Immunotherapies have emerged as a revolutionary modality for cancer treatment, and a variety of immune-based approaches are currently being investigated in the field of prostate cancer. Despite the 2010 approval of sipuleucel-T, subsequent progress in prostate cancer immunotherapy development has been limited by disappointing results with novel vaccination approaches and by prostate cancer’s general resistance to immune checkpoint blockade. Nevertheless, there remains strong preclinical and clinical evidence to suggest that prostate cancer is a susceptible target for immune therapies. Innovative strategies for vaccine development, adoptive cell transfer, alleviation of immunosuppression in the tumor microenvironment, and combinatorial approaches using existing drugs and novel immune agents hold great promise for improving the treatment of prostate cancer. The first article in this two-part series will provide an overview of both past and present therapeutic vaccination strategies for the promotion of antitumor immunity against prostate cancer. Later, in Part 2, we will discuss novel areas of clinical development and identify the trends that may define the future of prostate cancer immunotherapy.
Prostate cancer is the most commonly diagnosed malignant tumor in American men and the second leading cause of cancer-related mortality. Even with recent advances in multimodality therapy for localized disease, relapse occurs in 30% of patients,while men with metastatic disease ultimately develop therapeutic resistance despite the advent of novel cytotoxic drugs, anti-androgen therapies, and radiopharmaceuticals. Immunologic approaches have long been of interest in prostate cancer because the disease has several characteristics that theoretically make it a suitable immunotherapy target. The prostate is a nonessential organ whose tissues produce multiple tumor-associated antigens (TAAs) for which specific T-cell populations targeting them have been identified. These T cells can potentially serve as the central effectors of adaptive antitumor immunity. Additionally, the relatively slow growth kinetics of prostate cancer may provide a longer window for the development of effective immune responses. Despite these potential advantages, prostate cancer is generally thought to be a “cold” tumor, with limited T-cell infiltration and minimal responses to date to single-agent immune checkpoint therapies. Prostate cancer has a relatively low tumor mutation burden,[4,5] which has frequently been considered an indicator of a tumor’s poor inherent responsiveness to checkpoint inhibition; in addition, emerging data are identifying the presence of specific genetic phenotypes that are associated with the development of less immunogenic intratumoral landscapes. Furthermore, prostate cancer tumors have been known to downregulate human leukocyte antigen (HLA) class I expression, induce T-cell apoptosis, increase immunosuppressive cytokines, and increase suppressive regulatory T cell (Treg) populations in order to evade immune surveillance.[7,8] Consequently, there is a significant need to develop approaches that can circumvent the inherent immunosuppression of the prostate cancer tumor microenvironment. Clinical applications of immunotherapeutic approaches in prostate cancer have yielded mixed results, but spurred by the success of sipuleucel-T, the first therapeutic vaccine approved for use in human cancer, numerous novel vaccination approaches that enhance antitumor immunity are now being investigated (Table).
Sipuleucel-T consists of autologous peripheral blood–derived mononuclear cells cultured with a prostatic acid phosphatase (PAP) and granulocyte-macrophage colony-stimulating factor (GM-CSF) fusion protein. Sipuleucel-T was approved for use in the setting of asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer on the basis of three trials whose results demonstrated clinical efficacy. An integrated analysis of two of the trials, D9901 and D9902A, demonstrated an improved median survival in those treated with sipuleucel-T of 23.2 months vs 18.9 months for placebo, which was equivalent to a 33% reduction in the risk of death (hazard ratio [HR], 1.5; 95% CI, 1.1–2.05; P = .011). It should be noted, however, that overall survival (OS) was a secondary endpoint in these studies, and that the primary endpoint of improved progression-free survival (PFS) was not met. Concerns have also been raised over the pooling of data from two independent studies and over possible inequivalence of baseline disease characteristics among the compared subgroups. The subsequent IMPACT trial randomized 512 patients with metastatic castration-resistant prostate cancer in a 2:1 ratio to sipuleucel-T or the control treatment and found a significant 4.1-month increase in OS for the therapy group, although with no difference in time to progression; there were no major differences in adverse effects between the two arms.
Despite these results and the subsequent US Food and Drug Administration approval of sipuleucel-T, its widespread adoption has been hampered by the involved manufacturing process, concerns about detrimental effects of the leukapheresis procedures, the limited therapeutic window and magnitude of clinical benefit, and questions raised by the discordance between the PFS and OS outcomes. Of particular importance is the recognition of this phenomenon of improved survival without changes in PFS as a recurrent theme in immunotherapy trials. This has been noted in several other clinical contexts, including in pre-approval trials of checkpoint inhibitors in metastatic melanoma and renal cell carcinoma,[12,13] and it raises the important question of what are the most appropriate parameters for measuring efficacy in the age of novel immunotherapies.
Although the exact mechanism of action of sipuleucel-T is not known, correlative studies provide insight into clinical predictors of response and immunologic effects of the therapy. Retrospective analyses have suggested increased benefit in patients with more favorable prognostic features, such as lower baseline prostate-specific antigen (PSA) and lactate dehydrogenase (LDH) levels and better performance status. Increased tumor burden is generally believed to correspond to greater systemic immunosuppression, and the suggestion of a later onset of action of sipuleucel-T based on the delayed separation of Kaplan-Meier survival curves has led to recent recommendations to consider sipuleucel-T vaccination early in the treatment of metastatic castration-resistant prostate cancer.
