Current status of immunological therapies for prostate cancer.
ABSTRACT: Considerable progress has been made in prostate cancer immunotherapy over the last year, and two agents have completed phase III testing. This review will discuss the most promising immune-directed strategies in development for prostate cancer, outlining interventions that mitigate tumor-induced tolerance and highlighting several combination immunotherapy approaches.A pivotal phase III study using Sipuleucel-T, an autologous prostatic acid phosphatase (PAP)-loaded dendritic cell immunotherapy, in men with metastatic castration-resistant prostate cancer (CRPC) demonstrated a survival advantage over placebo. By contrast, two phase III studies of GVAX, an allogeneic tumor cell vaccine, in a similar patient population failed to show a survival benefit of GVAX or GVAX/docetaxel over standard docetaxel/prednisone. Other strategies currently in clinical development include the ProstVac poxviral vaccine, a PAP-encoding DNA vaccine, and immune checkpoint inhibitory approaches.Although Sipuleucel-T may receive FDA approval for patients with metastatic CRPC, challenges remain in identifying immunotherapy strategies that overcome immune tolerance, especially when disease burden is substantial. An emerging paradigm focuses on using immunotherapy together with checkpoint antagonists or in combination with conventional therapies in patients with early-stage disease. Such approaches are likely to yield optimal results, but must carefully be explored in well designed phase II studies before moving forward.
Project description:At present, sipuleucel-T represents the only approved immunotherapy for prostate cancer. Sipuleucel-T is an autologous cellular therapy, which primes autologous antigen-presenting cells against the prostatic acid phosphatase (PAP) antigen. For patients with metastatic castrate-resistant prostate cancer (CRPC) who are asymptomatic or minimally symptomatic, sipuleucel-T monotherapy is one of the standard of care treatment options pre- or postdocetaxel. With the approval of new treatments, including abiraterone and enzatutamide, sequencing and combination of these treatments with sipuleucel-T represent unanswered questions facing the field. Whereas steroids that are coadministered with abiraterone and chemotherapy have long been thought to be immunosuppressive, early results show that concurrent abiraterone and prednisone does not significantly impact the ability to develop immune responses to this treatment. Additional clinical data are needed to elucidate optimal sequencing of therapeutic agents in CRPC. Several novel immunotherapies are currently in development, and enrollment in clinical trials should be considered. These include PROSTVAC-VF, a viral vaccine that encodes PSA and T-cell costimulatory molecules, which is currently undergoing phase III clinical trials. DNA plasmid-based vaccines targeting different antigens, including PAP, also are under investigation. Immune checkpoint blockade with ipilimumab, a monoclonal antibody against CTLA-4, which is approved for metastatic melanoma, also is being evaluated. Whereas this treatment failed to show significant improvement in overall survival in CRPC patients treated with docetaxel, results from a phase III trial in the predocetaxel setting are pending. Conventional therapies for prostate cancer, such as radiation and hormonal therapy, may have immunomodulatory effects. Future areas for research include the sequencing and combination of immunotherapies as well as other conventional therapies.
Project description:The effective treatment of castrate-resistant prostate cancer (CRPC) has proven to be very challenging. Until recently, docetaxel was the only therapeutic demonstrated to extend overall patient survival. Yet recently, a considerable number of new therapeutics have been approved to treat CRPC patients. These remarkable advances now give new tools for the therapeutic management of late-stage prostate cancer. In this review, we will examine mechanistic and clinical data of several newly approved therapeutics including the chemotherapeutic cabazitaxel, antiandrogen enzalutamide, endocrine disruptor abiraterone acetate, immunotherapy sipuleucel-T, and bone-targeting radiopharmaceutical alpharadin. In addition, we will examine other promising therapeutics that are currently in Phase III trials.
Project description:Previous vaccination studies in patients with castration-resistant prostate cancer (CRPC) showed improved survival without prolongation of progression-free survival (PFS). This might be explained by enhanced efficacy of subsequent therapies because of heightened immune status. We therefore evaluated the efficacy of chemotherapy in CRPC patients after immunotherapy. We retrospectively analyzed 28 patients who were treated with ipilimumab and GVAX, an allogeneic vaccine, and 21 patients who were randomized to GVAX or no vaccination. To study whether immune status was related to the efficacy of chemotherapy, frequencies of myeloid and lymphocyte subsets were determined. Of 28 patients treated with GVAX and ipilimumab, 23 patients received docetaxel and 13 patients mitoxantrone. Median PFS after docetaxel was 6.4 mo (range 0.8-11.2), while median PFS after mitoxantrone was markedly longer than expected (4.8 mo; range 1.4-13.7). High CD8+ICOS+ Tcell/Treg and pDC/mMDSC ratios were associated with relatively long PFS after mitoxantrone, suggesting a correlation between activated immune status and benefit of mitoxantrone. Analysis of 21 patients, randomized to GVAX or not, revealed a median PFS after docetaxel of 9.9 mo for vaccinated patients and 7.1 mo for unvaccinated patients. Interestingly, PFS after mitoxantrone (n = 14) was significantly longer in vaccinated patients as compared to controls (5.9 vs. 1.6 mo, p = 0.0048). In conclusion, mitoxantrone seems more effective in CRPC patients after immunotherapy, which may be related to the immune-stimulating effect of mitoxantrone in patients with heightened antitumor immunity. As this was a retrospective study with limited sample size, prospective studies are warranted to definitively show proof of principle.
