Provenge (sipuleucel-T)

P1, N=12, Recruiting, University of Oklahoma | Trial completion date: Feb 2024 --> May 2024 | Trial primary completion date: Feb 2024 --> May 2024

Evaluation of tumor-infiltrating lymphocytes revealed a 2-14-fold higher influx of sip-T and a significant increase in IFN-γ producing CD8+ T cells and NKT cells within the tumor microenvironment (TME) in the IL-15 group. In conclusion, we put forward evidence that IL-15 treatment can enhance the functional antitumor immunity of sip-T, providing rationale for combining IL-15 or IL-15 agonists with sip-T to treat patients with mCRPC.

P2, N=26, Recruiting, Yale University | Not yet recruiting --> Recruiting

P1, N=12, Recruiting, University of Oklahoma | Trial completion date: Jul 2027 --> Feb 2024 | Trial primary completion date: May 2024 --> Feb 2024

This is the first study to evaluate the sip-T product using CyTOF, and the first pre-clinical in vivo prostate tumor modeling of sip-T. IL-15 treatment significantly enhances anti-tumor efficacy, effector immune cell activation and tumor infiltration, and reverses key mediators of immune suppression. Studies with modified IL-15 cytokines are ongoing and will be presented.

Therapies received prior to Ra-223 were androgen receptor pathway inhibitors (75.4%), chemotherapy (32.1%), sipuleucel-T (13.7%) and bone health agents (73.7%). Ra-223 was utilized as a combination therapy by 26.0% of the overall population, predominately with enzalutamide... Nearly half of men completed 5+ cycles of Ra-223 therapy in a large US cohort of relatively young mCRPC men with private health insurance. Advanced disease state with short survival and low comorbidity were key factors associated with lower completion of 5+ cycles. The findings highlight the importance of utilizing Ra-223 early after mCRPC diagnosis, when the probability of >6-month survival is higher, to enhance treatment completion that has been shown to result in better outcomes.

P1, N=12, Recruiting, University of Oklahoma | Not yet recruiting --> Recruiting | Initiation date: Oct 2023 --> Jan 2024

Provenge (sipuleucel-T) is an autologous cancer-vaccine-based immunotherapy approved for men with asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC)...Current Protocols published by Wiley Periodicals LLC. Basic Protocol 1: Sample collection and DC isolation Basic Protocol 2: Determination and application of fluid shear stress Basic Protocol 3: Flow cytometry analysis of DCs after FSS stimulation.

P3, N=400, Not yet recruiting, Dendreon

P2, N=26, Not yet recruiting, Yale University

P3, N=450, Active, not recruiting, Dendreon | Trial completion date: May 2023 --> Feb 2024 | Trial primary completion date: May 2023 --> Dec 2023

Since regulatory approval of the vaccine therapy sipuleucel-T in the biomarker-unselected population, there has not been much success with immunotherapy treatment in advanced prostate cancer...On the horizon, novel drugs using bispecific T-cell engager (BiTE) and chimeric antigen receptors (CAR) technology are being explored and have shown promising early efficacy in this disease. Here we discuss the features of the tumour microenvironment that predispose to immune resistance and rational strategies to enhance antitumour responsiveness in advanced prostate cancer.

Median OS was consistent regardless of whether the agents were administered sequentially or concurrently, including after NDI update. Results suggest that sipuleucel-T induces an immunologic prime-boost effect after initial sipuleucel-T exposure, even when combined with ARTAs.

This activity is supported by educational grants from AstraZeneca Pharmaceuticals LP, Bayer HealthCare Pharmaceuticals, Janssen Biotech Inc, administered by Janssen Scientific Affairs LLC, Lilly, Merck, and Sanofi. Key clinical and biological factors in the selection of therapy for newly diagnosed mCRPC; influence of earlier use of secondary hormonal therapy and chemotherapy on current management approaches Key findings from clinical trial and real-world data sets exploring the efficacy and safety of sipuleucel-T Optimal patient selection for treatment with sipuleucel-T; importance of early identification of appropriate candidates Data sets defining the role of secondary hormonal therapies for patients with mCRPC, including those who have received one of these agents in an earlier disease setting Role of the CDK4/6 pathway in prostate cancer proliferation and resistance to androgen receptor (AR)-targeted therapy Available efficacy and safety findings with CDK4/6 inhibitors for mCRPC Design, eligibility criteria and primary and secondary endpoints of the Phase II/III CYCLONE 2 trial evaluating first-line abiraterone and prednisone with or without abemaciclib for mCRPC

