Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
J Immunother Cancer. 2023 Mar;11(3). doi: 10.1136/jitc-2022-006262.
The prostate tumor microenvironment (TME) is immunosuppressive, with few effector T cells and enrichment of inhibitory immune populations, leading to limited responses to treatments such as immune checkpoint therapies (ICTs). The immune composition of the prostate TME differs across soft tissue and bone, the most common site of treatment-refractory metastasis. Understanding immunosuppressive mechanisms specific to prostate TMEs will enable rational immunotherapy strategies to generate effective antitumor immune responses. Daratumumab (anti-CD38 antibody) and edicotinib (colony-stimulating factor-1 receptor (CSF-1R) inhibitor) may alter the balance within the prostate TME to promote antitumor immune responses.
Daratumumab or edicotinib will be safe and will alter the immune TME, leading to antitumor responses in localized prostate cancer.
In this presurgical study, patients with localized prostate cancer received 4 weekly doses of daratumumab or 4 weeks of daily edicotinib prior to radical prostatectomy (RP). Treated and untreated control (Gleason score ≥8 in prostate biopsy) prostatectomy specimens and patient-matched pre- and post-treatment peripheral blood mononuclear cells (PBMCs) and bone marrow samples were evaluated. The primary endpoint was incidence of adverse events (AEs). The secondary endpoint was pathologic complete remission (pCR) rate.
Twenty-five patients were treated (daratumumab, n=15; edicotinib, n=10). All patients underwent RP without delays. Grade 3 treatment-related AEs with daratumumab occurred in 3 patients (12%), and no ≥grade 3 treatment-related AEs occurred with edicotinib. No changes in serum prostate-specific antigen (PSA) levels or pCRs were observed. Daratumumab led to a decreased frequency of CD38 T cells, natural killer cells, and myeloid cells in prostate tumors, bone marrow, and PBMCs. There were no consistent changes in CSF-1R immune cells in prostate, bone marrow, or PBMCs with edicotinib. Neither treatment induced T cell infiltration into the prostate TME.
Daratumumab and edicotinib treatment was safe and well-tolerated in patients with localized prostate cancer but did not induce pCRs. Decreases in CD38 immune cells were observed in prostate tumors, bone marrow, and PBMCs with daratumumab, but changes in CSF-1R immune cells were not consistently observed with edicotinib. Neither myeloid-targeted agent alone was sufficient to generate antitumor responses in prostate cancer; thus, combinations with agents to induce T cell infiltration (eg, ICTs) will be needed to overcome the immunosuppressive prostate TME.
前列腺肿瘤微环境（TME）具有免疫抑制性，效应 T 细胞较少，抑制性免疫群体丰富，导致对免疫检查点疗法（ICTs）等治疗的反应有限。前列腺 TME 的免疫组成在软组织和骨骼中不同，骨骼是治疗耐药转移的最常见部位。了解前列腺 TME 中特定的免疫抑制机制将能够实现合理的免疫治疗策略，以产生有效的抗肿瘤免疫反应。达雷妥尤单抗（抗 CD38 抗体）和依维莫司（集落刺激因子 1 受体（CSF-1R）抑制剂）可能改变前列腺 TME 内的平衡，以促进抗肿瘤免疫反应。
达雷妥尤单抗或依维莫司将是安全的，并将改变免疫 TME，导致局限性前列腺癌的抗肿瘤反应。
在这项术前研究中，局部前列腺癌患者在接受根治性前列腺切除术（RP）前接受 4 周每周剂量的达雷妥尤单抗或 4 周每日依维莫司治疗。评估了治疗和未治疗的对照（前列腺活检中 Gleason 评分≥8）前列腺切除术标本以及患者匹配的术前和术后外周血单核细胞（PBMC）和骨髓样本。主要终点是不良事件（AE）的发生率。次要终点是病理完全缓解（pCR）率。
25 名患者接受了治疗（达雷妥尤单抗，n=15；依维莫司，n=10）。所有患者均无延迟接受 RP。达雷妥尤单抗治疗相关的 3 级 AE 发生在 3 例患者（12%）中，依维莫司未发生≥3 级治疗相关 AE。未观察到血清前列腺特异性抗原（PSA）水平或 pCR 的变化。达雷妥尤单抗导致前列腺、骨髓和 PBMC 中肿瘤内 CD38 T 细胞、自然杀伤细胞和髓样细胞的频率降低。依维莫司治疗后，前列腺、骨髓和 PBMC 中 CSF-1R 免疫细胞无一致变化。两种治疗均未诱导 T 细胞浸润前列腺 TME。
达雷妥尤单抗和依维莫司在局部前列腺癌患者中安全且耐受良好，但未诱导 pCR。达雷妥尤单抗治疗后，前列腺肿瘤、骨髓和 PBMC 中的 CD38 免疫细胞减少，但依维莫司治疗后 CSF-1R 免疫细胞无一致变化。单独使用髓样靶向药物不足以在前列腺癌中产生抗肿瘤反应；因此，需要与诱导 T 细胞浸润的药物（例如 ICTs）联合使用，以克服免疫抑制性前列腺 TME。