Project description:Prostate cancer is the most common noncutaneous cancer and the second leading cause of death from cancer in men in most western countries. Advanced prostate cancer is typically sensitive to androgen-deprivation therapy, but invariably progresses to the castration-resistant state. Most current prostate cancer treatments are based on cytotoxicity directed against tumor cells via androgen-deprivation therapy or chemotherapy. Chemotherapy with docetaxel represents the standard first-line treatment in patients with castration-resistant prostate cancer (CRPC). Following progression after treatment with docetaxel, cabazitaxel (XRP6258)-prednisone treatment leads to a significantly longer overall survival (OS) time than with mitoxantrone-prednisone. Several other novel agents are currently being evaluated, including sipuleucel-T, abiraterone acetate, and MDV3100, as well as the radionuclide alpharadin. The cell-based immunotherapy sipuleucel-T produces longer OS times in chemotherapy-naïve patients, whereas the androgen biosynthesis inhibitor abiraterone acetate results in longer OS times following docetaxel. It is envisioned that these agents will change the standard of care for patients with metastatic CRPC. This review focuses on the clinical development of cabazitaxel and abiraterone acetate.
Project description:Prostate cancer (PC) is the most commonly diagnosed noncutaneous malignancy in American men. PC, which exhibits a slow growth rate and multiple potential target epitopes, is an ideal candidate for immunotherapy. GVAX for prostate cancer is a cellular immunotherapy, composed of PC-3 cells (CG1940) and LNCaP cells (CG8711). Each of the components is a prostate adenocarcinoma cell line that has been genetically modified to secrete granulocyte-macrophage colony-stimulating factor. Hypothesizing that GVAX for prostate cancer could be effective in a neoadjuvant setting in patients with locally advanced disease, we initiated a phase II trial of neoadjuvant docetaxel and GVAX. For the trial, the clinical effects of GVAX were assessed in patients undergoing radical prostatectomy (RP).Patients received docetaxel administered at a dose of 75 mg/m(2) every 3 weeks for 4 cycles. GVAX was administered 2-3 days after chemotherapy preoperatively for four courses of immunotherapy. The first dose of GVAX was a prime immunotherapy of 5×10(8) cells. The subsequent boost immunotherapies consisted of 3×10(8) cells. After RP, patients received an additional six courses of immunotherapy. Pathologic complete response, toxicity, and clinical response were assessed. The primary endpoint of the trial was a pathologic state of pT0, which is defined as no evidence of cancer in the prostate.Six patients completed neoadjuvant docetaxel and GVAX therapy. No serious drug-related adverse events were observed. Median change in prostate-specific antigen (PSA) following neoadjuvant therapy was 1.47 ng/ml. One patient did not undergo RP due to the discovery of positive lymph nodes during exploration. Of the five patients completing RP, four had a downstaging of their Gleason score. Undetectable PSA was achieved in three patients at 2 months after RP and in two patients at 3 years after RP.Neoadjuvant docetaxel/GVAX is safe and well tolerated in patients with high-risk locally advanced PC. No evidence of increased intraoperative hemorrhage or increased length of hospital stay postoperatively was noted. These results justify further study of neoadjuvant immunotherapy.
Project description:The management of men with metastatic castration-resistant prostate cancer (CRPC) has taken several leaps forward in the past year, with the demonstration of improved overall survival with three novel agents (sipuleucel-T, cabazitaxel with prednisone and abiraterone acetate with prednisone), and a significant delay in skeletal-related events observed with denosumab. The pipeline of systemic therapies in prostate cancer remains strong, as multiple agents with a diverse array of mechanisms of action are showing preliminary signs of clinical benefit, leading to more definitive phase III confirmatory trials. In this review, which represents part 1 of a two-part series on metastatic CRPC, we will summarize the mechanisms of resistance to hormonal and chemotherapies and discuss the evolving landscape of treatment options for men with CRPC, with a particular focus on currently approved and emerging treatment options following docetaxel administration, as well as prognostic factors in this post-docetaxel state. As docetaxel remains the standard initial systemic therapy for men with metastatic CRPC for both palliative and life-prolonging purposes, knowledge of these evolving standards will help to optimize delivery of care and long-term outcomes.
