sipuleucel-T Therapy Research Articles

Association Between Black Race And Improved Survival Following Sipuleucel-T Immunotherapy In Metastatic Castrate-Resistant Prostate Cancer: Implications For Immune Biology And Integration Of Radiation Therapy With Immunotherapy

The biology of prostate cancer in black patients may differ from white patients. For example, recent data suggests that black patients may harbor tumors that are more sensitive to radiation or immune-directed therapy. Sipuleucel-T, a cell-based immunotherapy approved for use in men with metastatic castrate-resistant prostate cancer (mCRPC), is currently also being studied in early-stage non-metastatic prostate cancer. To explore possible immunologic differences and opportunities for synergy with radiation therapy, we examined the association between race and overall survival (OS) among patients receiving sipuleucel-T therapy for mCRPC using a novel real-world database. Using the CancerLinQ database, we identified 474 patients with mCRPC managed with sipuleucel-T. We used Cox modeling to examine the association between race (black vs white) and OS, with or without adjustment for other prognostic variables (age, prior systemic therapy, and prostate-specific antigen [PSA]), and performed subgroup analyses stratifying by the median PSA (16.6 ng/mL). In secondary analyses, we used Cox modeling to estimate treatment-free survival following sipuleucel-T and we used competing risks regression to model time to initiation of a subsequent systemic therapy. Median follow-up was 38.8 months. Black patients (n = 68) experienced significantly improved OS compared to white patients (n = 406) (median 43.1 months vs 30.2 months, hazard ratio [HR] = 0.638, 95% confidence interval [CI] 0.443-0.920, p = 0.016). These results persisted on multivariable analysis (adjusted HR 0.542, 95% CI 0.371-0.792, p = 0.002). Among patients with PSA > 16.6 ng/mL, median OS was 37.7 months vs 20.3 months (HR = 0.463, 95% CI 0.277-0.775, p = 0.003). For patients with PSA < = 16.6 ng/mL, there was no significant difference in median OS (43.1 months vs 40.6 months, HR = 0.842, 95% CI 0.487-1.456, p = 0.538). There were no significant differences in treatment-free survival (HR = 0.777, 95% CI 0.581-1.040, p = 0.090) or initiation of a subsequent systemic therapy (HR = 1.287, 95% CI 0.802-2.065, p = 0.295) by race. Black patients were more likely to receive subsequent cabazitaxel therapy compared to white patients (26.5% vs 15.0%, p = 0.019) but there were no significant differences in the receipt of other therapies (docetaxel, abiraterone, enzalutamide, radium-223). Among men with mCRPC who received sipuleucel-T, black patients had significantly longer OS compared to white patients but no difference in the time to subsequent systemic therapy, mirroring the results of prior immunotherapy studies. This finding may reflect differences in the underlying immune biology of prostate cancer in black versus white patients and may have implications for the integration of radiation therapy and immunotherapy in prostate cancer.

Targeting prostate cancer stem-like cells by an immunotherapeutic platform based on immunogenic peptide-sensitized dendritic cells-cytokine-induced killer cells

BackgroundAutologous cellular immunotherapy or immune enhancement therapy has demonstrated some promising benefits for prostate cancer. T cell-based immunotherapy or sipuleucel-T therapy has yielded certain beneficial responses and a slight improvement on the overall survival of patients with metastatic castration-resistant prostate cancer (mCRPC) as shown in some clinical trials, suggesting that prostate cancer is immunoresponsive.MethodsIn this study, we developed an adaptive cytokine-induced killer cell (CIK)-based immunotherapeutic application targeting the prostate cancer stem-like cells (PCSCs). In this therapeutic platform, dendritic cells (DC) were isolated from the peripheral blood mononuclear cells (PBMCs) and preloaded or sensitized with immunogenic peptides derived from two PCSC-associated cell membrane molecules, CD44 and EpCAM, followed by co-culture with the expanded peripheral blood lymphocyte (PBL)-derived CIK cells. The in vitro cytotoxic activity of DC-activated CIK cells against PCSCs was determined by CCK8 and TUNEL assays, and the in vivo anti-tumor effect of DC-activated CIK cells on prostate cancer xenograft tumors was evaluated in subcutaneous and orthotopic xenograft models.ResultsOur results showed that the peptide-sensitized DC-CIK cell preparation manifested significant in vitro cytotoxic activity against the PCSC-enriched prostatospheroids and also in vivo anti-tumor effect against prostate cancer xenografts derived from the PCSC-enriched prostatospheroids.ConclusionsTogether, our established immunogenic peptide-sensitized DC-CIK-based cell preparation platform manifests its potential immunotherapeutic application in targeting the PCSCs and also prostate cancer.

