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Background Immune checkpoint blockade (ICB) has limited activity in unselected patients with castration-resistant prostate cancer (CRPC). The combination phase I/II Quick Efficacy Seeking Trial (QuEST1, NCT03493945) was designed to generate a tumor-directed immune response with BNVax (a vaccine targeting the transcription factor brachyury, involved in invasion and metastasis) and facilitate the resulting anti-tumor activity with ICB (with bintrafusp alfa (BA), a bifunctional agent providing dual inhibition of PD-L1 and TGF-β) and a lymphocyte stimulating immunocytokine (the IL-15 receptor superagonist NAI (N-803), Anktiva®). Previously, a manageable safety profile and promising anti-tumor activity was reported with the triplet regimen of BNVax+BA+NAI, producing sustained PSA responses in 7/24 patients (29%, 6 with pMMR disease), that included two confirmed radiographic partial responses, compared to PSA responses in 1/13 patients (8%) with the doublet regimen of BNVax+BA.1 2 Here, we characterize the peripheral immunome, compare changes between treatment arms, and evaluate associations with clinical response.Methods Comprehensive immune profiling included evaluation of complete blood counts, serum analytes, PBMC subsets, TCR diversity, and RNA expression profiles in peripheral blood serially collected from patients with CRPC receiving the triplet (n=24) and doublet (n=13) therapies.Results Absolute lymphocyte count (ALC) was increased from baseline to two weeks with the triplet regimen, with a greater magnitude of increase (8-fold) observed compared to the doublet. Patients receiving the triplet also had greater increases in total NK cells, refined NK subsets expressing activation/adhesion markers, ratios of effector to suppressor cells, proinflammatory serum analytes, gene expression profiles related to NK and T cell activity, and TCR diversity, than patients receiving the doublet. Several immune parameters at baseline were associated with clinical response to the triplet, including higher frequencies of CD4 + and CD8+ T cells expressing 41BB and lower frequencies of suppressor cells. A multivariable logistic regression model of serum analyte levels at baseline effectively predicted clinical response (accuracy=0.941, p=0.00026). Changes in immune cell subsets and serum analytes also associated with clinical response, including greater increases in NKp30+ mature NK cells (11-fold) at two weeks, and serum IFN-g (4-fold) at ten weeks.Conclusions These findings demonstrate increased clinical activity with enhanced ALC levels and immune activation of both NK and T cells with the addition of NAI to tumor-targeted vaccine and ICB. These data support the continued investigation of easily accessible peripheral biomarkers, including ALC, in patients with CRPC and suggest that evaluation of multiple circulating biomarkers may be beneficial in predicting clinical response.References Redman JM, Madan RA, Karzai F, Cordes L, Marte J, Williams N, Hankin A, Toney N, Donahue RN, Steinberg S, Soon Shiong P, Schlom J, Turkbey E, Gulley JL. 1631P Results from the quick efficacy seeking trial (QuEST1) arm combining BN-brachyury (BNVax) + bintrafusp alfa (BA) + nogapendekin alfa inbakicept-pmln (N-803) in castration-resistant prostate cancer (CRPC). Annals of Oncology, Volume 35, S984 - S985.Redman J, Madan RA, Karzai F, Bilusic M, Cordes L, Marte J, Manu M, Williams, N. Hankin A, Floudas C, Abdul Sater H, Gatti-Mays M, Strauss J, Steinberg S, Dahut W, Schlom J, Gulley J. 616MO Efficacy of BN-brachyury (BNVax) + bintrafusp alfa (BA) + N-803 in castration-resistant prostate cancer (CRPC): Results from a preliminary analysis of the Quick Efficacy Seeking Trial (QuEST1). Annals of Oncology, Volume 31, S511.Ethics Approval All subjects gave written informed consent. Study protocol ( NCT03493945) was approved by the NIH’s IRB, and conducted in accordance with institutional and federal guidelines.