Effect of androgen deprivation therapy combined with nivolumab on the systemic antitumor immune response in castration-sensitive prostate cancer.
Bibliographic record
Abstract
e17503 Background: To date, immunotherapy has limited efficacy in castration-resistant prostate cancer. However, we previously reported that androgen deprivation therapy (ADT) has significant immunomodulatory effects and can induce a complex immune cell infiltrate before castration-resistance develops. Therefore, we designed an ongoing clinical trial to assess the effects of immunotherapy plus ADT in men with recurrent castration-sensitive prostate cancer (CSPC) (NCT03689699). We hypothesized that PD-1 blockade given at the time of castration could induce systemic anti-tumor immune responses with epitope spreading and modulate key circulating cytokine networks. Methods: 15 patients with recurrent CSPC were treated with nivolumab (480mg) every 4 weeks for 8 weeks followed by nivolumab plus degarelix for an additional 16 weeks. Sera was collected at 3 time points: pre-treatment, after nivolumab alone (8 weeks) and at completion of therapy with nivolumab plus degarelix (24weeks). To assess the therapeutic effects on systemic humoral immune responses and to evaluate for induction of epitope spreading, we analyzed treatment-induced serum IgGs against an array of self-antigens over time. We also performed a 44-parameter electrochemiluminescence assay to measure the effects of therapy on innate cytokines and the Th1/Th2 and Th17 pathways. Results: ADT combined with PD-1 blockade led to significant changes in systemic immunity including induction of humoral antigen spread with IgG responses to secondary tumor antigens including PSA, KLK2, K-Ras and modulation of key circulating cytokines. We observed a significant increase in mean levels of IFN-gamma (8.68 +/- 10.74 pg/ml vs 9.53 +/- 7.36 pg/ml), an increase in IL-10 (0.37 +/- 0.29 pg/ml vs 0.66 +/- 0.53 pg/ml) and a decrease in IL-8 (106.7 +/- 275.47 pg/ml vs 25.49 +/- 23.09 pg/ml) when comparing cytokine levels before and after nivolumab plus degarelix respectively. Conclusions: ADT plus nivolumab led to significant changes in systemic immunity and overall appeared to promote a pro-inflammatory state. This immune response also appeared tumor specific with induction of humoral responses against secondary tumor antigens. However we also observed changes in targetable immunosuppresive cytokines like interleukin-8 and are currently testing whether ADT plus combined PD-1 and IL-8 blockade can further promote robust anti-tumor immune responses in prostate cancer. Clinical trial information: NCT03689699 .
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".