Relevance of dendritic cell therapy in prostate cancer biology essay

Prostatic adenocarcinoma remains one of the most prevalent and least understood of all human malignancies. Cancer of the prostate is primarily a disease of the elderly men. It is rarely sets in before the age of 50 years and majority of people diagnosed are over 60 years. Pathologic evidence suggests that neoplastic changes of the prostate epithelium begin early in a man’s adult life, but do not become clinically evident or relevant until decades later. Some patients live out their lives with a prostate cancer that remains stable for decades without treatment. In other cases, the cancer grows aggressively, responds poorly to therapy, and causes death within a few years. The natural history of this enigmatic disease is heterogeneous, ranging from a benign and indolent course to one that rapidly progresses, causing significant morbidity and mortality (1; 2). Prostate cancer is now the fifth most common cancer in the world (in terms of number of new cases), and the second in terms of importance in men. Incidence varies according to the ethnicity. The disease is less prevalent in Asians and Africans are reported to have the highest death rate of prostatic cancer. About 10% of cases have a family member also been diagnosed with Prostate cancer, and a significantly increased risk has been observed in men whose first-degree relatives were also diagnosed with Prostatic cancer, suggesting genetic predisposition. Specific chromosomal abnormalities have not been established yet. A complete understanding of the causes that lead to prostate cancer remains ambiguous (3). Obesity, age and family history are reported to be the primary risk factors. There are certain scientific literature have suggested but no shown enough proof that high fat rich diet may increase the risk of developing prostatic adenocarcinoma by increasing the levels of testosterone, which has been found to affect the growth of the prostate. A relationship between nodular hyperplasia and carcinoma have not been established yet. The role of sex hormones in prostate cancer is also debatable and poorly understood. It has been reported that interdict of prostatic carcinoma can be achieved with exogenous estrogens and orchiectomy, but higher levels of serum androgens or notable change in their metabolism have not been shown systematically in patients with the disease. The role of androgens in prostatic carcinoma may be agreeable, being required for the maintenance of the neoplastic prostatic epithelium cells, which also have androgen receptors like their normal counterparts. In majority of cases of prostate cancer, prostatic intraepithelial neoplasia (PIN) characterized by presence of dysplastic epithelium in the foci of glands lined by dysplastic epithelium, is observed. PIN is considered to be the forerunner of invasive carcinoma. At times early and advanced carcinoma of the prostate may be asymptomatic at the time of diagnosis and about 80% of patients have advanced or metastatic disease at the time of diagnosis. Symptoms include dysuria, difficulty of micturition, or increasing urinary frequency and others effects of metastatic tumor. Scarcity of prognostic markers presents a major challenge for the clinical management of castration resistant prostate cancer and for stratification of patients into clinical trials. Nomograms based on clinic pathological parameters (eg, performance status, extent of metastasis, prostate-specific antigen [PSA], lactate dehydrogenase, alkaline phosphatase, and hemoglobin) show only moderate predictive accuracy. Hence, novel biomarkers that enable more accurate risk prediction for castration-resistant prostate cancer are needed.

The Prostate Specific antigen

Prostate-specific antigen (PSA) is a glycoprotein with expression mainly confined to the epithelial lining of the prostate glands. Disruption of the normal prostatic architecture due to inflammation, infection or cancer leads to the leakage of PSA into the general circulation. US Food and Drug Administration (FDA) in 1986 approved the use of measuring PSA levels to monitor treatments for prostate cancer and, in 1994, approved PSA testing for disease detection. PSA testing has been lately debated for its low sensitivity and specificity as a diagnostic tool for prostate cancer detection. The value of PSA testing for preventing prostate cancer mortality has been evaluated in two recently published randomized trials, one of which supports the use of testing PSA (5), whereas the second trial does not support the use of PSA testing (6). Nevertheless, the mortality rate from prostate cancer has shown a declining trend over the past decade, and there are some data to indicate that the initiation of this decline coincides with the adoption of PSA testing. The American Urological Association (AUA) has recommended PSA screening for men with an estimated ten-year life expectancy (7). From an immunological aspect, PSA is a target antigen in diverse immunotherapeutic approaches for prostate cancer, most notably a poxvirus-based vaccine known as ProstVac VF (8).

