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.[4] 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.[5] 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)[9] and vaccines with viral platforms such as the prostate-specific antigen (PSA)-targeted vaccine (PROSTVAC),[10] 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.[11] 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[12] 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[13] and others[14] 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.[14] Work by Drake et al[15] 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.[16] 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.[17] 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,[20] 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.
Using Sipuleucel-T in Clinical Practice Today
There are a plethora of treatment recommendations for patients with metastatic castration-
resistant prostate cancer; a practitioner has to take time to discern which therapy is best and when to implement it.[18,19]
So, when should sipuleucel-T be introduced in current treatment algorithms? As seen in the Figure, there are many opportunities to incorporate sipuleucel-T into the treatment armamentarium. There are data to support its impact on the intratumoral milieu, as seen in the neoadjuvant studies of Fong et al.[21] Data now indicate that sipuleucel-T not only is associated with the presence of APCs, but also with the generation of cytotoxic T cells, along with durability of immune responsiveness. Are these observations enough to recommend use of sipuleucel-T along the treatment continuum? The answer is “yes”-but caution is advised, given the uncertainty of whether its lack of an antitumor effect radiographically is meaningful for a patient with more advanced disease in whom tumor burden and antigen presence are both high but in whom an immune response could also likely be dampened.
The issue is how to use the drug and reap some benefit that may have a clinical impact on future treatment. It is essential to have a frank discussion with the patient regarding expectations of how the drug will impact his disease and how long he should be observed before PSA anxiety and/or disease progression takes over. Similarly, might this therapy be better used in combination with or after failure of enzalutamide, or with other immune modulators, including the checkpoint inhibitors-especially those that may target the programmed death 2 pathway? The answers to these questions are not yet available, but that does not mean that there is no utility to the therapy. How to use immunotherapy along the disease continuum for solid tumors is still a work in progress, as is determining how to safeguard against potential side effects that could be life altering.
KEY POINTS
- Immune therapies such as sipuleucel-T can be considered along the spectrum of disease progression; potential benefits and expectations for “response” should be addressed with the patient prior to therapy.
- Antitumor efficacy of sipuleucel-T might be enhanced by the use of other immunologic/biologic therapies, including checkpoint inhibitors and vaccines, or by the use of drugs that may affect the intratumoral milieu within bone, such as radium-223 or other bone-seeking agents. These treatments are currently under study in clinical trials.
- Sipuleucel-T should not be used in the neoadjuvant setting or for patients with progressive and/or symptomatic prostate cancer.
- The benefit of sipuleucel-T in the setting of biochemically relapsed prostate cancer remains uncertain at this time; a frank discussion regarding the lack of data to support its role in this early stage of disease is needed.
In recent years, the implementation of sipuleucel-T has become an integral part of routine clinical practice for urologists.[22-28] Some patients are no longer being transferred to oncology practices once castration resistance has emerged, and more patients are being treated with multiple antiandrogens prior to even seeing a medical oncologist. Similarly, the introduction of docetaxel and abiraterone in patients with noncastrate metastatic disease to bone at diagnosis is serving as an impetus for urologists to oversee treatment with these agents themselves. It should be stressed that prostate cancer care in general should be multidisciplinary and include not only the treating urologists and oncologists but also primary care/internal medicine physicians, who should be aware of oncologic agent–associated side effects that may have an impact on longstanding medical conditions.[29] Sipuleucel-T, along with the androgen receptor–directed antiandrogens, offer an advantage to urologists because they are recommended and endorsed by both the American Urological Association and the National Comprehensive Cancer Network as therapeutic options that can be considered before chemotherapy initiation-thereby securing a role for the urologist to offer treatment to patients with metastatic castration-resistant prostate cancer. Shore et al[26] has presented a treatment algorithm for management of the different clinical scenarios that might be encountered by the practicing urologist and has offered recommendations for each of these. One of the recommendations is not using immunotherapy in patients with nonmetastatic castration-resistant disease in the absence of a clinical trial. There was also a recommendation to not consider immunotherapy in patients with metastatic castration-resistant prostate cancer with poor performance status who had received prior docetaxel; in the case of sipuleucel-T, this included not using it in patients with symptomatic metastatic castration-resistant prostate cancer with poor performance status and no prior docetaxel.
Conclusions-and a Look Ahead
Sipuleucel-T will continue to remain a constant in the treatment algorithm for patients with metastatic castration-resistant prostate cancer. Attempts to improve upon its efficacy remain ongoing, but it is questionable whether this drug will continue to be used with a frequency equivalent to that of abiraterone, enzalutamide, or radium-223. There has been a significant shift in treatment patterns since the advent of sipuleucel-T in 2010, due not just to the approval of this first cellular immunotherapy for prostate cancer patients, but also to the fact that four other treatment options for this population have been approved since then. A majority of patients prefer an “immediate” antitumor effect such as can be provided by abiraterone or enzalutamide. In addition to the convenience of being able to just “take a pill,” patients’ expectations are that the drug will begin working immediately and that they will not have to wait several months for it to take effect. The fact that sipuleucel-T is not characterized by convenience and immediacy of results was pointed out by Jaroslawski and Toumi.[30] Concerns about cost-effectiveness (or the lack thereof) have also played a pivotal role in sipuleucel-T’s relative lack of success.[24]
An issue that has tainted its usefulness in the European market has been sipuleucel-T’s failure to meet the National Institute for Health and Care Excellence (NICE) criteria for recommending treatments for patients whose life expectancy is considered to be less than 2 years-which require (among other things) that they have the potential to prolong life beyond what currently available treatments are able to do. After reviewing several clinical trials, the committee reviewed data from the original IMPACT trial[12] and found that while the median OS in the control patients who never received chemotherapy was 22 months, these patients could have received salvage therapies that might have had a beneficial impact on their survival.
Sipuleucel-T is here to stay irrespective of advances-or the lack thereof-with other immunologic platforms. However, the need for novel immune therapies in prostate cancer remains a high priority.
Financial Disclosure:The author has no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.
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