Natural killer cells in graftversus-host disease and graft-versus-leukemia - Immune Biology of Allogeneic Hematopoietic Stem Cell Transplantation - page 344

polymorphism was associated with higher responses to rituximab therapy
in patients with follicular non-Hodgkin's lymphoma. Other monoclonal
antibodies have been developed that also mediate NK cell ADCC, includ-
ing trastuzumab (Her2 on breast cancer), alemtuzumab (CD52 on chronic
lymphocytic leukemia (CLL)), and cetuximab (epidermal growth factor
receptor on colorectal cancer) [117] , and CD16 polymorphisms have also
been associated with the efficacy of using other monoclonal antibodies to
mediate ADCC.

While each monoclonal antibody described can trigger NK cell function,
combinations of antibodies may enhance NK cell responses. For example,
engagement of inhibitory KIRs with HLA on the tumor can inhibit CD16
signaling by inhibiting tyrosine kinase activation [118] . Blockade of inhibi-
tory KIRs in combination with tumor-targeted monoclonal antibodies may
increase CD16-mediated ADCC. Anti-CD137 antibodies in combination with
rituximab have been shown to increase degranulation and IFN-γ production
[119] . Upon engagement of CD16 with rituximab-coated lymphoma cells,
CD137 is upregulated on the NK cell and addition of an agonist against CD137
increased NK-cell-mediated ADCC. A similar effect was also observed using
a combination of anti-CD137 and trastuzumab to eliminate breast cancer
cells [119] . Other drugs such as lenalidomide, currently used in the treatment
of multiple myeloma, have also been shown to enhance NK-cell-mediated
ADCC in combination with rituximab [120] . However, in a later study lenalid-
omide was shown to decrease CD20 expression on CLL, thereby decreasing
rituximab-induced ADCC [121] , so one must be careful in combining thera-
pies. Lenalidomide has also been shown to be useful at increasing ADCC of
targets coated with trastuzumab or cetuximab [122] . An alternative to combi-
nation drug therapy is to combine NK-stimulating cytokines. IL-2, IL-12, and
IL-21 have all been shown to enhance NK-cell-mediated ADCC [123] . One
step further is to combine adoptive transfer of activated NK cells stimulated
either alone with cytokines or with a genetically modified cell line to increase
NK-cell-mediated ADCC of antibody-coated tumors.

348

In addition to monoclonal antibodies, bispecific antibodies have also
been developed. Simply, a bispecific antibody will involve the fusion of
two monoclonal antibodies, one directed at the effector cell and the other
directed at the tumor cell. CD16 is commonly used to bind to the NK cell
and various target-cell-specific antigens have been used, including CD19
(B-cell lymphomas) [124] .

Histone deacetylase (HDAC) and proteasome inhibitors have also been shown
to sensitize tumors to NK cell killing. Bortezomib, a proteasome inhibitor,
has been shown to upregulate death receptors such as Fas and TRAIL-R2/
DR5 [125] and induce apoptosis through Fas/FasL and TRAIL/DR5 interac-
tions, both expressed by NK cells. Bortezomib has been shown to be effective
in inducing apoptosis of quiescent CD34 + cells in chronic myelogenous leu-
kemia patients and increasing the efficacy of ex vivo -expanded adoptively
transferred autologous NK cells [126] . Depsipeptide, an HDAC inhibitor, has
also been shown to sensitize tumors to NK-cell-mediated apoptosis through
the upregulation of death receptors [127] . Another HDAC inhibitor, valproic
acid, has been shown to induce expression of ULBP1, MICA, and MICB on
AML blasts, increasing NK cell killing [128] .