Activated Lymphocyte Recruitment Into the Tumor Microenvironment Following Preoperative Sipuleucel-T for Localized Prostate Cancer

Abstract

BackgroundSipuleucel-T is a US Food and Drug Administration–approved immunotherapy for asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC). Its mechanism of action is not fully understood. This prospective trial evaluated the direct immune effects of systemically administered sipuleucel-T on prostatic cancer tissue in the preoperative setting.MethodsPatients with untreated localized prostate cancer were treated on an open-label Phase II study of sipuleucel-T prior to planned radical prostatectomy (RP). Immune infiltrates in RP specimens (posttreatment) and in paired pretreatment biopsies were evaluated by immunohistochemistry (IHC). Correlations between circulating immune response and IHC were assessed using Spearman rank order.ResultsOf the 42 enrolled patients, 37 were evaluable. Adverse events were primarily transient, mild-to-moderate and infusion related. Patients developed T cell proliferation and interferon-γ responses detectable in the blood following treatment. Furthermore, a greater-than-three-fold increase in infiltrating CD3+, CD4+ FOXP3-, and CD8+ T cells was observed in the RP tissues compared with the pretreatment biopsy (binomial proportions: all P < .001). This level of T cell infiltration was observed at the tumor interface, and was not seen in a control group consisting of 12 concurrent patients who did not receive any neoadjuvant treatment prior to RP. The majority of infiltrating T cells were PD-1+ and Ki-67+, consistent with activated T cells. Importantly, the magnitude of the circulating immune response did not directly correlate with T cell infiltration within the prostate based upon Spearman’s rank order correlation.ConclusionsThis study is the first to demonstrate a local immune effect from the administration of sipuleucel-T. Neoadjuvant sipuleucel-T elicits both a systemic antigen-specific T cell response and the recruitment of activated effector T cells into the prostate tumor microenvironment.

Neoadjuvant sipuleucel-T induces both Th1 activation and immune regulation in localized prostate cancer

“…4 We now show that neoadjuvant sipuleucel-T elicits Th1 response that includes CXCL10 and a CD8 expression signature. To our knowledge, this is the first report to confirm that intratumoral Th1 immune response are specifically induced by sipuleucel-T treatment and are consistent with the Th1 immune responses that have been detected in the circulating T cells.…”

“…For all five paired cases examined, an upregulation of Th1/Th2 ratio was observed with treatment (p < 0.01, Figure 1E). We had previously shown that sipuleucel-T treatment was associated with an increase in infiltration of CD3+, CD4+Foxp3- and CD8+T cells into the tumor microenvironment 4 To confirm reliability of the calculated lymphocyte scores, we assessed their correlation with CD3, CD8, Foxp3 and CD20 staining by immunohistochemistry (IHC), scored by the frequency of positive staining at the tumor interface. The total T cells, CD8 T cells and Treg scores were significantly correlated with IHC scores for CD3, CD8 and Foxp3, respectively (p = 0.02).…”

“…Indeed, we have shown that lymphocytes induced by sipuleucel-T are localized are excluded from the tumor center. 4 This phenotype can be associated with a TGF-beta signature in bladder cancer. 8 While that presence of Th1 response associates with a PSA decrease on treatment, induction of inhibitory checkpoints was associated with PSA rise on treatment.…”

“…Tissue samples were derived from a single-arm, multicenter phase II trial of neoadjuvant sipuleucel-T treatment in men with localized prostate cancer administered prior to planned R. 4 Eligible patients had a normal complete blood count, adequate hepatic and renal function, tissue available from a pretreatment prostate biopsy, and were negative for HIV, HTLV-1 and −2, and hepatitis B and C. All subjects gave written informed consent to participate in the protocol approved by the Institutional Review Boards (IRBs) of each participating institution (NCT00715104). Subjects received sipuleucel-T at the standard two-week intervals for three planned doses prior to RP.…”

“…Immunohistochemical analysis showed that neoadjuvant sipuleucel-T induced T cell infiltration into the tumor (CD8 + > CD4 + FOXP3 − > CD4 + FOXP3 + ) with an activated phenotype (CD3 + Ki67 + , CD3 + PD-1 + ) at the tumor interface 4 More recently, utilizing deep sequencing of the TCRβ CD3 region in the same patient cohort, we showed that neoadjuvant sipuleucel-T decreased the diversity of circulating TCR repertoire while increased the diversity of TCR repertoire in the tumor tissue. This resulted in a greater overlap between the peripheral and intratumoral TCR sequences, which may represent recruitment of antigen-specific T cells from the periphery into the tumor tissue.…”