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Dendritic Cell-Based Vaccines for the Treatment of Cancer
-James J. Mulé, Ph.D.,
Maude T. Lane Professor of Surgical Immunology, Department of Surgery,
Director, Tumor Immunotherapy Program
Although standard modalities of treatment for human cancer — radiation,
chemotherapy and surgery — have had some impact on the course of
this disease, it is clear from the substantial death rate from progressive
tumor growth that new, improved approaches are needed.
Immunotherapy
Immunotherapy is a strategy that has gained much interest as a possible
fourth modality for the treatment of cancer. Substantial tumor regressions
have occurred in certain advanced cancer patients following adoptive immunotherapy
with immune lymphocytes, yet several significant factors exist that limit
the potential broader success of this therapeutic approach. These limitations
include:
- Altered trafficking
patterns of antitumor effector cells following expansion in tissue culture.
The vast majority of intravenously injected effector cells do not traffic
to cancer deposits upon intravenous injection, which may be due to loss
of critical homing/adhesion molecules as a direct outcome of tissue
culture. The transferred cells often may become trapped in (and destroyed
by) the lungs, liver and spleen. Very high costs of supplies and labor
are associated with tissue culture expansions of effector cells for
adoptive transfer into patients (e.g., expansions to at least 1011 cells
are often required); the methodologies employed are cumbersome and time
consuming.
- Since ablative
chemotherapy or radiation therapy is not generally administered as a
standard regimen in most adoptive immunotherapy protocols, tumor-induced,
active immune suppression are known to exist in cancer patients receiving
transferred immune effector cells, which may inhibit their antitumor
activity.
- Low incidence of
tumor antigen-reactive immune T cells in cancer patients (at a frequency
often <1 in 100,000 to <1 in 1,000,000 circulating peripheral
blood (PB) lymphocytes) often makes it difficult to isolate and achieve
large-scale
tissue culture expansion of these effector cells, which cease to expand
in number and/or lose their ability to destroy cancer cells after prolonged
tissue culture.
In an attempt to overcome these limitations and substantially increase
the frequency of antitumor effector cells in the body, we have focused
our efforts on the use of powerful, antigen-presenting cells —
dendritic cells (DC) — in a vaccine approach to augment the host’s
immune response to the growing cancer.
Tumor Lysate-Pulsed Dendritic Cell Vaccines
Dendritic cells can elicit primary immune responses by their potent capacity
to present antigens to lymphocytes (Figure 1). The highly efficient nature
of DC as antigen-presenting cells raises the possibility of uncovering,
in tumor-bearing hosts, very low levels of immune T cell reactivity to
poorly-immunogenic tumors that are virtually undetectable by other means.
The establishment of DC cultures from the peripheral blood of adult patients
has raised the very important possibility of now using these cells as
immunotherapeutic agents for the treatment of a variety of both solid
and hematologic human tumors (1).
In pre-clinical animal studies, we have shown that tumor antigen-pulsed
DC can elicit potent tumor-specific effector T cell activity (2,3). This
observation has been made in a variety of histologically-distinct tumors,
including sarcoma, breast carcinoma, lymphoma and melanoma. Importantly,
we have found that DC serving as potent antigen-presenting cells allow
whole disrupted tumor (lysates) to be used as a source of tumor antigen(s)
for presentation — circumventing the need for viable fresh tumor
cells and thus the establishment of tumor cell lines in tissue culture,
which is particularly difficult to achieve for certain human cancers (e.g.,
breast). Since human cancers have recently been shown to elicit multiple
specific immune responses in the patient, our approach of using whole
tumor lysates pulsed onto DC offers the potential advantage of augmenting
a broader T cell immune response to tumor-associated antigens that would
not be obtained by pulsing DC with single, or perhaps several defined
tumor peptides. Such a strategy might decrease the potential of tumor
“escape” from immune recognition.
In a variety of mouse tumor models, we have shown that tumor lysate-pulsed
DC can induce potent, tumor-specific immune effector cells in tissue culture
(2-4). More importantly, immunization of mice with tumor lysate-pulsed
DC can mediate substantial reduction (70% or greater) in the number of
established lung metastases (5). Figure 2 shows a representative experiment
of DC-based vaccine therapy of lung metastases from a breast tumor in
these treated animals.
Phase I Clinical Trials
With my colleagues Alfred E. Chang, M.D., James D. Geiger, M.D., and Raymond
Hutchinson, M.D., we have initiated a phase I clinical trial (UMCC 9702)
of tumor lysate-pulsed DC-based vaccination administered in the setting
of adult and pediatric patients with advanced solid tumors (Figure 3).
Endpoints of the trial are evaluation of treatment-related toxicity and
stimulation of immunity. DC are pulsed with a lysate of the patient’s
own tumor and with a defined antigen (Keyhole Limpet Hemocyanin; KLH)
and administered intradermally every other week for a total of three immunizations
over a six-week period. The dose escalation in cohorts of 3-6 patients
is 1, 10, and 100 million DC per injection. KLH is employed as a marker
antigen to evaluate the potency of the vaccine, which assesses the capacity
of the patient’s immune system to adequately respond to a known test
antigen.
Our future studies will include combining the administration of tumor
lysate-pulsed DC with certain immune-stimulating recombinant cytokines
(e.g., Interleukin-2) to further enhance the antitumor activity of the
vaccine. In addition, we plan to undertake a clinical trial in patients
with advanced breast cancer to evaluate the effects of tumor lysate-pulsed
DC immunization post-autologous peripheral blood stem cell transplantation
(Figure 4) (6). The potential advantages of this strategy are listed in
Table 1, which are based on the results from pre-clinical animal models.
The capacity of DC to “educate” the earliest daughter progeny
T cells developing from human hematopoietic stem cells (during immune
reconstitution) to recognize residual breast cancer cells will be evaluated
at varying time points after the transplant. This strategy may result
in the production of large numbers of circulating, tumor-fighting immune
effector cells against minimal residual disease in the treated patient.
References
- Chen B-G, Shi Y,
Smith JD, et al. The role of TNF-alpha in modulating the quantity of
peripheral blood-derived, cytokine-driven human dendritic cells and
its role in enhancing the quality of dendritic cell function in presenting
soluble antigens to CD4+ T cells in vitro. Blood. (in press), 1998.
- Cohen PJ, Cohen
PA, Rosenberg SA, et al. Murine epidermal Langerhans cells and splenic
dendritic cells present tumor-associated antigens to primed T cells.
Eur J Immunol. 24:315, 1994.
- Cohen PA, Cohen,
PJ, Rosenberg, SA, et al. CD4+ T cells from mice immunized to syngeneic
sarcomas recognize distinct, non-shared tumor antigens. Cancer Res.
54:1055, 1994.
- Geraghty PJ, Fields
RC, and Mulé JJ. Vaccination with tumor-pulsed splenic dendritic
cells mediates immunity to a poorly-immunogenic tumor. Surg Forum. 47:459,
1996.
- Fields R, Shimizu
K, and Mulé JJ. Murine dendritic cells pulsed with whole tumor
lysates mediate potent antitumor immune responses in vitro and in vivo.
Submitted for publication.
- Choi D, Walsh M,
Hoffmann S, et al. Dendritic cell-based vaccines in the setting of peripheral
blood stem cell transplantation: CD34+ cell-depleted mobilized peripheral
blood can serve as a source of potent dendritic cells. Submitted for
publication.
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