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News Archive: Michigan Oncology Journal Summer 98

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

  1. 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.
  2. 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.
  3. 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.
  4. 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.
  5. 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.
  6. 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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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.