Vaccine-based immunotherapy for prostate cancer. (2000)

After a long period of smoldering activity in cancer immunotherapy, interest in cancer vaccines has caught fire. This interest is reflected in the logarithmic increase in the number of open clinical trials for the treatment of prostate and other cancers. The renewed enthusiasm has been fanned largely by a more sophisticated understanding of the intricacies of immune system regulation and by the availability of better reagents (recombinant cytokines, dendritic cells, etc) to manipulate the immune response.

The concept of active immunotherapy of cancer is based on the theory that tumor cells escape detection and destruction by the host’s immune system through various strategies: deficient tumor antigen processing and presentation, lack of immune costimulation, production of inhibitory factors by tumor cells, and insufficient helper activity from CD4 cells. One method of inducing the immune system to recognize and destroy cancer cells is cancer vaccination. Cancer vaccines attempt to facilitate the presentation of tumor antigens to the immune system; typically, in conjunction with factors that augment immune system activation, generating cellular and humoral antitumor activity.

Several distinct approaches to prostate cancer vaccination are currently being investigated. One important factor is the choice of material used as the tumor antigen. Some investigators have used irradiated, intact autologous prostate cancer cells derived from patients’ own tumors or allogeneic prostate cancer cells from previously established prostate cancer cell lines, such as LNCaP and PC-3. Others have used prostate cancer cellular homogenates, which contain a multitude of poorly defined tumor- and non-tumor-specific antigens, or have used more well-defined single antigens; often, prostate-specific proteins, such as PSA, prostate-specific membrane antigen (PSMA), or the cancer-associated mucin MUC-1.1 Another important factor is the method chosen to augment the normally muted immune response to these antigens. Approaches currently being evaluated include the use of dendritic cells, which are highly efficacious in presenting antigens to T cells, and the use of various cytokines, such as tumor necrosis factor, interleukin (IL)-2, IL-4, IL-10, IL-12, and granulocyte-macrophage colony-stimulating factor (GM-CSF), to improve the immune system’s response to the desired antigens.

GM-CSF is a potent inducer of hematopoietic differentiation, stimulating the production of macrophages and dendritic cells from monocyte precursors. In vivo administration of exogenous GM-CSF induces differentiation of bone marrow-derived antigen presenting cell-like macrophages, which are critical for antigen presentation to T cells. In addition, GM-CSF also stimulates the activation of quiescent dendritic cells. In 1997, Simons and associates2 at Johns Hopkins University in Baltimore reported on the feasibility, safety, and bioactivity of a GM-CSF-gene transduced autologous tumor vaccine for patients with metastatic renal cell carcinoma. Although initial clinical responses were limited, this vaccine was shown to induce a specific immune response to tumor cells. Recently, Simons and colleagues reported the results of a small phase I study investigating the feasibility and safety of prostate cancer vaccines using autologous prostate cancer cells similarly engineered to express GM-CSF in patients with metastatic prostate cancer (first review).

Prostate cells express tissue-specific proteins, such as PSA and PSMA, which represent a unique potential antigenic target for antitumor immune response targeted specifically to prostate cells. Sanda and coworkers at the University of Michigan have explored the use of a vaccinia viral vector carrying the PSA complementary DNA (cDNA) as a potential vaccination strategy for prostate cancer patients (second review). Since PSA is already present in patients as a “self” protein, it should be nonimmunogenic. It is possible, however, that once PSA is processed by antigen-presenting cells in the context of the vaccinia virus, it may enter different processing and packaging pathways, unmasking PSA peptide epitopes that can generate a humoral and cellular immune response. Alternatively, vaccinia virus proteins may act as an adjuvant to augment an otherwise weak anti-PSA response.

Finally, the characterization of dendritic cells, thought to be the most powerful antigen-presenting cells of the body, has stimulated intense interest as a potential cancer vaccine reagent. Dendritic cells are bone marrow-derived “professional” antigen-presenting cells. They have distinct pathways of differentiation that can be subdivided into myeloid- and lymphoid-derived lineages. Dendritic cells are vital for the stimulation of cytotoxic and helper T-cells because of their ability to recognize, phagocytose, and process antigens in the peripheral tissues, which they transport to and present in secondary lymphoid organs. In the clinical setting, a convenient source of myeloid-derived dendritic cells is peripheral blood monocytes, which can be induced to differentiate into dendritic cells using GM-CSF and IL-4. Dendritic cell-based tumor vaccines have produced encouraging early results in various cancers, such as melanoma and renal cell carcinoma. Murphy and colleagues3–6 from Washington University have done extensive preclinical and clinical research on dendritic cell-based immunotherapy of prostate cancer. Moreover, they have studied a prostate cancer vaccine strategy using autologous dendritic cells as a vehicle to present prostate antigens, such as PSMA-derived peptides to T cells (third review).

Numerous centers around the country are investigating use of new tumor vaccines to treat patients with prostate cancer and other tumors. Preclinical and early clinical data suggest that tumor vaccine therapies are feasible and safe. Most trials report only mild systemic side effects, such as hypotension, fever, chills, and fatigue; reactions at the vaccination site, such as erythema, swelling, and pruritus; and discomfort during injection. These approaches have shown that a systemic immune response to human prostate cancer can be generated, although clinical importance of the current generation of tumor vaccines remains to be established in phase II and III studies.