Emerging Role of Immunotherapy in the Management of Prostate Cancer
Emerging Role of Immunotherapy in the Management of Prostate Cancer
There has been a resurgence of interest in developing noncytotoxic immune therapies for patients with either hormone-naive biochemically relapsed post-primary therapy or castrate metastatic prostate cancer. The rationale for developing an immunotherapeutic approach has been based on the overexpression and underglycosylation of a wide variety of altered "self" molecules including prostate-specific antigen (PSA), acid phosphatase (ACP), prostate stem cell antigen (PSCA), and prostate-specific membrane antigen (PSMA), which can serve as targets for immune recognition and attack. In addition, such a strategy could theoretically make use of the patient's immune system to fight the tumor particularly if their disease is of reasonably low volume. A variety of immunotherapeutic approaches have been explored through phase I, II, and now phase III trials demonstrating that immunologic tolerance could be broken, as evidenced by the development of high-titer antibodies and T-cell responses specific for the tumor. What appears to be revolutionizing the immunotherapy field is the combination of vaccines with cytokines or immune modulators, which not only potentiate immune reactivity in vivo but foster dramatic antitumor responses. This review explores the challenges now faced in establishing a role for immune therapies for prostate cancer treatment.
Therapeutic antitumor immunity or immunotherapy for prostate cancer has been an attractive treatment option for all stages of prostate cancer, given its seemingly broad application and low toxicity profile. Its appeal has been based on the idea that the evolution of cancer is due to a defect in immune surveillance and that the body can use other aspects of its immune system to fight the cancer. Vaccination against cancer is not new—in fact, the front page of The Globe from Toronto on July 17, 1925, boasted of a novel report by Gye and Barnard in the Lancet suggesting that a virus caused cancer and that "while it would be an exaggeration to say a cure for cancer is in sight, the new announcement is expected to indicate probabilities of finding a method of vaccination against cancer."
Have we made strides since that time? A variety of precedents have established the success of vaccines in certain cancers, especially melanoma. We now know that some anti-inflammatory responses and autoimmune phenomena, as seen with depigmentation or vitiligo, can herald antitumor immunity. Many who have followed the immunotherapy literature would say the development of such approaches has run the gamut of investigation, from whole-cell vaccines to cell extracts, to purified membranes expressing the antigen, to purified antigen, to protein, peptides, and ultimately DNA.
Given the diversity of expression of multiple antigens on a cancer cell surface, it remains unclear which of these are specifically associated with the cancer and should be the appropriate target(s) for therapeutic direction. Despite multiple approaches, no one approach has been shown to have a superior impact on slowing cancer growth or inducing disease remission. Antigens expressed on tumor cells may be "self" antigens—molecules derived from the breakdown of normal cell membranes or remnants of cells infected by or destroyed by bacteria or viruses or tumor cells. Those abnormal antigens are taken up by scavenger cells known as antigen-presenting cells or dendritic cells (called Langerhans cells in the skin), digested, and broken down into peptides, which are then presented to the T cell for recognition and, hopefully, subsequent destruction.
Much of what we have learned in designing immunotherapeutic approaches has been based on antigens isolated from infectious diseases. An antigen, while foreign to the immune system, may be insufficient to generate an immune response. Not only must it be immunogenic, but the immune system must "see" it in order to determine whether recognition is feasible. In the cases of altered self antigens, the immune system may see this molecule as self and therefore not be triggered to induce a response. However, if one were to try to make the immune system become aware of this altered molecule, immunizing with this isolated molecule may be insufficient and mandate that something be done to make the body react to it. This includes using a carrier molecule to make the molecule look larger in addition to revving up the immune system with a natural or synthetic chemical known as an adjuvant.
