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Please note: This article is part of the Cancer Center's News Archive and is here for historical
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Immunomodulation Following Bone Marrow Transplantation
-Joseph P. Uberti, M.D.,
Assistant Professor of Internal Medicine,
Interim Director of the Adult Blood and Marrow Stem Cell Transplantation
Bone marrow and peripheral blood stem cell transplantation
(PBSCT) are established curative therapies for various malignant
and nonmalignant disorders (1, 2). In spite of the success
of the procedure, one of the major causes for failure after
PBSCT remains relapse. Attempts to intensify the preparative
regimen after allogeneic transplant, although providing more
anti-tumor activity, often have no overall benefit because
of the increased level of regimen- related toxicity. Studies
that have looked at tandem transplants in the autologous setting
often have shown no benefit in survival when the patients
undergoing tandem transplants are compared to historical controls.
Due to this limitation, we are investigating various biologic
and immunologic therapies post-bone marrow transplant (BMT)
in order to decrease the rate of relapse. There are several
reasons for investigating the use of immunotherapy after BMT.
After BMT, patients are often in a state of minimal residual
disease that may be more likely to respond to immunologic
manipulation. The advantage is that tumor-induced, active
immune suppression and previously acquired defects in T cell
signaling known to occur in patients with malignancies, should
be minimized (3, 4). The re-establishment of the immune repertoire
post-transplant may occur without the immunosuppressive effects
of the tumor burden that are known to exist in cancer patients.
Dendritic Cell Immunization Post-Bone Marrow Transplant
Researchers at the University of Michigan Comprehensive Cancer
Center are actively investigating the immunization of patients
against their tumor cells post-bone marrow transplant. In
general, immunologic recovery after bone marrow transplant
is delayed, making attempts at immunization difficult. As
an example, immunization with tetanus or diptheria toxoids
does not result in the development of antigen-specific T cell
responsiveness when administered during the first three months
after transplant. While the precise mechanisms of the immune
defects are not known, it is possible that the defect may
be within the afferent arm of the immune response at the level
of antigen processing and presentation. It is now well established
that dendritic cells (DC) are highly potent antigen-presenting
cells (APC) of bone marrow origin that stimulate both primary
and secondary T and B cell responses (5). Animal studies have
indicated that dendritic cells are preferentially responsible
for sensitization of naive T cells in their first exposure
to antigen (6). Methods are now available to generate sizable
numbers of highly enriched dendritic cells, both in humans
and in rodents by culturing progenitor cells in the presence
of Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF),
Tumor Necrosis Factor (TNF), and/or Interleukin-4 (IL-4) (7,
8). More recently, a study has shown that the ex vivo generation
of dendritic cells from hematopoietic precursors in patients
with breast cancer overcomes a defect in their ability to
activate T cells (9).
The ability to establish dendritic cell cultures from the
peripheral blood of adult patients has raised the possibility
of using these cells as an immunotherapeutic agent for the
treatment of a variety of human tumors. As an example, tumor
vaccines have been successfully developed using autologous
dendritic cells pulsed ex vivo with tumor-specific idiotype
protein from patients with follicular B-cell lymphomas (10).
Therefore, immunization with dendritic cells pulsed with antigens
of interest after a BMT may circumvent any immune defects
and provide a method to target and accelerate immune reconstitution.
To evaluate this hypothesis, we have initiated a trial to
test whether dendritic cells can be used to immunize patients
post-transplant. The initial study will investigate the ability
to immunize patients soon after a transplant with the protein
Keyhole Limpet Hemocyanin (KLH). Based on previous studies
of immune reconstitution post-BMT, patients will be unable
to develop a standard immune response to this antigen when
immunization is carried out by traditional methods. This study
will investigate whether this defect may be overcome by an
immunization strategy carried out on pulsed dendritic cells.
As shown in Figure 1, the precursor for dendritic cell production
will be isolated by standard leukapheresis techniques and
stored from patients who are about to undergo PBSCT. Once
the patient has recovered from the transplant, the dendritic
cells will be expanded in vitro and pulsed with the KLH antigen.
After pulsing, the dendritic cells will be used to immunize
the patient. The response to this dendritic cell immunization
will be assessed two to four weeks after the last injection.
We predict that patients will have an attenuated response
to immunization with the protein alone, but this response
will be greatly augmented by using pulsed dendritic cells
for the immunization. If the study shows that the use of dendritic
cells enhances the immune response to the protein, it will
allow us to design future trials using immunotherapy following
autologous peripheral blood stem cell transplantation in patients
with malignancies. The next step after completing the protocol
is to investigate the possibility of immunizing patients by
pulsing the patients own dendritic cells with tumor lysates.
We are in the process of initiating the protocol and accruing
- Thomas E, Storb R, Clift RA, Fefer A, Johnson FL, Neiman
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- Gabrilovich DI, Kavanaugh D, Corak J, Nadaf-Rahrov S,
Cunningham T, Carbone DP. Defective function of dendritic
cells in patients with breast cancer can be overcome by
generation of these cells from precursors, a new approach
to cancer immunotherapy (Meeting abstract). Proc Annu Meet
Am Soc Clin Oncol. 15:A1040, 1996.
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Please note: The articles listed in the Cancer Center's News Archive are here for historical
purposes. The information and links may no longer be up-to-date.