PO.IM01.17 · 免疫学
使用生物活性分子联合治疗提高免疫检查点阻断疗效
Improving immune checkpoint blockade efficacy using combination therapy with bioactive molecules
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
免疫检查点阻断(ICB)疗法,如aPD-1和aPD-L1,可重新激活T细胞以对抗肿瘤。虽然这些疗法已改变了癌症治疗格局,近半数美国癌症患者符合ICB治疗条件,但其疗效有限,应答率变异性高且总体偏低。旨在提高ICB应答率的大量投入主要集中于将其他疗法与ICB联合,数千项测试抗PD-1或抗PD-L1联合其他药物的临床试验即为明证。然而,这一巨大投入仅带来了微小改善,凸显了亟需一种创新、简化的方法来识别可增强ICB疗效的化合物这一关键未满足需求。为填补这一空白,我们开发了一个高通量筛选(HTS)药物发现平台,可高效筛选与ICB具有协同作用的化合物。限制ICB疗效的一个主要机制是复杂的肿瘤微环境(TME),其中包括呈免疫抑制性(M2)表型并抑制T细胞募集、增殖和功能的肿瘤相关巨噬细胞(TAM)。TAM的丰度与多种癌症的不良预后相关,使TAM成为与ICB协同作用化合物的首要靶点。为识别可减少TAM免疫抑制的潜在靶点,我们经验证的HTS采用了骨髓来源巨噬细胞与脾脏来源CD4+和CD8+ T细胞的离体共培养系统。在与小分子文库孵育后,评估培养物中T细胞活性的增加;因此,该测定旨在识别可减弱髓单核细胞依赖性T细胞抑制、并在与ICB联合时增强T细胞活性的小分子。使用该HTS,我们筛选了超过3270种生物活性小分子,识别出128种表现出TAM调节活性的化合物。在这128种化合物中,7种与抗PD-1协同,6种与抗PD-L1协同。有一种化合物同时与抗PD-1和抗PD-L1协同。这些化合物在同基因小鼠乳腺癌模型中进行了体内评估,以评价抗肿瘤效应。事实上,将这些药物与抗PD-1/抗PD-L1联合,显著减缓了对抗PD-1/抗PD-L1单药治疗普遍耐药的三阴性乳腺癌(TNBC)模型(EMT6)中的肿瘤生长。通过以靶点无关和肿瘤无关的方式应对TME和免疫逃逸所带来的挑战,我们的平台有潜力发掘出新颖的、变革性的ICB联合疗法,在多种恶性肿瘤中具有广泛的转化潜力。
查看英文原文 English abstract
Immune checkpoint blockade (ICB) therapies, such as aPD-1 and aPD-L1, reactivate T cells to fight tumors. While these therapies have transformed cancer treatment, with nearly half of U.S. cancer patients eligible for ICB therapy, their efficacy is limited, with highly variable and generally low response rates. Significant investments aimed at improving ICB response rates have primarily focused on combining therapies with ICB, as demonstrated by the thousands of clinical trials testing anti-PD-1 or anti-PD-L1 with additional agents. However, this significant investment has only resulted in marginal improvements, underscoring a critical unmet need for an innovative, streamlined approach to identify compounds that enhance ICB efficacy. To address this gap, we developed a high-throughput screen (HTS) drug discovery platform that efficiently screens compounds for synergy with ICB. One primary mechanism that limits ICB efficacy is the complex tumor microenvironment (TME), which includes tumor-associated macrophages (TAMs) that take on an immunosuppressive (M2) phenotype and suppress T cell recruitment, proliferation, and function. The abundance of TAMs correlates with poor prognosis in numerous cancers, making TAMs a prime target for compounds that synergize with ICB. To identify potential targets that can reduce TAM immunosuppression, our validated HTS uses an ex vivo co-culture system of bone marrow-derived macrophages and spleen-derived CD4 + and CD8 + T cells. After incubation with small molecule libraries, cultures are evaluated for increased T cell activity; thus, this assay aims to identify small molecules that diminish myelomonocytic cell-dependent T cell suppression and enhance T cell activity when combined with ICB. Using this HTS, we screened over 3270 bioactive small molecules, identifying 128 that showed TAM-modulating activity. Of those 128 compounds, seven synergized with anti-PD1 and six with anti-PD-L1. One compound synergized with both anti-PD-1 and anti-PD-L1. These compounds were evaluated in vivo in syngeneic murine breast cancer models to assess anti-tumor effects. Indeed, combining these agents with anti-PD-1/anti-PD-L1 significantly slowed tumor growth in triple-negative breast cancer (TNBC) models (EMT6), which are generally resistant to anti-PD-1/anti-PD-L1 monotherapy. By tackling the challenges posed by the TME and immune evasion, in a target- and tumor-agnostic manner, our platform has the potential to uncover novel, transformative ICB combination therapies with broad translational potential across multiple malignancies.
利益披露 Disclosure
B. F. Keefe, None..
A. S. Rolig, None.