Mechanistically, sipuleucel-T has demonstrated robust activation of antigen-presenting cells (APCs), antigen-specific T-cell responses, and increases in cytokines associated with T-cell activation. The number of APCs and their activation, as measured by CD54 upregulation, have positively correlated with improved OS. Interestingly, sipuleucel-T has also resulted in humoral antigen spread to a variety of targets beyond PAP, with immunoglobulin (Ig) G responses to PSA and LGALS3 that have correlated with improved OS. A neoadjuvant trial of sipuleucel-T prior to radical prostatectomy found that treatment could increase the frequency of activated CD4+ and CD8+ T cells in the tumor microenvironment, particularly at the interface with adjacent benign tissue. The broad stimulation of systemic immunity, along with the recruitment of possible effector T cells to tumor by sipuleucel-T, provides a further rationale for combining vaccination approaches with other activators of T-cell function. This robust immunologic response also suggests the need to consider further studies evaluating vaccination in the neoadjuvant and adjuvant settings for localized disease, when vaccination may enable the development of sustained antitumor immune surveillance.
Other Vaccine Approaches
Despite the approval of sipuleucel-T, a variety of alternate vaccine approaches have had much less success in the management of prostate cancer. GVAX is a cellular vaccine consisting of irradiated cells from PC-3 and LNCaP prostate cancer cell lines that are modified to constitutively express GM-CSF.[19,20] The theoretical advantages of this approach include the opportunity to induce immunologic responses to multiple TAAs and the possibility of mass-producing vaccines that can be administered without the need for HLA matching. Ultimately, two phase III trials to test the therapeutic efficacy of GVAX were undertaken. The VITAL-1 trial comparing GVAX to docetaxel plus prednisone in asymptomatic castration-resistant prostate cancer was terminated after a futility analysis demonstrated a less than 30% chance of meeting the improved survival endpoint. VITAL-2, which compared the combination of GVAX and docetaxel to docetaxel and prednisone was also stopped after an interim analysis showed an increased risk of death in the GVAX arm. Clinical development of GVAX was ultimately halted.
PROSTVAC (PSA-TRICOM) is a cancer vaccine composed of a series of poxviral vectors (vaccinia during the initial priming vaccine and fowlpox for all boosts) engineered to express PSA and a triad of human T-cell costimulatory molecules (B7.1, intercellular adhesion molecule 1, and lymphocyte function-associated antigen 3).[23,24] A phase II study of 125 patients with minimally symptomatic metastatic castration-resistant prostate cancer randomized to placebo or PROSTVAC with adjuvant GM-CSF did not demonstrate improvement in the primary PFS endpoint but showed an increased median OS of 25.1 vs 16.6 months (HR, 0.56; P = .0061). A similar trial by the National Cancer Institute that allowed for enrollment of patients with symptomatic or visceral metastatic castration-resistant prostate cancer demonstrated a median OS of 26.6 months, with 12/32 patients demonstrating PSA decline. Patients with lower-risk disease as defined by a Halabi model–predicted survival of > 18 months at the time of treatment had a particularly notable duration of survival (median OS, 37.3 months), suggesting the possibility that vaccination provides the greatest benefit for patients with lower tumor burden or a less aggressive phenotype. In the setting of biochemical recurrence after definitive local therapy, 63% of patients treated with PROSTVAC in conjunction with GM-CSF were progression-free at 6 months, and there was a notable reduction in PSA doubling time following treatment.
Based on the promising phase II data in patients with metastatic castration-resistant prostate cancer, PROSPECT (ClinicalTrials.gov identifier: NCT01322490), a global phase III trial enrolling 1,297 patients with metastatic castration-resistant prostate cancer, was undertaken to evaluate the efficacy of PROSTVAC-VF ± GM-CSF. Unfortunately, this trial was stopped in September 2017 when a preplanned interim analysis found the therapy to be unlikely to meet its OS endpoint.
Despite the disappointing results of the PROSPECT trial, there are compelling data to demonstrate the immunogenicity of PSA-encoding poxviral vaccines. An aggregate evaluation of blood T-cell responses across seven early poxviral vaccine trials showed 57% of patients (59/104) with a twofold or greater increase in PSA-specific T cells following the vaccine. Interestingly, a majority of these patients also demonstrated the phenomenon of antigen-spreading, with documented T-cell response to non-PSA antigen targets. A similar vaccination strategy incorporating only a single costimulatory molecule (B7.1) was administered in conjunction with radiotherapy for localized prostate cancer and was found to produce a significant increase in PSA-specific T cells compared with radiotherapy alone. Consequently, PROSTVAC has been administered in combination with escalating doses of ipilimumab in a phase I trial in metastatic castration-resistant prostate cancer. This trial demonstrated no significant increase in adverse events with the combination compared with ipilimumab alone, with 14/24 chemotherapy-naive patients (58%) experiencing PSA decline, and with 6/24 having declines of > 50%; moreover, the median OS in this trial was a robust 31.6 months. Currently, the optimal clinical contexts and combination strategies for PROSTVAC remain questions of interest, with ongoing trials being conducted in the localized (NCT02326805, NCT03315871, NCT00096551), neoadjuvant (NCT02506114, NCT02153918), adjuvant (NCT02772562), biochemical recurrence (NCT00450463, NCT01875250), metastatic castration-sensitive prostate cancer (NCT02649855), and castration-resistant prostate cancer (NCT01867333, NCT02933255) settings.
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