Cancer Immune Therapy Edited by G. Stuhler and P. Walden ...

has been to further mature these cells using monocyte-derived conditioning medium
or TNF-a [100]. Other differentiating or ªmaturingº agents include a cocktail of
TNF-a, IL-1b, IL-6 and prostaglandin E2 [101], and calcium ionophores [102]. These
more-differentiated Mo-DCs have greater stimulatory activity in cellular assays in vitro
and also appear to be active in vivo, but comparative migration data with blood
DCs is not available. At a practical level how the preparations are made is absolutely
critical, e.g. the use of PBMCs or CD14-selected monocytes, the presence of serum,
etc. The prolonged culture period and numerous components involved make the
good manufacturing practice (GMP) quality requirements a serious exercise. Several
commercial companies are now providing this facility.
The third possible cell preparation is to use one or more of the natural blood DC population(s)
circulating in a patient [103±105]. These might be postulated to be in the
most appropriate stage of the DC ªlife cycleº for use (Fig. 9.1). Blood DCs were used
for the first clinical DC therapeutic trial, which used low-grade NHL patients [106].
Fig. 9.1 The DC Life Cycle. Hematopoietic stem
cells in bone marrow produce DCs into the blood
stream. Blood myeloid DCs and lymphoid DCs
use adhesion molecules and chemokine receptors
(CD62L,CXCR3 and CCR5) to traffic to peripheral
tissues (CD11c + myeloid) or directly to
lymph nodes (DC123 + lymphoid) via HEVs. In
peripheral tissues immature myeloid DCs which
encounter antigens and accompany microbial
products (TNFand lipopolysaccharide) and signals
from activated Tcells (CD40L) start to differentiate.
These DCs move toward lymphatics
9.5 DC Preparations for Immunotherapy
using chemokine receptors (CCR7),whose ligand
SLC,is found both in lymphatic endothelium and
in secondary lymphoid tissue. In the lymph node
mature DCs produce chemokines,which attract
naive and activated Tcells. Complex interactions
with the local microenvironment (perhaps including
lymphoid DCs) increase co-stimulatory molecules,optimize
antigen presentation,and induce
further lymphocyte activation and the production
of effector and memory T lymphocytes. DCs also
contribute to B lymphocyte activation and antibody
production. (see color plates page XXVI)
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