Induction of Immunity
Active vs Passive Approaches
Immunity to a particular molecule can be generated either passively or actively. In the former case, the immune system is not actively responding to the immunogen administered. In lieu of the body's own reaction, a drug such as a monoclonal antibody—which exquisitely targets a particular antigen—has already been generated, and one is "passively" conferred the immunity against that molecule by the antibody. Active immunity is the body's own response to a treatment, that is, the ability to generate a humoral or cellular immune response to an immunogen. Each subserves a different purpose in generating a reaction to tumor antigens.
Passive Immunity: Immunotherapy With Monoclonal Antibodies
Prostate-specific membrane antigen (PSMA) is one of several self antigens that has served as a potential target for immunologic approaches, with strategies including DNA and protein vaccines in addition to monoclonal antibodies.[2-11] PSMA is a type II integral transmembrane protein and a member of a superfamily of zinc-dependent exopeptidases, including carboxypeptidases A and G2, and peptidases T and V.[2-4] While highly expressed in prostate cancer cells and initially thought to be a specific marker for prostate cancer, its expression has been found in the brain and salivary gland. It is also expressed in nonprostatic solid tumor neovasculature (eg, renal cell carcinoma),[5-7] making it a reasonable target for immune therapies such as vaccine strategies and radiopharmaceutical targeting with monoclonal antibodies.[9-14]
As a type II transmembrane glycoprotein, PSMA is a large extracellular globular-like molecule with an intracellular segment. It is expressed at levels over a 1,000-fold greater than the minimal expression seen in the kidney, proximal small intestine, and salivary gland. It is also upregulated in the androgen-resistant state. Second-generation humanized forms of a monoclonal antibody against the external domain of PSMA (J591) developed by Bander et al[12,14] have been conjugated to iodine and yttrium, as well as to lutetium in an effort to image all sites of metastases, especially in bone. These studies have shown 100% specificity and sensitivity for sites in bone and have been extended to other malignancies including renal cell cancer.
• Clinical Trials—Two recent trials show good tolerability of alternative radiopharmaceuticals that have been coupled to J591 monoclonal antibody. Bander et al performed a phase I study in 35 patients with androgen-independent prostate cancer to assess the safety, maximum tolerated dose (MTD), pharmacokinetics, organ dosimetry, targeting, human anti-J591 response, and biologic activity of lutetium-177-labeled J591. Of the 35 patients, 16 received up to three doses. Myelosuppression was dose-limiting at 75 mCi/m2, with the MTD established at 70 mCi/m2. Targeting to all known sites of disease (ie, bone and lymph nodes) was seen in all 30 patients. No patient developed a human anti-J591 antibody response to dehumanized J591 irrespective of the number of doses. Biologic activity lasting 3 to 8 months was seen in four patients, who had a at least a 50% decline in prostate-specific antigen (PSA) levels. Biomarker stabilization was seen in 16 patients for a median of 60 days.
Morris et al also studied unlabeled and indium-111 (111In)-labeled J591 in a similar population. Two groups of seven patients with androgen-independent disease were studied. One group of patients received unlabeled J591 before the labeled antibody; the other received both together. The agent was well-tolerated, and biodistribution of 111In-labeled J591 was comparable in both groups, with half-lives of 0.96, 1.9, 2.75, and 3.47 days for the 10-, 25-, 50-, and 100-mg doses, respectively. Hepatic saturation occurred by the 25-mg dose. Antibody-dependent cell-mediated cytotoxicity was proportional to dose, with one patient showing a greater than 50% decline in PSA.
Self antigens identified on prostate cancer cells and cell lines appear on the normal counterparts of the tumor cells derived from the organ in question, yet change in very subtle ways with malignant transformation. This is particularly true of the mucin family (ie, MUC-1 and MUC-2, which are present normally within glandular elements and become overexpressed and underglycosylated with malignancy). It is unclear why the immune system does not see these altered self antigens expressed on the new tumor cells as foreign and enables them to grow. However, strategies have focused on means of educating the immune system to recognize these molecules and break immunologic tolerance, thereby allowing the body to respond to what is then perceived as a foreign rather than a self antigen.