scholarly journals Dramatic response to combination pembrolizumab and radiation in metastatic castration resistant prostate cancer

2020 ◽  
Vol 12 ◽  
pp. 175883592093608
Author(s):  
Harry J. Han ◽  
Yun Rose Li ◽  
Mack Roach ◽  
Rahul Aggarwal
Keyword(s):  
Prostate Cancer ◽  
Immune Checkpoint ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Response To Treatment ◽  
Small Subset ◽  
Castration Resistant Prostate Cancer ◽  
Durable Response ◽  
Castration Resistant ◽  
Previously Treated

Immune checkpoint inhibitors targeting PD-1 and PD-L1 have demonstrated anti-tumor activity in several advanced solid malignancies. In previously treated metastatic castration resistant prostate cancer (mCRPC), a small subset of patients have a therapeutic response to checkpoint inhibition. Those who do respond to anti-PD-1/PD-L1 therapy have a marked, durable response to treatment, suggesting some derive long-term benefit from immune checkpoint blockade. In other cancers, one strategy to increase the efficacy of immune checkpoint blockade is to combine it with a pro-immune stimulatory agent, such as radiation. Here we present a case of a patient with heavily treated mCRPC who had a significant tumor response to concurrent pembrolizumab and radiation therapy to the primary prostatic mass. We review the growing evidence supporting the use of this combination therapy in other cancers and its potential benefit and safety in mCRPC. Our report highlights a potential therapeutic approach that should be further investigated in previously treated mCRPC.

scholarly journals Immune Checkpoint Blockade for Prostate Cancer: Niche Role or Next Breakthrough?

2020 ◽  
pp. e89-e106
Author(s):  
Daniel Vargas P. de Almeida ◽  
Lawrence Fong ◽  
Matthew B. Rettig ◽  
Karen A. Autio
Keyword(s):  
Prostate Cancer ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Single Agent ◽  
Small Subset ◽  
Castration Resistant Prostate Cancer ◽  
Primary Resistance ◽  
Cancer Management ◽  
Castration Resistant

A number of trials have evaluated the use of single-agent immune checkpoint inhibitors for the treatment of metastatic castration-resistant prostate cancer (mCRPC). The benefit appears to be limited to a small subset of patients, such as those with tumors with microsatellite instability, highlighting the importance of biomarkers to identify which patients may be more likely to respond. Given the lack of efficacy for most patients with mCRPC, our understanding of the mechanisms of primary resistance to checkpoint inhibitors and of the tumor immune microenvironment in prostate cancer is critical. Knowledge gained in these key areas will allow for the identification of novel combination therapies that will circumvent resistance mechanisms and should be tested in clinical trials. Improving our understanding of the effects of androgen deprivation therapy on immune cells and of the most favorable disease setting (e.g., biochemically recurrent vs. castration-resistant prostate cancer) may aid in the optimal use of checkpoint inhibitors in combination with other agents. If successful, this may move immune checkpoint inhibitors into the treatment armamentarium of prostate cancer management.

Responsiveness to Immune Checkpoint Inhibitors Is Associated With a Peripheral Blood T-Cell Signature in Metastatic Castration-Resistant Prostate Cancer

2020 ◽  
pp. 1374-1385
Author(s):  
Donjete Simnica ◽  
Minke Smits ◽  
Edith Willscher ◽  
Lorenzo F. Fanchi ◽  
Iris S.H. Kloots ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
T Cell ◽  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Small Subset ◽  
Castration Resistant Prostate Cancer ◽  
Cell Repertoire ◽  
Treatment Benefit ◽  
Cell Clusters ◽  
Castration Resistant

