The last several years have seen an increase in the number of clinical trials using vaccine immunotherapy for the treatment of prostate cancer. The trials have used a variety of target antigens that have been shown to be associated with prostate and prostate cancer cells. These include PSA (5
), prostatic acid phosphatase (15
), prostate specific membrane antigen (19
), telomerase (22
), Thomsen-Friedenreich antigens (24
), mucins (25
), carbohydrates (26
), and HLA-associated peptides (27
). A variety of vectors have been used in the immunization process: dendritic cells (10
), vaccinia virus (5
), fowlpox virus (5
), liposomes (9
), plasmids, (13
), and chemical conjugates (24
The results from previous trials vary in terms of patient populations studied (hormone dependent vs. independent) and in levels of positive results, which include the induction of antigen-specific immune responses, decreases in levels of serum PSA and in rates of change in PSA velocity, and measures of clinical responses (29
). To date, no single vaccine immunotherapy has proven definitely superior to others in terms of clinical benefit, and other phase II and III trials continue to be planned or conducted. The results of some of these vaccine trials raise the possibility that an increase in PSADT may represent a possible surrogate marker for increased time to progression, or overall survival in immunotherapy studies, and that absolute PSA responses may not constitute an obligatory step for the ultimate demonstration of clinical benefit of immunotherapy approaches in prostate cancer. Furthermore, the T-cell stimulation index may have important correlation with clinical vaccine efficacy, as seen in the phase III trial by Small et al (26
). These developing notions further support the current proposal for clinical development of our Ad/PSA vaccine.
Anti-PSA immune responses were detected in 50% or more of our patients, including antibody and/or T cell responses. An interesting association of injection vehicle and immune response was noted. A higher number of patients vaccinated with aqueous vaccine developed anti-PSA antibody responses as compared to patients vaccinated with the matrix vaccine. The opposite appeared true for anti-PSA T cell responses, with matrix-injected patients demonstrating more cellular responses than did aqueous-injected patients. Also interesting is the finding that antibody responses correlated more with increases in PSADT than with patient survival, whereas T cell responses correlated with survival. Conclusions from the secondary objectives of generating anti-PSA antibody and T cell reactivity and from clinical responses as measured by changes in PSADT and survival times are tenuous due to the small number of patients enrolled in this phase I study. Any verification of the observations must wait for the completion of additional studies.
It is important to keep in mind that the generation of anti-tumor immune responses that may have therapeutic benefits are not only dependent upon the use of strong immunogens such as a viral vaccine carrying the transgene for a tumor associated antigen, but also on the ability to overcome negative regulatory elements. These latter conditions include the breaking of immune tolerance to the antigen as well as the effects of regulatory cells and molecules that include, but not confined to, regulatory T cells (32
), myeloid-derived suppressor cells (33
), indolamine dioxygenase (34
), and arginase (35
In order to determine whether vaccination of prostate cancer patients with the Ad/PSA vaccine will result in a therapeutic benefit we have recently initiated a phase II trial of the vaccine in men with recurrent prostate cancer. Two different patient populations will be enrolled into one of two protocols in the phase II study. In the first protocol patients with newly recurrent prostate cancer, as determined by a continuous rise in serum PSA, will be enrolled into one of two arms (A & B). The ideal patient population to determine a therapeutic benefit of a new treatment, particularly immunotherapy, is one with minimal disease burden. The low tumor burden should allow therapies, particularly those relying on antigen-specific effector T lymphocytes, to destroy all of the cancerous tissues and cells. The first therapeutic arm (Arm A) will enroll men with recent evidence of recurrence following surgery or radiation therapy for their primary tumor and receive the Ad/PSA vaccine alone in three separate injections each 30 days apart. The second therapeutic arm (Arm B) will enroll men with recurrent disease who will undergo androgen depletion therapy. The choice of this additional patient population is based upon published documentation that inflammation and the generation of immune responses are augmented by hormone withdrawal (36
). Mercader, et al., in attempts to demonstrate an enhanced termination of tolerance to prostate associated antigens documented CD4+ and CD8+ T cell infiltrates in benign prostates and in prostate tumors of men undergoing androgen withdrawal (36
). Roden and co-workers published data demonstrating that T cell levels and T cell proliferation were increased in mice following castration (37
) while Drake, et al. reported breaking tolerance to antigens associated with the TRAMP prostate tumors in mice (38
). Therefore, we propose to vaccinate men beginning 14 days after the initiation of androgen depletion therapy using the same three injection protocol. Patients deemed eligible for entry into protocol 1 will be randomized into Arm A or Arm B using a card selection method. In the second protocol we plan to enroll prostate cancer patients with hormone-refractory metastatic disease. This group of patients is similar to the population that constituted the majority of patients in the phase I toxicity trial reported in this publication. Patients in this trial will have low burden of disease, despite the fact that they are hormone refractory, i.e., have negative bone scans and/or low serum PSA.
In summary, we report here the absence of serious adverse events in patients injected with a single dose of an Ad/PSA vaccine, either delivered as an aqueous suspension or in a collagen matrix, even at the highest doses possible with the current vaccine preparation. In addition, anti-PSA immune responses were detected in a percentage of patients, with the highest percentage (68%) found in T cell responses. A phase II study is in progress to verify the immunologic and clinical observations from this phase I study.