.05). The addition of gemcitabine, reduced most lymphocyte subsets (p<0.05). In Group B, the proportion of lymphocytes remained unchanged during the study period. There was no difference in overall survival, progression free survival and survival rate at one year comparing the two groups.

Discussion: Patients with advanced pancreatic carcinoma had impaired immune functions. Lenalidomide augmented T cell reactivities, which were abrogated by gemcitabine. However, addition of lenalidomide to gemcitabine seemed to have no therapeutic impact compared to gemcitabine alone in this non-randomized study.

Trial registration: ClinicalTrials.gov NCT01547260.

Fig 1. CONSORT Flow Diagram for the patients screened for and enrolled in part II.

Corresponding data for patients enrolled in part I, has been published in Ullenhag GJ et al, PLOS ONE, 2015; 10(4).

Fig 2

Absolute numbers of subsets of T cells at baseline (BL), at the end of cycle 1 (End C1) and at the end of cycle 2 (End C2) in part II patients treated with either lenalidomide monotherapy during cycle 1 with the addition of gemcitabine from cycle 2 (Arm A) (Left column) (Fig 2 A, C, E and G) or gemcitabine monotherapy during cycle 1 with the addition of lenalidomide from cycle 2 (Arm B) (Right column) (Fig 2 B, D, F and H). Changes in the absolute numbers of CD4+ T cells (A, B), CD8+ T cells (C, D), HLA-DR positive CD+4 T cells (E, F) and HLA-DR positive CD8+ T cells (G, H) over the treatment course, n = number of patients analysed at each time-point. P-values refer to the comparison with BL, End C1 and End C2 by one way ANOVA with repeated measures. The box, with a line indicating median, represents the 25^th and 75^th percentiles. The top and bottom whiskers represent the 90^th and 10^th percentiles, respectively.

Fig 3

Absolute numbers of subsets of effector and effector memory T cells at baseline (BL), at the end of cycle 1 (End C1) and at the end of cycle 2 (End C2) in part II patients treated with either lenalidomide monotherapy during cycle 1 with the addition of gemcitabine from cycle 2 (Arm A) (Left column) (Fig 3 A, C, E and G) or gemcitabine monotherapy during cycle 1 with the addition of lenalidomide from cycle 2 (Arm B) (Right column) (Fig 3 B, D, F and H). Changes in the absolute numbers of CD8+ effector T cells (CD45RA+CCR7-CD8+) (C, D), CD8+ effector memory T cells (CD45RA-CCR7-CD8+) (G, H), CD4+ effector T cells (CD45RA+CCR7-CD4+) (A-B) and CD4+ effector memory T cells (CD45RA-CCR7-CD4+) (E, F) over the treatment course. n = number of patients analysed at each time-point. P-values refer to the comparison with BL, End C1 and End C2 by one way ANOVA with repeated measures. The box, with a line indicating median, represents the 25^th and 75^th percentiles. The top and bottom whiskers represent the 90^th and 10^th percentiles, respectively.

Fig 4

Absolute numbers of NKT-cells (CD3+CD56+CD16+) and regulatory T cells (T_reg)(CD4+CD25+CD127-Foxp3+) at baseline (BL), at the end of cycle 1 (End C1) and at the end of cycle 2 (End C2) in part II patients treated with either lenalidomide monotherapy during cycle 1 with the addition of gemcitabine from cycle 2 (Arm A) (Left column) (Fig 4 A and C) or gemcitabine monotherapy during cycle 1 with the addition of lenalidomide from cycle 2 (Arm B) (Right column) (Fig 4 B and D). Changes in the absolute numbers of NKT-cells (A, B) and regulatory T cells (C, D) over the treatment course. n = number of patients analysed at each time-point. P-values refer to the comparison with BL, End C1 and End C2 by one way ANOVA with repeated measures. The box, with a line indicating median, represents the 25^th and 75^th percentiles. The top and bottom whiskers represent the 90^th and 10^th percentiles, respectively.

Fig 5. Cumulative overall survival (OS) (solid black line) and progression-free survival (PFS) (solid grey line) from the start of study treatment until death (OS) and clinical and/or radiological signs of disease progression (PFS), respectively, for all patients in the study.

Number of evaluable patients for OS = 33 out of 33, for PFS = 29 out of 33.