Lenalidomide as immune adjuvant to a dendritic cell vaccine in chronic lymphocytic leukemia patients

Eur J Haematol. 2018 Jul;101(1):68-77. doi: 10.1111/ejh.13065. Epub 2018 May 22.

Abstract

Objectives: We previously showed that immunization with ex vivo- generated autologous dendritic cells loaded with apoptotic tumor cells (Apo-DC) potentiated tumor-specific immunity in chronic lymphocytic leukemia (CLL) patients. Here, we evaluated safety and immunogenicity of Apo-DC in combination with lenalidomide, granulocyte-macrophage colony-stimulating factor (GM-CSF), and low-dose cyclophosphamide (CTX).

Methods: Ten previously untreated patients with slowly progressing CLL received 5 Apo-DC vaccinations and lenalidomide orally for 24 weeks either alone (cohort I, n = 5) or together with subcutaneous GM-CSF and intravenous CTX (cohort II, n = 5). Tumor-specific T-cell responses were measured by proliferation and IFN-γ ELISPOT assays. Immune monitoring was performed by flow cytometry.

Results: Dose-limiting toxicity was observed in 3/10 patients, 2 in cohort I and one in cohort II. One patient developed autoimmune hemolytic anemia and another grade 4 thrombocytopenia. Vaccine-induced immune responses were seen in 5/5 and 4/5 patients in cohort I and II, respectively. The expression of immune checkpoints on T cells did not change significantly.

Conclusions: Lenalidomide alone or in combination with GM-CSF and low-dose CTX as immune adjuvant to the Apo-DC vaccine elicited tumor-specific T-cell responses in CLL patients. However, unexpected toxicity was observed and caution is suggested in further exploring this drug as immune adjuvant in CLL.

Keywords: chronic lymphocytic leukemia; dendritic cell vaccination; immunotherapy; lenalidomide.

Publication types

  • Clinical Trial

MeSH terms

  • Adjuvants, Immunologic / administration & dosage*
  • Adjuvants, Immunologic / adverse effects
  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Anemia, Hemolytic, Autoimmune / diagnosis
  • Anemia, Hemolytic, Autoimmune / etiology
  • Anemia, Hemolytic, Autoimmune / immunology
  • Anemia, Hemolytic, Autoimmune / pathology
  • Apoptosis
  • Cancer Vaccines / therapeutic use*
  • Combined Modality Therapy / methods*
  • Cyclophosphamide / therapeutic use
  • Cytokines / biosynthesis
  • Cytokines / immunology
  • Cytotoxicity, Immunologic / drug effects
  • Dendritic Cells / cytology
  • Dendritic Cells / immunology
  • Dendritic Cells / transplantation*
  • Disease Progression
  • Female
  • Granulocyte-Macrophage Colony-Stimulating Factor / therapeutic use
  • Humans
  • Injections, Intravenous
  • Injections, Subcutaneous
  • Lenalidomide
  • Leukemia, Lymphocytic, Chronic, B-Cell / immunology
  • Leukemia, Lymphocytic, Chronic, B-Cell / pathology
  • Leukemia, Lymphocytic, Chronic, B-Cell / therapy*
  • Male
  • Middle Aged
  • Thalidomide / administration & dosage
  • Thalidomide / adverse effects
  • Thalidomide / analogs & derivatives*
  • Thrombocytopenia / diagnosis
  • Thrombocytopenia / etiology
  • Thrombocytopenia / immunology
  • Thrombocytopenia / pathology
  • Transplantation, Autologous
  • Tumor Cells, Cultured
  • Vaccination / methods*

Substances

  • Adjuvants, Immunologic
  • Cancer Vaccines
  • Cytokines
  • Thalidomide
  • Granulocyte-Macrophage Colony-Stimulating Factor
  • Cyclophosphamide
  • Lenalidomide