Multiple immunotherapy platforms have been investigated for prostate cancer, but sipuleucel-T still remains the sole approved autologous cellular immune product that can be used in men with asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer. While preliminary data for specific checkpoint inhibitors suggest benefit for some patients, leading to durable responses, it has been clear that sipuleucel-T can affect not only the intratumoral milieu but also systemic immune populations. This means that the immune system can respond to sipuleucel-T in such a way that it may also effect an immunomodulatory response to other current and future treatments. It is clear that sipuleucel-T is here to stay; nevertheless, efforts to enhance its efficacy continue. A challenge that continues to be investigated is the question of how and when to use this immune therapy as part of the current continuum of competing approved agents.
The Immunologic Nature of Prostate Cancer
It is ironic that prostate cancer, the first solid tumor malignancy with an approved cellular immunotherapy for patients with either asymptomatic or minimally symptomatic castration-resistant disease, is not an immunologically robust cancer. The impact on prostate cancer of a new class of immunologic agents, the checkpoint inhibitors, has been limited to a small percentage of patients who have had durable benefit.[1-3] One explanation that has been put forth for its limited susceptibility to checkpoint inhibitors is that it is not as hypermutated a disease as other genitourinary malignancies, such as bladder or kidney cancers. However, there are other hypotheses that attempt to explain the lack of efficacy of immune approaches other than that represented by sipuleucel-T. One is the notion that some tumors may be immune “deserts” (ie, there are different mechanisms of response and immune escape that govern how the tumor responds to an immune therapy).[5,6] In addition, some tumors can be described as “inflamed” or “noninflamed.” Tumors that are inflamed are likely to have lymphocytes surrounding them (tumor-infiltrating lymphocytes [TILs]), along with activated cytotoxic T lymphocytes (CD8+) that secrete interferon-gamma (IFN-γ), as well as TILs that express programmed death ligand 1 (PD-L1), a T-cell inhibitory receptor ligand. It should be noted that prostate tumors at various stages may have significant immune infiltrates—consisting of T cells (CD3+), helper T cells (CD4+), and CD8+ cells—but despite these infiltrates, no antitumor effects are noted. Some malignant prostate cells have been found to be FOXP3−, CD25−; and some FOXP3+, CD25+. It is unclear whether this is due to various inhibitory immune factors or cells such as myeloid-derived suppressor cells or inhibitory natural killer cells. On the other hand, noninflamed tumors are likely not to be immunologically “savvy”—that is, there are minimal or no lymphocytic infiltrates, and there is no expression of PD-L1 and low antigenic expression. However, noninflamed tumors may be highly proliferative despite these negative features. These tumors may, in fact, be genomically stable.
In prostate cancer the relationship between TILs and survival remains unclear, although some reports have suggested a correlation between TILs and poor prognosis. Similarly, high TIL infiltrate has been associated with increased risk of recurrence, future metastasis, and poor cancer-specific survival. Other alterations to the immune landscape that can modify immunologic response include increasing levels of V-domain immunoglobulin suppressor of T-cell activation (VISTA).[7,8] While prior immune therapies, including cellular vaccines such as the granulocyte-macrophage colony-stimulating factor (GM-CSF)–secreting vaccine (GVAX) and vaccines with viral platforms such as the prostate-specific antigen (PSA)-targeted vaccine (PROSTVAC), had initially shown antitumor efficacy or potential improvement in overall survival (OS) in the phase II setting, the reasons for lack of efficacy and failure to meet primary OS endpoints in phase III trials remain speculative. Similarly, preclinical studies have supported the efficacy of different forms of immunotherapies, demonstrating robust antitumor effects, but these early findings have not translated into clinical benefit.
The novelty of sipuleucel-T comes from its success as the first approved immune therapy for a solid tumor, the first to show improvement in OS (although not in time to progression), and the first “personalized” therapy for cancer. While understanding the mechanism of action was not felt initially to be a concern as long as a survival benefit was seen, nevertheless, data by Sheikh et al and others showed that T-cell activating cytokines were detected following the second and third infusion of the immune product and that antigen-specific T cells could be detected as early as following the initial treatment; T-cell proliferation and IFN-γ production supported these findings. Overall, it appeared that the cumulative number of antigen-presenting cells (APCs) generated, as well as APC number (which reflects infiltration specifically to the tumor site) and total nucleated cells, correlated with statistically significant OS. Immune responses to specific antigens could be observed in 78% of patients and also appeared to correlate to OS. Further data support the likelihood that antigen spreading is an additional mechanism that contributes to the efficacy of sipuleucel-T. Work by Drake et al using more finessed assays now indicates that while T-cell proliferation was seen with sipuleucel-T, many of the cells proved to be effector cells capable of cytotoxic activity. An association was also found between the magnitude of the antigen-specific T-cell cytotoxicity that persisted at week 26 and OS.
