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News Archive: Michigan Oncology Journal Summer 98

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 Program

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 patients.

References

1. Thomas E, Storb R, Clift RA, Fefer A, Johnson FL, Neiman PE, et al. Bone-marrow transplantation (first of two parts). N Engl J Med. 292:832-843, 1975.
2. Thomas ED, Storb R, Clift RA, Fefer A, Johnson L, Neiman PE, et al. Bone-marrow transplantation (second of two parts). N Engl J Med. 292:895-902, 1975.
3. Sondak VK, Wagner PD, Shu S, Chang AE. Suppressive effect of visceral tumor on the generation of antitumor T cells for adoptive immunotherapy. Arch Surg. 126:442-446, 1991.
4. Mizoguchi H, O’Shea JJ, Longo DL, Loeffler CM, McVicar DW, Ochoa AC: Alterations in signal trans-duction molecules in T lymphocytes from tumor-bearing mice. Science. 258:1795-1798, 1992.
5. Stingl G, Bergstresser PR. Dendritic cells: a major story unfolds. Immunol Today. 16:330-333, 1995.
6. Steinman RM, Gutchinov B, Witmer MD, Nussenzweig MC. Dendritic cells are the principal stimulators of the primary mixed leukocyte reaction in mice. J Exp Med. 157:613-627, 1983.
7. Romani N, Gruner S, Brang D, Kampgen E, Lenz A, Trockenbacher B, et al. Proliferating dendritic cell progenitors in human blood. J Exp Med. 180:83-93, 1994.
8. Bernhard H, Disis ML, Heimfeld S, Hand S, Gralow JR, Cheever MA. Generation of immunostimulatory dendritic cells from human CD34+ hematopoietic progenitor cells of the bone marrow and peripheral blood. Cancer Res. 55:1099-1104, 1995.
9. 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.
10. Hsu FJ, Benike C, Fagnoni F, Liles TM, Czerwinski D, Taidi B, Engleman EG, Levy R. Vaccination of patients with B-cell lymphoma using autologous antigen-pulsed dendritic cells. Nature Med. 2:52-58, 1996.

 

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