Biological effects and clinical significance of lenalidomide-induced tumour flare reaction in patients with chronic lymphocytic leukaemia: in vivo evidence of immune activation and antitumour response.
Lenalidomide has demonstrated impressive antileukaemic effects in patients with chronic lymphocytic leukaemia (CLL). The mechanism(s) by which it mediates these effects remain unclear. Clinically, CLL patients treated with lenalidomide demonstrate an acute inflammatory reaction, the tumour flare reaction that is suggestive of an immune activation phenomenon. Samples from CLL patients treated with lenalidomide were used to evaluate its effect on the tumour cell and components of its microenvironment (immune cellular and cytokine). Lenalidomide was unable to directly induce apoptosis in CLL cells in vitro, however it modulated costimulatory (CD80, CD83, CD86) surface molecules on CLL cells in vitro and in vivo. Concurrently, we demonstrated that NK cell proliferation was induced by lenalidomide treatment in patients and correlated with clinical response. Cytokine analysis showed increase in levels of TNF-α post-lenalidomide treatment, consistent with acute inflammatory reaction. Furthermore, the basal cytokine profile (high IL-8, MIG, IP-10 and IL-4 levels and low IL-5, MIP1a, MIP1b, IL12/p70) was predictive of clinical response to lenalidomide. Collectively, our correlative studies provide further evidence that the antileukaemic effect of lenalidomide in CLL is mediated not only through modulation of the leukaemic clone but also through elements of the tumour microenvironment.
Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY, USA. chanan-khan.asher@mayo.edu
Asher A
AA
Chanan-Khan
Kasyapa
K
Chitta
Noreen
N
Ersing
Aneel
A
Paulus
Aisha
A
Masood
Taimur
T
Sher
Abhisek
A
Swaika
Paul K
PK
Wallace
Terry L
TL
Mashtare
Greg
G
Wilding
Kelvin
K
Lee
Myron S
MS
Czuczman
Ivan
I
Borrello
Naveen
N
Bangia
D018122:B7-1 Antigen / Q000096:biosynthesis / Q000276:immunology; D051940:B7-2 Antigen / Q000096:biosynthesis / Q000276:immunology; D023201:CD40 Ligand / Q000096:biosynthesis / Q000276:immunology; D016207:Cytokines / Q000097:blood / Q000276:immunology; D006801:Humans; D016130:Immunophenotyping; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology; D000077269:Lenalidomide; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000097:blood / Q000188:drug therapy* / Q000276:immunology*; D008213:Lymphocyte Activation / Q000187:drug effects; D020935:MAP Kinase Signaling System / Q000187:drug effects; D013792:Thalidomide / Q000031:analogs & derivatives* / Q000627:therapeutic use; D015854:Up-Regulation / Q000187:drug effects
D018122:B7-1 Antigen; D051940:B7-2 Antigen; C497964:CD86 protein, human; D016207:Cytokines; D023201:CD40 Ligand; D013792:Thalidomide; D000077269:Lenalidomide