Thus, there is still a need for novel immunologic approaches, as well as for the identification of unique antigens that may serve as targets. Such approaches might include the combination of immune platforms with biologic agents—eg, immune modulators with antiandrogens such as enzalutamide; or cytokines with GM-CSF, checkpoint inhibitors, or even bone-seeking radiopharmaceuticals. It is imperative that these new therapeutic approaches target the intratumoral milieu, thereby leading to direct or indirect recruitment of immune cells that migrate to the site of the cancer cells to induce an antitumor effect. While the multiple mechanisms of an immune therapy might include antigen spreading, antibody-dependent cell-mediated cytotoxicity, or direct cytotoxicity, it is rare that a direct on-target effect occurs without the involvement of multiple cellular and humoral pathways. These observations have led to further combinatorial approaches involving sipuleucel-T, which have the potential to augment tumor immunity and future biologic responses to other drugs.
Research Into Optimizing Use of Sipuleucel-T: Combinations, Earlier Disease, Specific Populations
In a recent study, sipuleucel-T was combined with escalating doses of ipilimumab in patients with progressive metastatic castration-resistant prostate cancer. Although this was a small study, the addition of ipilimumab at 1 mg/kg was well tolerated. Statistically significant increases in serum immunoglobulin (Ig) M and IgG-IgM specific for the fusion protein used in sipuleucel-T (PA2024, which is a fusion of prostatic acid phosphatase [PAP] and GM-CSF) and PAP occurred. The levels of immunoglobulins increased markedly following the addition of ipilimumab compared with sipuleucel-T alone. The maintenance of blood levels of these immunoglobulins lasted from 5 to 15 months; repeat dosing may be feasible. This suggests that antibody enhancement may play a future role in slowing tumor progression.
Attempts to define the impact of sipuleucel-T in earlier-stage disease were reported by Antonarakis et al. Men who had biochemically relapsed prostate cancer following surgery, radiotherapy, or both and who had a PSA doubling time of ≤ 12 months in the absence of metastases were evaluated in a phase II trial to assess sequencing of sipuleucel-T and androgen deprivation therapy (ADT). Patients were randomized either to sipuleucel-T followed by ADT that was initiated 2 weeks after sipuleucel-T or to ADT followed by sipuleucel-T that started 12 weeks after ADT. Patients in both arms continued ADT for a total of 12 months. The primary endpoint was a specific T-cell response to PA2024 over time. T-cell proliferation specific for PA2024 was twofold higher in patients treated with sipuleucel-T followed by ADT compared with those who received ADT followed by sipuleucel-T. In addition, the development of PA2024-specific humoral responses correlated with a prolonged time to PSA progression that was deemed significant. Whether or not sequencing ADT with immune therapies or the impact of ADT itself has any bearing on immune responsiveness will need to be determined in further studies. There are retrospective studies to suggest a role for immune modulation with hormonal therapies such as gonadotropin-releasing hormone analogs, but there have been no prospective studies that sequentially monitor the immune environment over time and under the influence of these agents.
There continues to be interest in designing trials that attempt to successfully strategize how to utilize sipuleucel-T and make optimal use of its immunologic augmentation. Identifying drugs that will synergize with sipuleucel-T is one such approach, as seen in several studies.[14,17-19] However, identifying patients who could potentially benefit may be another approach. In a study led by Sartor et al, it was found that black patients unexpectedly had an additional median OS benefit of 9.3 months compared with white patients (37.3 vs 28.0 months) based on a large dataset from the
PROCEED registry. In addition, of those patients who had PSA levels below the median (26.8 ng/mL) at the time of treatment, those who were black have continued to have an OS benefit of almost 2 additional years compared with those who were white (54.3 vs 33.4 months). On multivariate analysis, black race was an independent baseline predictor of improved OS following treatment with sipuleucel-T.
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