Abstract Purpose: To evaluate whether prior sipuleucel-T immunotherapy modifies the relationship between baseline systemic inflammatory biomarkers and Lutetium-177 (177Lu)-labeled prostate-specific membrane antigen (PSMA) radiopharmaceutical therapy (RPT) response in metastatic castration-resistant prostate cancer (mCRPC). Background: Sipuleucel-T, an autologous cellular immunotherapy, induces durable antitumor immune responses in mCRPC with overall survival benefit independent of prostate-specific antigen (PSA) response. 177Lu-PSMA-RPT delivers targeted β radiation to PSMA-expressing tumor cells, inducing DNA damage and immunogenic cell death, yet exhibits heterogeneous PSA response. Elevated neutrophil-to-lymphocyte ratio (NLR) reflects myeloid-mediated immunosuppression, while elevated lactate dehydrogenase (LDH) may indicate tumor burden and hypoxia, both associated with worse PSMA-RPT outcomes. Whether prior immunotherapy modifies the association between these biomarkers and subsequent RPT response remains unclear. Methods: Retrospective analysis of 16 mCRPC patients treated with 177Lu-PSMA-RPT was performed, comparing the group with prior sipuleucel-T treatment (n=8) to age-matched immunotherapy-naive control group (n=8). Pretreatment biomarkers were absolute neutrophil count (ANC), absolute lymphocyte count (ALC), NLR (ANC/ALC), and LDH. Primary endpoint, %ΔPSA was calculated as: (post-treatment PSA - pretreatment PSA) / pretreatment PSA × 100%. Spearman rank correlation was used to evaluate associations between biomarkers and %ΔPSA. Biomarker distributions between groups were compared using Mann-Whitney U test. Combined biomarker effects on %ΔPSA were assessed using multivariable ordinary least squares regression. Results: Time from sipuleucel-T to RPT ranged 7-28 months. Median pretreatment biomarkers in sipuleucel-T vs controls were: ANC 4.69 vs 4.55 × 109/L, ALC 0.90 vs 1.10 × 103/μL, and LDH 221 vs 196 U/L. 5 of 8 sipuleucel-T patients showed PSA decline (62.5%, median −12.2%, −56% to +71%), compared to 2 of 8 controls (25%, median +13%, −4% to +89%). Pretreatment LDH showed a trend toward positive correlation with %ΔPSA in sipuleucel-T group (ρ = 0.627, p = 0.097), not in controls (ρ = 0.095, p = 0.823). ANC, ALC, and NLR demonstrated weak correlations with %ΔPSA in both cohorts (|ρ| 0.20). Mann-Whitney U test comparing %ΔPSA distributions between the cohorts yielded U = 20.000, p = 0.2345. Multivariable regression with LDH, ANC, and ALC explained 56% of %ΔPSA variance (R 2 = 0.561). Conclusions: In this exploratory analysis, prior sipuleucel-T treatment was associated with higher biochemical response rates to 177Lu-PSMA-RPT, despite less favorable baseline inflammatory biomarkers. Additionally, pretreatment LDH demonstrated a trend toward positive correlation with PSA percent change in sipuleucel-T-treated patients but not in controls. Given the small sample size, retrospective design, and limited statistical power, prospective studies with larger cohorts and serial immune monitoring are warranted to validate the findings. Citation Format: Farzana Z. Ali, Jeremie Calais, Johannes Czernin. Systemic Inflammatory Biomarkers and Lu-177-PSMA Radiopharmaceutical Therapy Response in Sipuleucel-T-Pretreated Metastatic Castration-Resistant Prostate Cancer abstract. In: Proceedings of the AACR Immuno-Oncology Conference (AACR IO): Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2026 Feb 18-21; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2026;14(2 Suppl):Abstract nr A031.
Ali et al. (Wed,) studied this question.
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