Final Analysis of the Ipilimumab Versus Placebo Following Radiotherapy Phase III Trial in Postdocetaxel Metastatic Castration-resistant Prostate Cancer Identifies an Excess of Long-term Survivors

Fizazi, Karim; Drake, Charles G.; Beer, Tomasz M.; Kwon, Eugene D.; Scher, Howard I.; Gerritsen, Winald R.; Bossi, Alberto; Eertwegh, Alfons J.M. van den; Krainer, Michael; Houédé, Nadine; Santos, Ricardo Vieira; Mahammedi, Hakim; Ng, Siobhan; Danielli, Riccardo; Franke, Fábio; Sundar, Santhanam; Agarwal, Neeraj; Bergman, Andries M.; Ciuleanu, Tudor; Korbenfeld, Ernesto; Sengeløv, Lisa; Hansen, Steinbjørn; McHenry, M. Brent; Chen, Allen; Logothetis, Christopher J.

doi:10.1016/j.eururo.2020.07.032

Cited by 107 publications

(69 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“… 21 22 While the phase III clinical trial combining ipilimumab with RT failed to show improved median survival in patients, long-term follow-up demonstrated superior OS in the ipilimumab-treated arm. 7 This trial irradiated a bone metastasis with a single fraction of RT at the start of ipilimumab and also included only patients who had received prior docetaxel chemotherapy.…”

Section: Discussionmentioning

confidence: 99%

“…5 6 Nevertheless, in the post-docetaxel trial, the survival rates in years 2-5 are superior in the ipilimumab arm, indicating that a small proportion of patients may derive a durable clinical benefit. 7 We undertook a phase II clinical trial combining ipilimumab with sipuleucel-T in chemotherapy-naïve patients with mCRPC, predicated on the observation that although sipuleucel-T can induce a Th1 immune response within the prostate cancer microenvironment, immunologic checkpoints including CTLA-4 are also induced. The timeline of the immunologic events induced by sipuleucel-T is not well understood, resulting in uncertainty as to the optimal timing of initiation of immune checkpoint inhibition following sipuleucel-T therapy.…”

Section: Introductionmentioning

confidence: 99%

“… 5 6 Nevertheless, in the post-docetaxel trial, the survival rates in years 2–5 are superior in the ipilimumab arm, indicating that a small proportion of patients may derive a durable clinical benefit. 7 …”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Pre-existing immune status associated with response to combination of sipuleucel-T and ipilimumab in patients with metastatic castration-resistant prostate cancer

Sinha

Zhang

Subudhi

et al. 2021

J Immunother Cancer

View full text Add to dashboard Cite

BackgroundSipuleucel-T is a US Food and Drug Administration-approved autologous cellular immunotherapy that improves survival in patients with metastatic castration-resistant prostate cancer (mCRPC). We examined whether administering ipilimumab after sipuleucel-T could modify immune and/or clinical responses to this treatment.MethodsA total of 50 patients with mCRPC were enrolled into a clinical trial (NCT01804465, ClinicalTrials.gov) where they received ipilimumab either immediately or delayed 3 weeks following completion of sipuleucel-T treatment. Blood was collected at various timepoints of the study. Luminex assay for anti-prostatic acid phosphatase (PAP) and anti-PA2024-specific serum immunoglobulin G (IgG) and ELISpot for interferon-γ (IFN-γ) production against PAP and PA2024 were used to assess antigen-specific B and T cell responses, respectively. Clinical response was defined as >30% reduction in serum prostate-specific antigen levels compared with pretreatment levels. The frequency and state of circulating immune cells were determined by mass cytometry by time-of-flight and statistical scaffold analysis.ResultsWe found the combination to be well tolerated with no unexpected adverse events occurring. The timing of ipilimumab did not significantly alter the rates of antigen-specific B and T cell responses, the primary endpoint of the clinical trial. Clinical responses were observed in 6 of 50 patients, with 3 having responses lasting longer than 3 months. The timing of ipilimumab did not significantly associate with clinical response or toxicity. The combination treatment did induce CD4 and CD8 T cell activation that was most pronounced with the immediate schedule. Lower frequencies of CTLA-4 positive circulating T cells, even prior to treatment, were associated with better clinical outcomes. Interestingly, these differences in CTLA-4 expression were associated with prior localized radiation therapy (RT) to the prostate or prostatic fossa. Prior radiation treatment was also associated with improved radiographic progression-free survival.ConclusionCombining CTLA-4 blockade with sipuleucel-T resulted in modest clinical activity. The timing of CTLA-4 blockade following sipuleucel-T did not alter antigen-specific responses. Clinical responses were associated with both lower baseline frequencies of CTLA-4 expressing T cells and a history of RT. Prior cancer therapy may therefore result in long-lasting immune changes that influence responsiveness to immunotherapy with sipuleucel-T and anti-CTLA-4.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Pre-existing immune status associated with response to combination of sipuleucel-T and ipilimumab in patients with metastatic castration-resistant prostate cancer