Case series of reports of pruritus and sipuleucel-T submitted to the Food and Drug Administration Adverse Event Reporting System

Sipuleucel-T, an autologous active cellular immunotherapy, is indicated for the treatment of asymptomatic or minimally symptomatic castration-resistant prostate cancer. The U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) received a report of pruritus without rash following the second dose of sipuleucel-T in a patient who had otherwise not started any new medications concurrent with the first and second doses of sipuleucel-T. No further sipuleucel-T was administered, but symptoms persisted for at least 6 weeks despite treatment with several medications aimed at symptomatic relief of pruritus. Rash is the only dermatologic adverse event included in the sipuleucel-T U.S. package insert. A search of the FAERS database yielded seven additional U.S. reports of pruritus and sipuleucel-T identified as the primary suspect medication; two of these occurred prior to the administration of sipuleucel-T (following leukapheresis). In data mining analyses, pruritus following sipuleucel-T was not reported more frequently than expected when compared to all other adverse event-drug/biologic combinations in FAERS. Thus, pruritus following sipuleucel-T administration was rarely, but not disproportionately, reported to FAERS. Although we cannot exclude the possibility that diabetes, malignancy, or other conditions may have contributed to pruritus in our index patient, in view of the timing of sipuleucel-T therapy and onset of symptoms, a drug/biologic-related reaction is plausible. In the appropriate clinical scenario, sipuleucel-T (or its components) should not be overlooked as a potential etiological agent in pruritus.

Randomized phase II trial of sipuleucel-T immunotherapy preceded by sensitizing radiation therapy and sipuleucel-T alone in patients with metastatic castrate resistant prostate cancer

BackgroundSipuleucel-T is an autologous cellular immunotherapy indicated for patients with asymptomatic or minimally symptomatic metastatic castration resistant prostate cancer (mCRPC). Since radiation therapy (RT) can suppress bone marrow function and immune responses, previous studies evaluating sipuleucel-T excluded patients who received RT less than or equal to 28 days prior to sipuleucel-T therapy. Recent evidence suggests that RT may act synergistically with immunotherapy to enhance and broaden antitumor immune response. MethodsPatients who met standard criteria for sipuleucel-T were randomized to receive sipuleucel-T alone (Arm A) or sipuleucel-T initiated 1 week after completing sensitizing RT to single metastatic site (Arm B). RT was delivered at 300cGy/day to 3000 cGy total. The primary endpoint was the ability to safely combine sipuleucel-T preceded by RT and generate sipuleucel-T with adequate product immune activation parameters. Secondary endpoints included the measurement of systemic immune responses to prostatic acid phosphatase (PAP), a target for sipuleucel-T immune therapy and PA20204 (recombinant fusion protein utilized in the generation of sipuleucel-T). Results51 pts were enrolled, 2 did not receive any sipuleucel-T because of vascular access problems and were excluded. 24 were treated on Arm A, 25 on Arm B. 47/49 patients received all 3 sipuleucel-T infusions. Median age was 66 yrs (range 45–90). Sipuleucel-T product parameters including: total nucleated cell (TNC) count, antigen presenting cell (APC) count were similar in both groups. Cumulative APC upregulation was higher in Arm A. 1 patient in Arm A demonstrated PSA response. Median progression free survival (PFS) was 2.46 months on Arm A and 3.65 months on Arm B (p = 0.06). Both arms showed similar increases in humoral responses to PA2024 and PAP. IFN-ƴ ELISPOT T-cell activation responses to PA20204 were observed in both arms, but were more robust in the Arm A (p = 0.028). Both arms were well-tolerated, with fatigue as the most common grade 2 adverse event (1 patient in Arm A and 3 patients in Arm B). ConclusionsSensitizing RT completed 1 week before generation of sipuleucel-T did not affect the majority of product parameters and the ability to deliver sipuleucel-T therapy. RT did not enhance the humoral and cellular responses associated with sipuleucel-T therapy.

A phase II randomized, double-blind study of sipuleucel-T followed by IDO pathway inhibitor, indoximod, or placebo in the treatment of patients with metastatic castration resistant prostate cancer (mCRPC).

