Alvarez-Fernández Carmen, Escribà-Garcia Laura, Caballero A C, Escudero-López Eva, Ujaldón-Miró Cristina, Montserrat-Torres Rosanna, Pujol-Fernández Paula, Sierra Jorge, Briones Javier
Hematology Service Hospital de la Santa Creu y Sant Pau Barcelona Spain.
Laboratory of Experimental Hematology-IIB Institut Recerca Hospital de la Santa Creu y Sant Pau Barcelona Spain.
Clin Transl Immunology. 2021 Apr 29;10(4):e1268. doi: 10.1002/cti2.1268. eCollection 2021.
Adoptive cell therapy (ACT) with mature T cells modified with a chimeric antigen receptor has demonstrated improved outcome for B-cell malignancies. However, its application for others such as Hodgkin lymphoma remains a clinical challenge. CD30 antigen, expressed in Hodgkin lymphoma cells, is absent in most healthy tissues, representing an ideal target of ACT for this disease. Despite that, efficacy of CD30-chimeric antigen receptor (CAR) T cells for Hodgkin lymphoma remains modest. Here, we have developed and tested a novel CD30-CAR T to improve efficacy of CD30-CAR therapy, using a targeting epitope within the non-cleavable part of CD30 receptor, and memory stem T cells (T) to improve engraftment, persistence and antitumor activity.
T cultures were generated and expanded and transduced at day 1 or 2 with a lentiviral vector encoding the CD30-CAR. Therapeutic experiments were performed using NSG mice injected with L540 (sc) or L428 (iv) and treated with CD30-CAR T cells when the tumor was established.
CD30-CAR T cells generated and expanded , despite CD30 expression and fratricide killing of CD30 CAR T cells, were not impaired by soluble CD30 and completely eradicated Hodgkin lymphoma , showing high persistence and long-lasting immunity. In addition, highly enriched CD30-CAR T products confer a survival advantage , in contrast to more differentiated CAR T cells, with higher tumor infiltration and enhanced antitumor effect.
This study supports the use of a refined CD30-CAR T cells with highly enriched T products to improve clinical efficacy of CAR T for Hodgkin lymphoma.
嵌合抗原受体修饰的成熟T细胞过继性细胞疗法（ACT）已显示出对B细胞恶性肿瘤有更好的疗效。然而，其在霍奇金淋巴瘤等其他疾病中的应用仍是一项临床挑战。CD30抗原在霍奇金淋巴瘤细胞中表达，在大多数健康组织中不存在，是ACT治疗该疾病的理想靶点。尽管如此，CD30嵌合抗原受体（CAR）T细胞治疗霍奇金淋巴瘤的疗效仍较为有限。在此，我们开发并测试了一种新型CD30-CAR T细胞，以提高CD30-CAR疗法的疗效，该细胞使用CD30受体不可裂解部分内的靶向表位，并使用记忆性干细胞T细胞（T）来改善植入、持久性和抗肿瘤活性。
在第1天或第2天用编码CD30-CAR的慢病毒载体转导并扩增T细胞培养物。使用注射L540（皮下）或L428（静脉内）的NSG小鼠进行治疗实验，当肿瘤形成时用CD30-CAR T细胞进行治疗。
尽管存在CD30表达以及CD30 CAR T细胞的自相残杀性杀伤，但所产生并扩增的CD30-CAR T细胞并未受到可溶性CD30的损害，并且完全根除了霍奇金淋巴瘤，显示出高持久性和持久免疫力。此外，与分化程度更高的CAR T细胞相比，高度富集的CD30-CAR T产物具有生存优势，具有更高的肿瘤浸润和增强的抗肿瘤作用。
本研究支持使用具有高度富集T产物的优化CD30-CAR T细胞来提高CAR T治疗霍奇金淋巴瘤的临床疗效。