Dendritic Cell Immunotherapy in Cancer

Discovery of the key role of DC in the immune response was first observations by Z. Cohn and R Steinman(24; 25) who through a variety of cell separation techniques enriched a population of lymphoid tissue cells that appeared much more talented at promoting alloreactive T cell proliferation than macrophages (26) . Immunotherapy with dendritic cells loaded with specific tumor antigens ex vivo has been studied extensively in animals (27). Dendritic cells (DC) are the antigen presenting cells (APCs) which possess the ability to stimulate naïve T cells (10; 11). DCs originate from the bone marrow and reside in a resting or immature state in nonlymphoid tissues in which they efficiently capture and process antigens, DCs differentiate and acquire the ability to produce cytokines responsible for the polarization of the immunological response. After inducing the T-cell response, it results in cell-mediated immunity. The T cells recognize fragments of the antigens bound to molecules of the MHC (Major Histocompatibility Complex) on the surfaces of APCs. Upon stimulation with successful antigen DCs undergo a maturation process that results in enhanced antigen presenting capacity and expression of MHC and co-stimulatory molecules and migration into secondary lymphoid organs in which they prime naive T cells (12-14). Because of their unique capacity to stimulate resting T cells, DCs are the promising option for immunization protocols particularly for the induction of antitumor immunity to patients with malignant disease (15; 16). Earlier studies have shown that DC vaccines are effective when primed with antigen derived from breast tumors (23). Because of their immunoregulatory properties and high efficiency, activated DCs are highly efficient at generating immune responses against Tumour associated antigens. DCs have been used in various clinical trials in order to elicit or amplify immunological responses against cancer and chronic infectious diseases (28). A set of methodological discoveries in the early 90s dramatically changed this picture by permitting the relatively simple in vitro differentiation of cells that shared membrane markers and functional capabilities with the so far described DC (29). The same strategy, of loading autologous DC with antigens expressed in cancer many clinical trials were undertaken in a series of 32 renal and breast cancer patients (79). Treatment option for men with metastatic, castration-resistant prostate cancer (CRPC) is limited, and patients have very few treatment options, particularly if the treatment is refractory for docetaxel (Taxotere). As a result, there is a need for novel approaches to therapy based on understanding of the interactions between the immune system and tumours immunology. This is especially relevant in the case of prostate cancer, as recent approval of an autologous cellular vaccine consisting of activated antigen-presenting cells loaded with prostatic acid phosphatase (PAP), sipuleucel-T (Provenge) by the US Food and Drug Administration. It marks the first antigen-specific DC based immunotherapy approved for cancer treatment. In a phase III clinical trial, treatment with sipuleucel-T, gave a median overall survival of 25. 8 months compared with 21. 7 months for placebo-treated patients, resulting in a 22% relative reduction in the risk of death (9). Burch and colleagues at the Mayo Clinic conducted the first Phase I clinical trial of sipuleucel-T in 1997. The trial enrolled 13 patients with metastatic CRPC, treated with two infusions of sipuleucel-T one month apart, followed by 3 monthly subcutaneous injections of PA2024 alone at one of three dosage levels (0. 3, 0. 6 or 1. 0 mg/injection). At the end of the study, all patients evaluated for immune response developed antigen-specific T-cells. A drop in serum PSA level of 50% or more was observed in three patients. No patients had response by radiological criteria. Toxicity included low-grade fever, mylagias and injection site reactions with some patients experiencing significant fatigue up to grade 3. Analysis of the antibody response from the trial also suggested that follow up injections of soluble antigen PA2024 did not contribute to sero conversion or increased antibody titer over and above the three infusions of activated dendritic cells (37). In recent times, vaccine based therapeutic products were under trials in CRPC, USA. Two randomized trials using the allogeneic vaccine G-VAX viral vectors have failed to demonstrate a survival benefit (30; 31). In these trials the viral vectors of poxvirus family have been used to deliver tumor (PSA) antigens to obtain an immunomodulatory effect. In another trial, 125 asymptomatic minimal CRPC patients received either PROSTVAC-VF (Bavarian Nordic, Kvistgaard, Denmark) or control viral vectors. The PROSTVAC-VF group showed an 8. 5-month improvement in median survival (24. 1 v/s. 16. 6 months in control patients). In view of above mentioned scientific evidences, it is very much desirable to have an immunotherapeutic agent which can trigger the desired immunological response, without causing much toxicity, to specifically target a particular type of carcinoma, even in patients with advance stage of the disease. (DC) based cancer vaccine research has emerged from the laboratories to human clinical trials. Conventional chemotherapeutic agents directly attack cancer cells, while cancer vaccine does not. The latter indirectly give damage to cancer cells by the activation of immune system. Therefore, we may need cancer vaccine-specific response evaluation criteria (38-40). It is becoming clear that to increase efficacy, research on DC immunotherapy needs a major breakthrough from preclinical animal models, resembling the human situation. Our understanding of cancer antigen-directed immune responses at the cellular and molecular level continues to grow, which should lead to further development of cancer immunotherapy. Many strategies are being devised to increase immunogenicity and to fight back the immunosuppressive mechanisms set up by tumours. Combination of DC based therapies and other immunotherapeutic approaches are likely to yield the most clinically worthy strategies for the future. A plethora of phase II trials have demonstrated immunological potency of cancer vaccines and potential clinical efficacy. Translation to clinical use would be a boon to thousand of end stage Prostate cancer patients who have very limited treatment options and the only option which can prolong life expectancy in case of metastatic prostate carcinoma.