Dendritic Cell-Based Cancer Immunotherapy
Edgar G. Engleman
The development of effective cancer vaccines depends
heavily on the ability to deliver target antigens to gen-
erate an immune response. Dendritic cells are the
most potent antigen-processing cells, capable of sensi-
tizing T cells to new and recall antigens. Dendritic cells
express high levels of major histocompatibility com-
plex class I and II antigens, which are crucial to cancer
immunotherapy, as well as a variety of important im-
munomodulatory proteins, adhesins, and a potent cy-
tokine. Dendritic cells must undergo activation to in-
duce an immune response, and this can be achieved
through the use of certain carrier proteins, adjuvants,
cytokines, or genetically engineered viruses. Dendritic
cells are scattered throughout many tissues of the
body, as well as bone marrow and peripheral blood.
Most studies have used dendritic cells from peripheral
blood; however, these cells are not prevalent in periph-
eral blood mononuclear cells. The cytokine, granulo-
cyte-macrophage colony-stimulating factor, has been
found to induce the maturation and enhance the via-
bility of dendritic cells isolated from peripheral blood.
Numerous clinical trials of antigen-pulsed dendritic
cells have been conducted in various types of cancer,
including non-Hodgkin lymphoma, multiple myeloma,
prostate cancer, malignant melanoma, colorectal can-
cer, and non–small cell lung cancer. These studies show
that antigen-loaded dendritic cell vaccinations are safe
and promising in the treatment of cancer. This review
discusses the use of dendritic cells in immunotherapy
and some of the clinical trials that have been con-
ducted.
Semin Oncol 30 (suppl 8):23-29. © 2003 Elsevier Inc. All
rights reserved.
T
HE DEVELOPMENT of effective cancer
vaccines relies not only on the identification
of target antigens, but also on approaches to de-
liver these antigens to generate an immune re-
sponse. Dendritic cells represent unique antigen-
producing cells capable of sensitizing T cells to
both new and recall antigens.
1
In fact, dendritic
cells are the most potent antigen-producing cells.
Dendritic cells express high levels of major his-
tocompatibility complex class I and II antigens. In
1990, Freudenthal and Steinman
2
showed that
these cells also express high levels of the im-
munomodulatory proteins B7.1 (CD80), B7.2
(CD86), CD40, and two adhesins, the intercellu-
lar adhesion molecule ICAM-1 (CD54) and the
lymphocyte function-associated protein LFA-3
(CD58). Dendritic cells can also produce IL-12, a
potent cytokine that activates interferon-
␥
–pro-
ducing cells.
GOALS OF THERAPY
The goal of dendritic cell-based cancer immu-
notherapy is to use dendritic cells to prime specific
antitumor immunity through the generation of
effector cells that attack and lyse tumors by intro-
ducing dendritic cells pulsed with tumor antigens
to patients. Originally, this was achieved by iso-
lating dendritic cells from patients with non-
Hodgkin’s lymphoma, loading the dendritic cells
with an antigen obtained from the patient’s tumor,
and reinjecting the antigen-loaded host cells back
into the patients.
In the past decade, much has been learned re-
garding the use of dendritic cells and their role in
the development of cancer vaccines. Contrary to
what was originally thought, dendritic cells are not
capable of inducing an immune response unless
they undergo activation. Current vaccine ap-
proaches may incorporate foreign carrier proteins,
adjuvants, cytokines, and genetically engineered
viruses in attempts to increase immunogenicity.
IN VITRO STUDIES OF HUMAN
DENDRITIC CELLS
Dendritic cells are derived from precursors in
bone marrow and are scattered in most tissues of
the body, including the blood, skin, heart, kidneys,
trachea, and bronchioles (Fig 1). The preliminary
group of trials involving dendritic cells for the
treatment of cancer used cells obtained from pe-
ripheral blood. However, because dendritic cells
constitute less than 0.5% of peripheral blood
mononuclear cells and die within a few days of
their isolation, these cells were not always readily
accessible for studies.
3
This problem was addressed in 1990 by Markowicz
From the Stanford Medical School Blood Center, Stanford Uni-
versity School of Medicine, Stanford, CA.
Dr Engleman has received research grant support from Immunex
Corporation.
Supported by National Institutes of Health grant no. HL57443,
and a grant from the State of California (9RT-0229).
Address reprint requests to Edgar Engleman, MD, 800 Welch
Rd, 2N, Stanford, CA 94305-5737.
© 2003 Elsevier Inc. All rights reserved.
0093-7754/03/3003-0804$30.00/0
doi:10.1016/S0093-7754(03)00229-X
23Seminars in Oncology, Vol 30, No 3, Suppl 8 (June), 2003: pp 23-29