3066 Background: The indoleamine 2,3-dioxygenase (IDO) pathway is a key counter-regulatory mechanism exploited by tumors in order to prevent and defeat anti-tumor immunity. Sipuleucel-T has overcome this tumor mediated anergy only in part by its ex-vivo sensitization. Small-molecule inhibitors of the IDO pathway, such as indoximod, are an increasingly validated class of potential cancer therapeutics. We tested the hypothesis whether targeting the IDO pathway by indoximod will inhibit Treg and abrogate tumor-mediated immunosuppression permitting a robust and sustained immune response to sipuleucel-T. Methods: Patient (pts) with mCRPC received either indoximod or placebo orally for 10 weeks after completion of sipuleucel-T therapy. In the absence of radiographic or clinical progression, pts were continued on study drug for 3 more months. Immune monitoring was done similar to IMPACT study (NEJM 2010; 363:411-422) starting prior to sipuleucel-T therapy. The primary endpoint was augmentation of immune response to PA2024 measured at 14 weeks. Secondary endpoints include safety, clinical efficacy (PFS, OS) and HR-QOL Results: Of the 63 pts with CRPC screened, 46 eligible pts were randomized to indoximod (n = 22) or placebo (n = 24). Pts tolerated therapy with indoximod with no significant difference in adverse events between two arms. There was no difference in PSA progression nor difference in the primary endpoint of immune response to PA2024 for 35 pts who have completed study and have samples analyzed. Median OS has not yet been reached in the study. Median radiographic PFS was 10.3 months in the treatment arm vs 4.1 months in placebo arm (p = 0.011), 4.1 months being similar to PFS in the pivotal ‘IMPACT’ study. More Pts continued to complete maximum treatment on indoximod arm (40.9% vs 25%). Conclusions: Treatment with indoximod post sipuleucel-T therapy is well tolerated and led to a significant improvement in radiographic and clinical progression. Augmentation of immune response to PA2024 by ELISPOT or ELISA might not be right biomarker for augmented response assessment while studying inhibition of IDO pathway. Clinical trial information: NCT01560923.

Evaluating immune responses after sipuleucel-T therapy

Following FDA approval of sipuleucel-T in 2010 for metastatic castration resistant prostate cancer (mCRPC), several studies have described the effect of sipuleucel-T on peripheral immune responses. Retrospective associations have also been made with immune responses and survival. A recently published study by Fong et al. was the first to characterize the immune response of sipuleucel-T in the tumor microenvironment. The findings of this study have been hypothesis generating, yet it remains unclear whether the peri-tumor immune response described is predictive of survival. Increasing evidence suggests that radiographic or PSA progression does not accurately reflect survival with sipuleucel-T and other immunotherapies. Finding an immune biomarker which can accurately reflect clinical benefit and validating it prospectively offers the potential for a predictive indicator of response in an area where none currently exists.

Targeted treatment of metastatic castration-resistant prostate cancer with sipuleucel-T immunotherapy.

ContextProstate cancer remains highly prevalent and has a poor clinical outcome once metastatic. Sipuleucel-T is an autologous cellular immunotherapy approved for the treatment of metastatic castration-resistant prostate cancer (mCRPC). Sipuleucel-T treatment extends survival but is independent of traditional short-term markers of treatment response observed with chemotherapy and contemporary hormonal treatments. Therefore, it is essential that clinicians understand the mechanism of action of sipuleucel-T and how this can translate in the clinic. ObjectiveThis article aims to summarize the current knowledge of sipuleucel-T therapy and its effects in mCRPC.Evidence acquisitionRelevant publications describing sipuleucel-T clinical data and information relating to immunotherapies were identified.Evidence synthesisTreatment with sipuleucel-T extends survival, with side effects being usually mild or moderate and manageable within the outpatient setting. The long-term immune responses generated by sipuleucel-T correlate with a survival benefit. Sipuleucel-T shows a greater magnitude of clinical benefit when used in patients earlier in the mCRPC setting.ConclusionsSipuleucel-T stimulates long-lived immune responses that translate into long-term clinical benefit. The treatment course (three infusions at weeks 0, 2, and 4) is associated with manageable side effects. Short-term markers of future benefit would be clinically useful, and information on effective treatment combinations or sequences is awaited.Patient summarySipuleucel-T treatment directs the patient’s own immune system to target and remove prostate cancer cells and increases life expectancy. Patients whose cancer is less advanced generally have a more ‘active’ immune system and may benefit the most from this treatment.