Sinha

Zhang

Subudhi

et al. 2021

J Immunother Cancer

View full text Add to dashboard Cite

show abstract

“…The rates of all-grade and grade 3/4 immunerelated AEs with ipilimumab were 63% and 26%, respectively [23]. In a recently reported preplanned long-term analysis, OS was significantly improved with ipilimumab [24]. OS rates in the ipilimumab arm were higher at 3 years (15.3% vs. 7.9%), 4 years (10.1% vs. 3.3%), and 5 years (7.9% vs. 2.7%) compared with placebo [24]; however, these data were analyzed after the primary OS analysis and hence must be considered as hypothesis-generating and not definitive.…”

Section: Ipilimumabmentioning

confidence: 98%

Evolving Role of Immunotherapy in Metastatic Castration Refractory Prostate Cancer

Rathi

McFarland

Nussenzveig

et al. 2020

Drugs

Self Cite

View full text Add to dashboard Cite

Immunotherapies have shown remarkable success in the treatment of multiple cancer types; however, despite encouraging preclinical activity, registration trials of immunotherapy in prostate cancer have largely been unsuccessful. Sipuleucel-T remains the only approved immunotherapy for the treatment of asymptomatic or minimally symptomatic metastatic castrate-resistant prostate cancer based on modest improvement in overall survival. This immune evasion in the case of prostate cancer has been attributed to tumor-intrinsic factors, an immunosuppressive tumor microenvironment, and host factors, which ultimately make it an inert ‘cold’ tumor. Recently, multiple approaches have been investigated to turn prostate cancer into a ‘hot’ tumor. Antibodies directed against programmed cell death protein 1 have a tumor agnostic approval for a small minority of patients with microsatellite instability-high or mismatch repair-deficient metastatic prostate cancer. Herein, we present an overview of the current immunotherapy landscape in metastatic castration-resistant prostate cancer with a focus on immune checkpoint inhibitors. We describe the results of clinical trials of immune checkpoint inhibitors in patients with metastatic castration-resistant prostate cancer; either as single agents or in combination with other checkpoint inhibitors, poly (ADP-ribose) polymerase (PARP) inhibitors, tyrosine kinase inhibitors, novel hormonal therapies, chemotherapies, and radioligands. Finally, we review upcoming immunotherapies, including novel monoclonal antibodies, chimeric-antigen receptor (CAR) T cells, Bi-Specific T cell Engagers (BiTEs), therapies targeting the adenosine pathway, and other miscellaneous agents.

show abstract

“…While monotherapy with both ipilimumab (anti-CTLA4) and PD-1 inhibitors have proved disappointing (2,3,126), recent long term follow of ipilimumab shows that despite low response rates those that do respond have enduring responses (127). The key will be to improve response rates and early data suggests that adding DC vaccination to immunotherapy may do just that.…”

Section: Improving T Cell Functionmentioning

confidence: 99%

Moving on From Sipuleucel-T: New Dendritic Cell Vaccine Strategies for Prostate Cancer

Sutherland

Horvath

et al. 2021

Front. Immunol.

View full text Add to dashboard Cite

Tumors evade the immune system though a myriad of mechanisms. Using checkpoint inhibitors to help reprime T cells to recognize tumor has had great success in malignancies including melanoma, lung, and renal cell carcinoma. Many tumors including prostate cancer are resistant to such treatment. However, Sipuleucel-T, a dendritic cell (DC) based immunotherapy, improved overall survival (OS) in prostate cancer. Despite this initial success, further DC vaccines have failed to progress and there has been limited uptake of Sipuleucel-T in the clinic. We know in prostate cancer (PCa) that both the adaptive and the innate arms of the immune system contribute to the immunosuppressive environment. This is at least in part due to dysfunction of DC that play a crucial role in the initiation of an immune response. We also know that there is a paucity of DC in PCa, and that those there are immature, creating a tolerogenic environment. These attributes make PCa a good candidate for a DC based immunotherapy. Ultimately, the knowledge gained by much research into antigen processing and presentation needs to translate from bench to bedside. In this review we will analyze why newer vaccine strategies using monocyte derived DC (MoDC) have failed to deliver clinical benefit, particularly in PCa, and highlight the emerging antigen loading and presentation technologies such as nanoparticles, antibody-antigen conjugates and virus co-delivery systems that can be used to improve efficacy. Lastly, we will assess combination strategies that can help overcome the immunosuppressive microenvironment of PCa.

show abstract

Final Analysis of the Ipilimumab Versus Placebo Following Radiotherapy Phase III Trial in Postdocetaxel Metastatic Castration-resistant Prostate Cancer Identifies an Excess of Long-term Survivors

Cited by 107 publications

References 41 publications

Pre-existing immune status associated with response to combination of sipuleucel-T and ipilimumab in patients with metastatic castration-resistant prostate cancer

Pre-existing immune status associated with response to combination of sipuleucel-T and ipilimumab in patients with metastatic castration-resistant prostate cancer

Evolving Role of Immunotherapy in Metastatic Castration Refractory Prostate Cancer

Moving on From Sipuleucel-T: New Dendritic Cell Vaccine Strategies for Prostate Cancer

Contact Info

Product

Resources

About