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Immunotherapy

By E. Roy Berger, MD, FACP
Published: Monday, Aug 16, 2010
SPECIAL FEATURE

Immunotherapy

Abstract

A paradigm shiftin oncology has been the development of biologic compounds that are not directly cytotoxic, but which can have significant anti-cancer effects. Immunotherapy represents one such biologic approach to cancer treatment, and prostate cancer is a good immunologic target since it is a highly differentiated gender-specific organ that expresses suitable antigens restricted to the prostate gland. Sipuleucel-T, an investigative active immunotherapy treatment, uses a novel method to stimulate the immune system to attack prostate cancer. Completed phase III studies with sipuleucel-T in metastatic androgen-independent prostate cancer patients show an increase in median overall survival and a mild toxicity profile that does not appear to preclude subsequent treatment with chemotherapy

Cancer Immunotherapy

The concept of using immunologic approaches to treat cancer was described in the literature as early as 1898 by Coley,and has continued since then as an active area of investigation. A key obstacle in this approach to treatment is the ability to entrain the immune response to attack a detected cancer, since the tumors that exist at the time of diagnosis of advanced metastatic disease have already demonstrated an ability to avoid elimination by the immune system. In prostate cancer, tissue-specific proteins such as prostate-specific antigen (PSA), prostatic acid phosphatase (PAP), and prostate-specific membrane antigen (PSMA)2,3 have been studied extensively. Animal models have demonstrated the ability to recognize and attack specific prostate cancer-related antigens resulting in the initiation of T-cellmediated immune responses.4-6 Several immunotherapy approaches are under current investigation for prostate cancer either by nonspecific methods of immunostimulation, exemplified by CTLA-4 receptor blockade, cytokine therapies such as interleukin 12, B7.1 ligand, or toll-like receptor-9-activating oligonucleotides;7-9 or by antigen-specific targeted therapies including whole-cell vaccines, viral vaccines, and anti-prostate antibody therapies. 2,3

Adenocarcinoma of the prostate accounts for nearly 30,000 deaths each year, second only to lung cancer in male cancer fatalities.10 Compared to other malignancies, prostate cancer has been considered relatively resistant to chemotherapy11 and only one chemotherapy treatment, docetaxel in combination with prednisone, has been shown to improve survival in androgen-independent metastatic disease.12 Median life expectancy of men with metastatic androgen independent prostate cancer (AIPC) is less than 2 years and the treatment goal in these patients is to extend survival and preserve physical  functionality. However, for the asymptomatic metastatic AIPC patient who is reluctant to undergo or is otherwise ineligible for chemotherapy, there is no alternative treatment approved by the Food and Drug Administration (FDA) that has been shown to extend survival, and further approaches that have lower toxicology profiles than current chemotherapeutics are needed. Prostate cancer in particular represents an ideal immunotherapy target since it is a highly difterentiated, gender-specific organ characterized by a number of proteins that are restricted to prostatic tissue such as PSA, PAP, and PSMA. PAP was chosen as a suitable target antigen because this protein is expressed at detectable levels in more than 95% of prostate cancers14,15 and

has been shown to be an eftective antigen in animal models.16

Sipuleucel-T Immunotherapy

Traditional passive immunization employs subcutaneous injections to deliver antigen to antigen presenting cells (APCs), which are present in the epidermis and dermis. In the standard passive immunization technique, multiple intradermal injections may be required to reach a sufficient number of professional APCs to have the potential to induce a strong immune response. Active immunotherapy stimulates the host’s intrinsic immone response and of the various active immunotherapy approaches under active study in prostate cancer, sipuleucel-T (APC8015, Dendreon Corporation, Seattle, WA) is the only agent to date that has reported the completion of phase III clinical trials.17


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