Sipuleucel-T immunotherapy in clinical practice: Patient characteristics, tolerability, and survival.

e15211 Background: Sipuleucel-T has been shown to provide survival benefit to men with minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC). In the 18 months following FDA approval of sipuleucel-T, we sought to characterize patients referred for consideration of sipuleucel-T, determine the tolerability of therapy, and evaluate survival outcomes in clinical practice. Methods: We reviewed the records of patients referred to our institution for consideration of sipuleucel-T. Clinical characteristics, disease characteristics, and previous treatments were identified. Tolerability and adverse events were characterized. Results: Patients with minimally symptomatic mCRPC were offered sipuleucel-T (n=90), whereas patients with ECOG&gt;1, progressive disease, or lack of metastases were not (n=11). Post chemotherapy patients started sipuleucel-T if their CD4 count was &gt;400 at least 3 weeks following chemotherapy. Treatments were well tolerated, with 96% completing an entire series. Three patients did not complete treatment due to disease progression. The biggest challenge with sipuleucel-T therapy was disease control immediately before, during and post therapy. Androgen receptor blockade with nilutamide or high dose bicalutamide was used to control the disease during this time. Mean patient age was 69.8±9.7 years and all had ECOG status of 0-1. 40% of patients had minimal metastases, while 36% and 19% had moderate or extensive metastases. Median survival time (MST) for men &gt;65 years who received sipuleucel-T was 17.6 months, whereas MST for men ≤65 years was not reached. There was no significant difference in overall survival (OS) between these groups (p=0.27). When stratified by disease burden, we found that OS of patients with extensive disease was shorter than men with mild or moderate disease burden (p=0.002 and p=0.04), with MST of 6.0 months. MST was not reached for men with mild and moderate disease burden. Conclusions: Sipuleucel-T is well tolerated in clinical practice for well-selected patients with asymptomatic or minimally symptomatic mCRPC. Patients with extensive metastatic disease, even when minimally symptomatic, did not appear to benefit from sipuleucel-T.

Sipuleucel-T for therapy of asymptomatic or minimally symptomatic, castrate-refractory prostate cancer: an update and perspective among other treatments

Sipuleucel-T is an autologous cell immunotherapy for castrate-refractory prostate cancer, with US Food and Drug Administration (FDA) approval in asymptomatic or minimally symptomatic prostate cancer. In this review we address the background of prostate cancer incidence and other available therapy onto which sipuleucel-T treatment has been added, with discussion of hormone-therapy, chemotherapy, and other investigational immunotherapies. The sipuleucel-T manufacturing process, toxicity and clinical benefit are reviewed, along with an examination of the issue of clinical benefit to survival, independent of apparent changes of prostate-specific antigen (PSA) levels. Sipuleucel-T therapy is appraised from clinician, patient and immunotherapeutic perspectives, with reference to the clinical data from the pivotal trial, the mechanism of action, and the treatment process.

Placebo-Controlled Phase III Trial of Immunologic Therapy with Sipuleucel-T (APC8015) in Patients with Metastatic, Asymptomatic Hormone Refractory Prostate Cancer

Sipuleucel-T (APC8015) is an investigational immunotherapy product designed to stimulate T-cell immunity against prostatic acid phosphatase. A phase III study was undertaken to evaluate the safety and efficacy of sipuleucel-T in a placebo-controlled study. A total of 127 patients with asymptomatic metastatic hormone refractory prostate cancer (HRPC) were randomly assigned in a 2:1 ratio to receive three infusions of sipuleucel-T (n = 82) or placebo (n = 45) every 2 weeks. On disease progression, placebo patients could receive APC8015F, a product made with frozen leukapheresis cells. Of the 127 patients, 115 patients had progressive disease at the time of data analysis, and all patients were followed for survival for 36 months. The median for time to disease progression (TTP) for sipuleucel-T was 11.7 weeks compared with 10.0 weeks for placebo (P = .052, log-rank; hazard ratio [HR], 1.45; 95%CI, 0.99 to 2.11). Median survival was 25.9 months for sipuleucel-T and 21.4 months for placebo (P = .01, log-rank; HR, 1.70; 95%CI, 1.13 to 2.56). Treatment remained a strong independent predictor of overall survival after adjusting for prognostic factors using a Cox multivariable regression model (P = .002, Wald test; HR, 2.12; 95%CI, 1.31 to 3.44). The median ratio of T-cell stimulation at 8 weeks to pretreatment was eight-fold higher in sipuleucel-T-treated patients (16.9 v 1.99; P < .001). Sipuleucel-T therapy was well tolerated. While the improvement in the primary end point TTP did not achieve statistical significance, this study suggests that sipuleucel-T may provide a survival advantage to asymptomatic HRPC patients. Supportive studies are underway.