Oncology Discovery, Bristol-Myers Squibb Co, Princeton, New Jersey, USA.
Oncology Discovery, Johnson and Johnson Limited, Spring House, Pennsylvania, USA.
J Immunother Cancer. 2021 Jan;9(1). doi: 10.1136/jitc-2020-001402.
Hematopoietic progenitor kinase 1 (HPK1 or MAP4K1) has been demonstrated as a negative intracellular immune checkpoint in mediating antitumor immunity in studies with HPK1 knockout and kinase dead mice. Pharmacological inhibition of HPK1 is desirable to investigate the role of HPK1 in human immune cells with therapeutic implications. However, a significant challenge remains to identify a small molecule inhibitor of HPK1 with sufficient potency, selectivity, and other drug-like properties suitable for proof-of-concept studies. In this report, we identified a novel, potent, and selective HPK1 small molecule kinase inhibitor, compound K (CompK). A series of studies were conducted to investigate the mechanism of action of CompK, aiming to understand its potential application in cancer immunotherapy.
Human primary T cells and dendritic cells (DCs) were investigated with CompK treatment under conditions relevant to tumor microenvironment (TME). Syngeneic tumor models were used to assess the in vivo pharmacology of CompK followed by human tumor interrogation ex vivo.
CompK treatment demonstrated markedly enhanced human T-cell immune responses under immunosuppressive conditions relevant to the TME and an increased avidity of the T-cell receptor (TCR) to recognize viral and tumor-associated antigens (TAAs) in significant synergy with anti-PD1. Animal model studies, including 1956 sarcoma and MC38 syngeneic models, revealed improved immune responses and superb antitumor efficacy in combination of CompK with anti-PD-1. An elevated immune response induced by CompK was observed with fresh tumor samples from multiple patients with colorectal carcinoma, suggesting a mechanistic translation from mouse model to human disease.
CompK treatment significantly improved human T-cell functions, with enhanced TCR avidity to recognize TAAs and tumor cytolytic activity by CD8+ T cells. Additional benefits include DC maturation and priming facilitation in tumor draining lymph node. CompK represents a novel pharmacological agent to address cancer treatment resistance.
在研究中，造血祖细胞激酶 1（HPK1 或 MAP4K1）已被证明是一种负性细胞内免疫检查点，可介导抗肿瘤免疫。HPK1 敲除和激酶失活小鼠的研究表明，抑制 HPK1 的活性是有必要的，这有助于研究 HPK1 在人类免疫细胞中的作用及其治疗意义。然而，目前仍然存在一个重大挑战，即需要确定一种具有足够效力、选择性和其他药物样特性的 HPK1 小分子抑制剂，以进行概念验证研究。在本报告中，我们鉴定了一种新型、有效且选择性的 HPK1 小分子激酶抑制剂化合物 K（CompK）。进行了一系列研究来探讨 CompK 的作用机制，旨在了解其在癌症免疫治疗中的潜在应用。
在与肿瘤微环境（TME）相关的条件下，用 CompK 处理人原代 T 细胞和树突状细胞（DC）。使用同源肿瘤模型评估 CompK 的体内药理学，然后进行人肿瘤的离体分析。
CompK 处理在与 TME 相关的免疫抑制条件下显著增强了人 T 细胞的免疫反应，并显著提高了 T 细胞受体（TCR）识别病毒和肿瘤相关抗原（TAA）的亲和力，与抗 PD-1 具有显著协同作用。动物模型研究，包括 1956 肉瘤和 MC38 同源模型，显示 CompK 与抗 PD-1 联合使用可改善免疫反应并具有极好的抗肿瘤疗效。从多位结直肠癌患者的新鲜肿瘤样本中观察到 CompK 诱导的免疫反应增强，提示从小鼠模型到人类疾病的机制转化。
CompK 处理显著改善了人 T 细胞的功能，增强了 TCR 对 TAA 的亲和力和 CD8+T 细胞对肿瘤的细胞溶解活性。其他益处包括肿瘤引流淋巴结中 DC 的成熟和启动促进。CompK 代表了一种新的药理学药物，可用于解决癌症治疗耐药性问题。
