Szostak Bartosz, Machaj Filip, Rosik Jakub, Pawlik Andrzej
a Department of Physiology , Pomeranian Medical University , Szczecin , Poland.
Expert Opin Investig Drugs. 2019 Feb;28(2):149-159. doi: 10.1080/13543784.2019.1559297. Epub 2018 Dec 30.
In cancer, the immune response to tumor antigens is often suppressed by inhibitors and ligands. Checkpoint blockade, considered one of the most promising frontiers for anti-cancer therapy, aims to stimulate the immune anti-cancer response. Agents such as cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) inhibitors offer prolonged survival with manageable side effects.
We summarize the recent clinical successes of CTLA-4 inhibitors and place a strong emphasis on those in early phase clinical trials, often in combination with other immune check-point inhibitors, i.e., programmed cell death protein 1 (PD-1) and BRAF/mitogen-activated protein kinase inhibitors.
Recent phase I and phase II clinical trials confirm the efficacy of anti-CTLA-4 therapy for treatment of cancers such as renal cell carcinoma. These studies also indicated increased efficacy with combined immune checkpoint blockade with PD-1 or Ras/Raf/mitogen-activated protein kinase/ERK kinase (MEK)/extracellular-signal-regulated kinase (ERK) inhibitors. Researchers must search for new immune targets that may enable more effective and safe immune checkpoint blockade and cancer therapy. This goal may be achieved by next-generation combination therapies to overcome immune checkpoint therapy resistance.
在癌症中，针对肿瘤抗原的免疫反应常常受到抑制剂和配体的抑制。检查点阻断被认为是抗癌治疗最有前景的前沿领域之一，旨在刺激免疫抗癌反应。诸如细胞毒性T淋巴细胞相关抗原4（CTLA-4）抑制剂等药物可延长生存期且副作用可控。
我们总结了CTLA-4抑制剂近期的临床成功案例，并重点关注那些处于早期临床试验阶段的药物，这些试验通常与其他免疫检查点抑制剂联合使用，即程序性细胞死亡蛋白1（PD-1）以及BRAF/丝裂原活化蛋白激酶抑制剂。
近期的I期和II期临床试验证实了抗CTLA-4疗法对治疗肾细胞癌等癌症的疗效。这些研究还表明，联合使用PD-1或Ras/Raf/丝裂原活化蛋白激酶/细胞外信号调节激酶（MEK）/细胞外信号调节激酶（ERK）抑制剂进行免疫检查点阻断可提高疗效。研究人员必须寻找新的免疫靶点，以实现更有效、更安全的免疫检查点阻断和癌症治疗。这一目标可通过新一代联合疗法来克服免疫检查点治疗耐药性来实现。