PURPOSE Although most patients with microsatellite instable (MSI) metastatic castration-resistant prostate cancer (mCRPC) respond to immune checkpoint blockade (ICB), only a small subset of patients with microsatellite stable (MSS) tumors have similar benefit. Biomarkers defining ICB-susceptible subsets of patients with MSS mCRPC are urgently needed. METHODS Using next-generation T-cell repertoire sequencing, we explored immune signatures in 54 patients with MSS and MSI mCRPC who were treated with or without ICB. We defined subset-specific immune metrics as well as T-cell clusters and correlated the signatures with treatment benefit. RESULTS Consistent overlaps between tumor and peripheral T-cell repertoires suggested that blood was an informative material to identify relevant T-cell signatures. We found considerably higher blood T-cell richness and diversity and more shared T-cell clusters with low generation probability (pGen) in MSI versus MSS mCRPC, potentially reflecting more complex T-cell responses because of a greater neoepitope load in the MSI subset. Interestingly, patients with MSS mCRPC with shared low pGen T-cell clusters showed significantly better outcomes with ICB, but not with other treatments, compared with patients without such clusters. Blood clearance of T-cell clusters on ICB treatment initiation seemed to be compatible with T-cell migration to the primary tumor or metastatic sites during the process of clonal replacement as described for other tumors receiving ICB. CONCLUSION The MSI mCRPC subset shows a distinct T-cell signature that can be detected in blood. This signature points to immune parameters that could help identify a subset of patients with MSS mCRPC who may have an increased likelihood of responding to ICB or to combination approaches including ICB.

scholarly journals Autophagy inhibition by targeting PIKfyve potentiates response to immune checkpoint blockade in prostate cancer

Nature Cancer ◽  
2021 ◽  
Author(s):  
Yuanyuan Qiao ◽  
Jae Eun Choi ◽  
Jean C. Tien ◽  
Stephanie A. Simko ◽  
Thekkelnaycke Rajendiran ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Immune Checkpoint ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Autophagy Inhibition

scholarly journals Immune Checkpoint Blockade for Metastatic Uveal Melanoma: Patterns of Response and Survival According to the Presence of Hepatic and Extrahepatic Metastasis

Cancers ◽  
2021 ◽  
Vol 13 (13) ◽  
pp. 3359
Author(s):  
Elias Koch ◽  
Anne Petzold ◽  
Anja Wessely ◽  
Edgar Dippel ◽  
Anja Gesierich ◽  
...  
Keyword(s):  
Skin Cancer ◽  
Uveal Melanoma ◽  
Hepatic Metastasis ◽  
Immune Checkpoint ◽  
Objective Response ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Response To Treatment ◽  
Extrahepatic Metastasis ◽  
The Impact

Background: Since there is no standardized and effective treatment for advanced uveal melanoma (UM), the prognosis is dismal once metastases develop. Due to the availability of immune checkpoint blockade (ICB) in the real-world setting, the prognosis of metastatic UM has improved. However, it is unclear how the presence of hepatic and extrahepatic metastasis impacts the response and survival after ICB. Methods: A total of 178 patients with metastatic UM treated with ICB were included in this analysis. Patients were recruited from German skin cancer centers and the German national skin cancer registry (ADOReg). To investigate the impact of hepatic metastasis, two cohorts were compared: patients with liver metastasis only (cohort A, n = 55) versus those with both liver and extra-hepatic metastasis (cohort B, n = 123). Data were analyzed in both cohorts for response to treatment, progression-free survival (PFS), and overall survival (OS). The survival and progression probabilities were calculated with the Kaplan–Meier method. Log-rank tests, χ2 tests, and t-tests were performed to detect significant differences between both cohorts. Results: The median OS of the overall population was 16 months (95% CI 13.4–23.7) and the median PFS, 2.8 months (95% CI 2.5–3.0). The median OS was longer in cohort B than in cohort A (18.2 vs. 6.1 months; p = 0.071). The best objective response rate to dual ICB was 13.8% and to anti-PD-1 monotherapy 8.9% in the entire population. Patients with liver metastases only had a lower response to dual ICB, yet without significance (cohort A 8.7% vs. cohort B 16.7%; p = 0.45). Adverse events (AE) occurred in 41.6%. Severe AE were observed in 26.3% and evenly distributed between both cohorts. Conclusion: The survival of this large cohort of patients with advanced UM was more favorable than reported in previous benchmark studies. Patients with both hepatic and extrahepatic metastasis showed more favorable survival and higher response to dual ICB than those with hepatic metastasis only.

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