Identifying senescence and immune biomarkers predictive of benefit to combined CDK4 and checkpoint blockade inhibition in patients with dedifferentiated liposarcoma

对于局部晚期或转移性高分化或低分化淋巴瘤患者， 去分化脂肪肉瘤（WD/DDLS）是罕见的并且经常被忽视的孤儿癌。有 在美国，每年约有1000名患者被诊断患有WD/DDLS，并且这些癌症通常不 对化疗有反应细胞周期蛋白依赖性激酶4/6（CDK 4/6）抑制剂的最新试验， 发现CDK 4基因在>90%的WD/DDLS中扩增，表明这些药物稳定了 在治疗前一直在生长，并显示出具有临床意义的中位无进展生存期（PFS）， 12周时为66%，但反应不常见。 为了提高缓解率和改善PFS获益，我们建议联合联合收割机和CDK 4/6抑制剂 palbociclib与抗免疫检查点PD 1的抗体联合使用。检查点抑制剂具有一定的活性， DDLS，导致约8%的患者部分缓解。CDK 4/6抑制剂已被证明可以增加 检查点抑制剂的功效以及促进乳腺癌患者和动物的抗肿瘤免疫 模型在反应性肿瘤中，CDK 4/6抑制剂触发衰老，导致细胞分泌促炎性物质， 细胞因子和生长因子（称为衰老相关分泌表型，或SASP），表明 这些药物可以增强抗肿瘤免疫力。 为了确定可能从这种联合治疗中获益的患者，我们将研究 使用来自拟定阶段患者的治疗前和治疗中活检标本的缓解和耐药性 2项palbociclib联合抗PD 1抗体INCMGA 0012的试验。这些研究将侧重于 先前确定为WD/DDLS中CDK 4/6通路诱导衰老所需的细胞标志物 (MDM2转换，钙粘蛋白18表达）;终末衰老标志物（Angplt 4），抗肿瘤免疫 反应;和基因表达。因此，我们的具体目标是：（1）评估CDK 4的安全性和有效性 Palbociclib联合INCMGA 0012的PD 1阻断作用在30例 WD/DDLS（结果：总反应率、PFS和总生存期）;（2）检查衰老的作用， 终末衰老和产生的SASP对联合治疗的反应，以及它们与 免疫应答;和（3）表征免疫微环境（特别是CD 8 + T细胞和PDL 1 + T细胞）。 肿瘤细胞）和肿瘤基因表达（用免疫组织化学和整体和单细胞评估 在Palbociclib和INCMGA 0012联合治疗之前和期间， 与临床反应和结果的相关性。 这项试验的成功完成可能会导致一种新的联合免疫疗法的引入 WD/DDLS策略，并确定预测性生物标志物，以选择最有可能在两种疾病中获益的患者 肉瘤和其它恶性肿瘤。

Few viable treatments exist for patients with locally advanced or metastatic well-differentiated or dedifferentiated liposarcoma (WD/DDLS), which are rare and often neglected orphan cancers. There are approximately 1000 patients per year in the US diagnosed with WD/DDLS, and these cancers generally do not respond to chemotherapy. Recent trials of cyclin-dependent kinase 4/6 (CDK4/6) inhibitors, motivated by the finding that the CDK4 gene is amplified in >90% of WD/DDLS, show these agents stabilize disease that had been growing prior to treatment and demonstrated clinically meaningful median progression-free survival (PFS) of 66% at 12 weeks but responses were uncommon. To enhance response rates and improve PFS benefit, we propose to combine the CDK4/6 inhibitor palbociclib with an antibody against the immune checkpoint PD1. Checkpoint inhibitors have some activity in DDLS, leading to partial responses in about 8% of patients. CDK4/6 inhibitors have been shown to increase the efficacy of checkpoint inhibitors and to promote antitumor immunity in breast cancer patients and animal models. In responsive tumors, CDK4/6 inhibitors trigger senescence, causing cells to secrete proinflammatory cytokines and growth factors (termed the senescence-associated secretory phenotype, or SASP), suggesting that these agents may enhance antitumor immunity. To identify patients likely to benefit from this combination therapy, we will investigate mechanisms of response and resistance using pre- and on-treatment biopsy specimens from patients on the proposed phase 2 trial of palbociclib combined with the anti-PD1 antibody INCMGA0012. These studies will focus on the cellular markers previously determined to be required for CDK4/6 inhibitor-induced senescence in WD/DDLS (MDM2 turnover, cadherin 18 expression); markers of terminal senescence (Angplt4), antitumor immune responses; and gene expression. Thus, our Specific Aims are to: (1) Assess the safety and efficacy of CDK4 inhibition using palbociclib in combination with PD1 blockade using INCMGA0012 in 30 patients with WD/DDLS (outcomes: overall response rate, PFS, and overall survival); (2) Examine the roles of senescence, terminal senescence and resultant SASP in response to the combination therapy and, their relationship with immune response; and (3) Characterize the immune microenvironment (specifically CD8+ T cells and PDL1+ tumor cells) and tumor gene expression (assessed with immunohistochemistry and both bulk and single-cell RNA sequencing) prior to and during combined treatment of palbociclib and INCMGA0012, and examine their association with clinical response and outcome. Successful completion of this trial may lead to the introduction of a novel combination immunotherapy strategy for WD/DDLS and identify predictive biomarkers for selection of patients most likely to benefit in both sarcoma and other malignancies.