Treatment landscape for metastatic castrate-resistant prostate cancer (mCRPC) has evolved beyond additional agents with ARPI and/or docetaxel, including other treatments with sipuleucel-T, radium, cabazitaxel, PARP inhibitors, and lutetium, which have specific indications and role in sequencing. Novel therapies remain critically needed after progression from lutetium.

Sponsored by Pharmaceutical/Biotech Company, Bayer AG. Overall, a lower % of pts discontinued initial ARI treatment, progressed to metastasis, or had AEs on daro vs enza/apa. In analyses adjusting for observed BL factors, pts on daro had considerably lower risk of DISC and PROG vs enza/apa. This study confirms daro’s strong efficacy and favorable tolerability profile in a RW setting.

Therapeutic cancer vaccines including sipuleucel- T , a prostatic acid phosphatase (PAP) targeted vaccine that improves survival in metastatic castration-resistant prostate cancer (mCRPC), can produce immune responses that translate to clinical benefit...Eighteen patients enrolled, and previous treatments included abiraterone or enzalutamide in 14 (78%), therapeutic cancer vaccine in 14 (78%), and chemotherapy in 4 (22%)...Analysis of antigen-specific T-cell responses pre and postavelumab treatment did not demonstrate changes in interferon-γ production or proliferation in response to PAP or PA2024. This unplanned analysis does not support the use of sequential therapeutic cancer vaccine therapy followed by programmed death ligand-1 inhibition in mCRPC.

Androgen deprivation therapy (ADT) plus Androgen Receptor Target Agents (ARTAs) or docetaxel are the actual standard of care in prostate cancer (PC). Several therapeutic options are available for pretreated patients: cabazitaxel, olaparib, and rucaparib for BRCA mutations, Radium-223 for selected patients with symptomatic bone metastasis, sipuleucel T, and 177 LuPSMA-617...The radionuclide Lu-PSMA-617 proved successful outcomes in pretreated mCRPC patients. Additional studies will better clarify the appropriate candidates to each strategy and the correct treatments' sequence.

In the past decade, new treatment options for mCRPC, including abiraterone, enzalutamide, docetaxel, cabazitaxel, sipuleucel-T, radium-223, Lu-PSMA-617, and Olaparib, have demonstrated a survival benefit in phase 3 trials. Bone-modifying agents have become part of the overall treatment strategy for mCRPC, in which denosumab and zoledronic acid reduce skeletal-related events...Tumors with gene alterations that affect homologous recombination repair, such as BRCA1 and BRCA2 alterations, are sensitive to poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitors in mCRPC. This review sought to highlight recent advances in systemic therapy for mCRPC and strategies to support patient selection and treatment sequencing.

CME Provider and Supporter(s): This event is organized and accredited by Research to Practice and supported through educational grants provided by Astellas and Pfizer Inc, AstraZeneca Pharmaceuticals LP, Bayer HealthCare Pharmaceuticals, Exelixis Inc, Janssen Biotech Inc, administered by Janssen Scientific Affairs LLC, Lilly, Merck, and Sanofi. Key clinical and biologic factors in the selection of therapy for patients with newly diagnosed mCRPC; impact of earlier use of secondary hormonal therapy and chemotherapy on current disease management approaches Key findings from clinical trial and real-world data sets exploring the efficacy and safety of sipuleucel-T; impact of patient age, race, PSA level and other factors on outcomes Optimal patient selection for sipuleucel-T; importance of early identification of candidates Biologic basis for combining PARP inhibitors with antiandrogen therapies for prostate cancer; rationale for the potential activity of these combinations in patients without homologous recombination repair (HRR) gene mutations Available and emerging data (eg, from the PROpel, MAGNITUDE and TALAPRO-2 trials) with PARP inhibitors combined with secondary hormonal agents for previously untreated mCRPC Rationale for the evaluation of CDK4/6 inhibitors among patients with mCRPC Design, eligibility criteria and primary and secondary endpoints of the Phase II/III CYCLONE 2 trial evaluating first-line abiraterone and prednisone with or without abemaciclib for mCRPC; estimated completion date