Project description:Sipuleucel-T is an autologous cellular immunotherapy that induces an immune response targeted against prostatic acid phosphatase (PAP) to treat asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer. In the phase III IMPACT study, sipuleucel-T was associated with a statistically significantly increased overall survival (OS) (median = 4.1?months) vs placebo. Patients with baseline prostate-specific antigen levels in the lowest quartile (?22.1?ng/mL) exhibited a 13-month improvement in OS with sipuleucel-T. Together, this led sipuleucel-T to be approved and recommended as first-line therapy in various guidelines for treatment of metastatic castration-resistant prostate cancer. This review discusses the varied findings about the mechanisms of action of sipuleucel-T, bringing them together to form a more coherent picture. These pieces include inducing a statistically significant increase in antigen-presenting cell activation; inducing a peripheral immune response specific to the target (PAP) and/or immunizing (PA2024) antigens; stimulating systemic cytotoxic T-lymphocyte activity; and mediating antigen spread (ie, increased antibody responses to secondary proteins in addition to PAP and PA2024). Each of these pieces individually correlates with OS. Sipuleucel-T also traffics T cells to the prostate and is associated with long-term immune memory such that a second course of treatment induces an anamnestic immune response. Prostate cancer does not have a strongly inflamed microenvironment, thus its response to immune checkpoint inhibitors is limited. Because sipuleucel-T is able to traffic T cells to the tumor, it may be an ideal combination partner with immunotherapies including immune checkpoint inhibitors or with radiation therapy.
Project description:In the last three years, five novel treatments have been shown to improve survival in metastatic castration-resistant prostate cancer (CRPC). These novel treatments have distinct mechanisms of action: tubulin-binding chemotherapy (cabazitaxel); immunotherapy (sipuleucel-T); CYP-17 inhibition (abiraterone); androgen receptor (AR) blockade (enzalutamide); and radioisotope therapy (radium-223). For a number of years, docetaxel was the only treatment with a proven survival benefit for patients with CRPC. Therefore, somewhat artificially, three treatment spaces for drug development in CRPC have emerged: pre-docetaxel; docetaxel combinations; and post-docetaxel. For patients progressing after docetaxel-based chemotherapy, treatment options available outside of clinical trials now include abiraterone, cabazitaxel and enzalutamide. Prospective data on how to best use these novel agents sequentially are not available. Clinicians face the difficult task of choosing between treatment options for individual patients to maximize patient benefit. Treatment evaluation in patients with CRPC remains challenging due to the predominance of bone metastatic disease and the lack of validated surrogate markers for survival. This review summarizes the data available with regards to sequencing of the novel treatments for CRPC.
Project description:The recent Food and Drug Administration approval of sipuleucel-T for metastatic castration-resistant prostate cancer and of the anticytotoxic T-lymphocyte antigen 4 antibody (Ipilimumab) for metastatic melanoma has led to a renewed interest in immunotherapy for prostate and other cancers. Ipilimumab has entered phase III testing for prostate cancer, as has a viral-based anti-prostate-specific antigen vaccine (ProstVac-VF). Complementing these phase III studies are a number of innovative phase II studies, aimed at bringing immunotherapy forward in the setting of less advanced disease, as well as a number of interesting trials combining immunotherapy with conventional therapy for prostate cancer.Although a number of immunotherapy trials have been initiated, few mature results are available at the current time. These data are likely to mature in the setting of an increasingly complex treatment paradigm in which multiple hormonal and novel agents are available.Immunotherapy for prostate cancer represents an attractive treatment approach, with the currently available agent sipuleucel-T providing a significant survival benefit without appreciable toxicity. Novel approaches to improve the efficacy of this and other immune-active agents are currently under evaluation.
Project description:The treatment options for patients with castration-resistant prostate cancer (CRPC), until very recently, only included docetaxel. In the past 10 months, newly Federal Drug Administration (FDA) approved agents in the United States have shown survival benefit for patients with CRPC. This review takes a closer look at these newer agents: sipuleucel-T (immune therapy) and cabazi-taxel (cytotoxic therapy). We also review the evidence supporting the FDA's approval of denosumab (bone-targeted therapy) as a treatment option for men with CRPC and bony metastases. Newer agents currently being investigated in phase III clinical trials for their potential role in metastatic CRPC are also reviewed. These agents include abiraterone (hormonal therapy), TAK-700 (hormonal therapy), MDV3100 (hormonal therapy), ipilimumab (immune therapy), zibotentan (endothelin-A receptor antagonist) and dasatinib (tyrosine kinase inhibitor). As ongoing studies using all the aforementioned agents continue to evolve, our understanding of how and where these agents fit into the treatment paradigm for patients with CRPC will become clearer.