肿瘤细胞治疗研究
英文原题：Peptide-scFv antigen recognition domains effectively confer CAR T cell multiantigen specificity.
免疫逃逸的出现是开发针对血液系统恶性肿瘤（包括急性髓系白血病（AML））的有效嵌合抗原受体（CAR）T细胞疗法的重大障碍。
免疫逃逸的出现是开发针对血液系统恶性肿瘤（包括急性髓系白血病（AML））的有效嵌合抗原受体（CAR）T细胞疗法的重大障碍。在此，我们通过将GRP78特异性肽抗原识别域与CD123特异性scFv结合，生成肽-scFv双特异性抗原识别域（78.123），证明了同时靶向两种抗原的可行性。为实现这一目标，我们测试了不同长度和灵活性的连接子，并进行了免疫表型和功能表征。我们证明，双特异性CAR T细胞能够成功识别并杀伤表达GRP78、CD123或同时表达两种抗原的肿瘤细胞，并且当两种抗原均表达时，与单特异性CAR T细胞相比具有改善的抗肿瘤活性。蛋白质结构预测表明，连接子长度和紧凑性影响所生成双特异性CAR的功能。因此，我们提出了一种用于预防AML免疫逃逸的双特异性CAR设计策略，该策略可扩展至其他肽-scFv组合。
The emergence of immune escape is a significant roadblock to developing effective chimeric antigen receptor (CAR) T cell therapies against hematological malignancies, including acute myeloid leukemia (AML). Here, we demonstrate feasibility of targeting two antigens simultaneously by combining a GRP78-specific peptide antigen recognition domain with a CD123-specific scFv to generate a peptide-scFv bispecific antigen recognition domain (78.123). To achieve this, we test linkers with varying length and flexibility and perform immunophenotypic and functional characterization. We demonstrate that bispecific CAR T cells successfully recognize and kill tumor cells that express GRP78, CD123, or both antigens and have improved antitumor activity compared to their monospecific counterparts when both antigens are expressed. Protein structure prediction suggests that linker length and compactness influence the functionality of the generated bispecific CARs. Thus, we present a bispecific CAR design strategy to prevent immune escape in AML that can be extended to other peptide-scFv combinations.
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