Most common 1L treatments included enzalutamide (30.7%), abiraterone acetate (29.9%), docetaxel (19.7%), sipuleucel-T (8.9%), and radium-223 (5.2%). HRR alterations were identified in about 1 in 5 tested patients initiating mCRPC treatment. Future studies should focus on understanding alteration testing strategies in diverse clinical practice settings to ensure patients with HRR alterations are identified in a timely manner and receive appropriate clinical management.

Avelumab plus carboplatin has an acceptable safety profile and was associated with a prolonged OS given the heavily pretreated population.

Despite FDA approval of sipuleucel-T in 2010, endeavors to use immune checkpoint inhibitors in unselected prostate cancer patients have not improved clinical outcomes...Cytokine-based therapies present an alternative immune strategy to target the pleiotropic prostate cancer tumor microenvironment beyond T-cells. Future immunotherapy strategies in prostate cancer should address these immune cell populations which may play more important roles in the prostate cancer tumor microenvironment.

To date, eleven BEVS-derived products have been approved for use, including four human vaccines [Cervarix against cervical cancer caused by human papillomavirus (HPV), Flublok and Flublok Quadrivalent against seasonal influenza, Nuvaxovid/Covovax against COVID-19], two human therapeutics [Provenge against prostate cancer and Glybera against hereditary lipoprotein lipase deficiency (LPLD)] and five veterinary vaccines (Porcilis Pesti, BAYOVAC CSF E2, Circumvent PCV, Ingelvac CircoFLEX and Porcilis PCV). As the demand for biotechnology increases, there has been a concomitant effort into optimizing yield, stability and protein glycosylation through genetic engineering and the manipulation of baculovirus vector and host cells. In this review, we summarize the strategies and technological advances of BEVS in recent years and explore how this will be used to inform the further development and application of this system.

Conclusions This is the first comprehensive study to evaluate the composition of sip-T from mCRPC patients using high dimensional CyTOF analysis, and serves as an important reference source for further modification and improvement of sip-T efficacy. Furthermore, our data is the first to show that the addition of IL-15 to sip-T could potentially enhance the efficacy of sip-T in mCRPC patients.

Sipuleucel-T (Provenge) is the first FDA approved immunotherapeutic agent for the treatment of asymptomatic or minimally symptomatic metastatic castrate resistant prostate cancer (mCRPC); demonstrating a benefit in overall survival...There is also a need to adjust strategies to overcome histologic barriers such as tissue hypoxia and dense stroma. The racial differences of immunological responses between men of diverse ethnicities also merit further investigation to improve the efficacy of immunotherapy and better patient selection in prostate cancer.

Sipuleucel-T is the only FDA approved autologous cellular immunotherapy for PCa targeting prostatic acid phosphatase (PAP), showing a 4.1 month survival benefit for metastatic castration-resistant prostate cancer patients...The vaccine induced secretory (IFNγ and TNFα) and cytotoxic CD8+ T cells and effector memory splenic T cells. Conclusions The periphery of patients with PCa exhibits immune responsiveness to the MutPAP42mer peptide and immunization of mice induces/expands T cell-driven, wild-type PAP immunity, and therefore, has the potential to drive protective anti-tumour immunity in patients with PCa.

Only Sipuleucel-T and the immune checkpoint inhibitor pembrolizumab are approved by the US FDA for the treatment of limited prostate cancer patients. The purpose of this review is to summarize emerging advances in prostate cancer immunotherapy, with a particular focus on the molecular mechanisms that lead to immune evasion in prostate cancer. At the same time, we also highlight some potential therapeutic targets to provide a theoretical basis for the treatment of prostate cancer.

This real-world study of mCRPC treatment indicates that men receiving sipuleucel-T and ARTAs had a longer median OS than patients receiving treatment with an ARTA alone, suggesting that leveraging mechanisms of action can be beneficial in treating patients with mCRPC.

Approval of the first therapeutic cancer vaccine, Sipuleucel-T, for the treatment of metastatic castration-resistant prostate cancer and the groundbreaking success and approval of immune checkpoint inhibitors and chimeric antigen receptor T cell therapy in the last decade, have driven an explosion of interest in and pursuit of novel cancer immunotherapy strategies. A broad range of modalities ranging from antibodies to adoptive T cell therapies is under investigation for the generalized treatment of a broad spectrum of cancers as well as personalized medicine. This chapter will focus on the recent advances, current strategies, and future outlook of immunotherapy development for the treatment of cancer.

The periphery of patients with PCa exhibits immune responsiveness to the MutPAP42mer peptide and immunization of mice induces/expands T cell-driven, wild-type PAP immunity, and therefore, has the potential to drive protective anti-tumor immunity in patients with PCa.

This is the first comprehensive study to evaluate the composition of sip T from mCRPC patients using high dimensional CyTOF analysis. Given the increasing use of CyTOF in translational research, this data set serves as an important reference source, which could be used in future studies to help guide therapeutic modulation of activation/exhaustion markers to improve sip T efficacy and enhance beneficial immune responses.

The only FDA approved DC-based immunotherapy to date is Sipuleucel-T, which utilizes a fusion protein to stimulate DCs ex vivo with GM-CSF and simultaneously deliver the antigen PAP for prostate cancer...Adaptive transfer of TMV-pulsed DCs to tumor bearing mice results in the inhibition of tumor growth, reduction in lung metastasis, and an increase in immune cell infiltration into the tumors. These observations suggest that DCs pulsed with TMVs containing GPI-GM-CSF and GPI-IL-12 can be further developed to be used as a personalized immunotherapy platform for cancer treatment.

Treatment with rhIL-7 led to a significant expansion of CD4+ and CD8+ T cells, and CD56 natural killer (NK) cells compared with observation after treatment with sip-T. The rhIL-7 treatment also led to improved antigen-specific humoral and T cell proliferative responses over time as well as to increased expression of activation markers and beneficial cytokines. This is the first study to evaluate the use of rhIL-7 after sip-T in patients with mCRPC and demonstrates encouraging results for combination approaches to augment beneficial immune responses.

The U.S Food and Drug Administration has approved Sipuleucel-T for the treatment of asymptomatic or minimally symptomatic metastatic castrate-resistant prostate cancer (mCRPC) and immune checkpoint inhibitor pembrolizumab for the treatment of all solid tumors, including prostate cancer, with impaired mismatch repair genes/microsatellite instability; however, the current clinical outcomes still need to be improved. As various immunosuppressive mechanisms coexist and cross-interact within the tumor microenvironment, different immunotherapy approaches may have to be combined and selected in a highly personalized way. It is hoped that this rapidly evolving field of immunotherapy will achieve successful treatment for mCRPC and will be applied to a wider range of prostate cancer patients.

Immunotherapy involving Sipuleucel-T has increasingly drawn attention for prostate cancer management...The immune response against prostate cancer was greatly suppressed when the antigen targets were knocked out using CRISPR-Cas9. (4) In summary, our results provide the first evidence that a vaccine based on a fusion protein consisting of Ag85B and a prostate cancer octapeptide epitope with complete Freund's adjuvant (CFA), triggers a robust immune response and inhibits tumor growth in murine prostate cancer.

P=N/A, N=15, Completed, Roswell Park Cancer Institute | Active, not recruiting --> Completed | Trial completion date: Jun 2021 --> Jan 2021

Black men had statistically significantly higher median concentrations of TH2-type (IL-4, IL-10, and IL-13) and inflammatory cytokines (IL-2, IL-12, and IL-6) compared to PSA-matched White men both at baseline and 52 weeks after sipuleucel-T (2-sided P < .05). No differences by race were seen in either the antigen-specific T cell response or in the humoral responses to the immunizing antigen PA2024 and select secondary antigens.

P2, N=36, Completed, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Active, not recruiting --> Completed

These results suggest that TGM4 is an immunogenic, prostate-restricted antigen with the potential for further development as an immunotherapy target.