作者: Ferrer, Irene ; Jiménez-Reinoso, Anaïs ; Molero-Abraham, Magdalena ; Zugazagoitia, Jon ; Nuñez-Buiza, Ángel ; Blanco, Belén ; Garrido-Martin, Eva M. ; Pareja, Eduardo ; Díez-Alonso, Laura ; Ramírez-Orellana, Manuel ; Rodriguez-Peralto, José Luis ; Nehme-Álvarez, Daniel ; Domínguez-Alonso, Carmen ; Álvarez-Vallina, Luis ; Cirauqui, Cristina ; Ramírez-Fernández, Ángel ; Paz-Ares, Luis ; Tobes, Raquel ; González-Murillo, África

Adoptive transfer of tumor-infiltrating lymphocytes (TIL) has shown remarkable results in melanoma, but only modest clinical benefits in other cancers, even after TIL have been genetically modified to improve their tumor homing, cytotoxic potential or overcome cell exhaustion. The required ex vivo TIL expansion process may induce changes in the T cell clonal composition, which could likely compromise the tumor reactivity of TIL preparations and ultimately the success of TIL therapy. A promising approach based on the production of bispecific T cell-engagers (TCE) by engineered T cells (STAb-T therapy) improves the efficacy of current T cell redirection strategies against tumor-associated antigens in hematological tumors. We studied the TCRβ repertoire in non-small cell lung cancer (NSCLC) tumors and in ex vivo expanded TIL from two unrelated patients. We generated TIL secreting anti-epidermal growth factor receptor (EGFR) × anti-CD3 TCE (TIL^STAb) and tested their antitumor efficacy in vitro and in vivo using a NSCLC patient-derived xenograft (PDX) model in which tumor fragments and TIL from the same patient were transplanted into hIL-2 NOG mice. We confirmed that the standard TIL expansion protocol promotes the loss of tumor-dominant T cell clones and the overgrowth of virus-reactive TCR clonotypes that were marginally detectable in primary tumors. We demonstrated the antitumor activity of TIL^STAb both in vitro and in vivo when administered intratumorally and systemically in an autologous immune-humanized PDX EGFR⁺ NSCLC mouse model, where tumor regression was mediated by TCE-redirected CD4⁺ TIL bearing non-tumor dominant clonotypes.

2024-02-14·Science Translational Medicine1区 · 医学

Engineered T cells secreting anti-BCMA T cell engagers control multiple myeloma and promote immune memory in vivo

1区 · 医学

Article

作者: Gómez-Rosel, Marina ; Penela, Petronila ; Romencín, Paola A ; Bueno, Clara ; Pérez-Pons, Alba ; Río, Paula ; Mayado, Andrea ; Albitre, Ángela ; Jara, Maria ; Sanz, Laura ; Martín-Antonio, Beatriz ; Aguilar-Sopeña, Óscar ; Segura-Tudela, Alejandro ; Roda-Navarro, Pedro ; Blanco, Belén ; Jiménez-Reinoso, Anaïs ; Ramírez-Fernández, Ángel ; Orfao, Alberto ; Tapia-Galisteo, Antonio ; Martínez-López, Joaquín ; Perez-Amill, Lorena ; Díez-Alonso, Laura ; Anguita, Eduardo ; Martínez, Alba ; Hangiu, Oana ; Juan, Manel ; Menéndez, Pablo ; Valeri, Antonio ; Álvarez-Vallina, Luis ; Falgas, Aïda ; Solé, Francesc ; Rubio-Pérez, Laura ; Arroyo-Ródenas, Javier ; Almagro, Laura ; Domínguez-Alonso, Carmen ; García-Ortiz, Almudena

Multiple myeloma is the second most common hematological malignancy in adults and remains an incurable disease. B cell maturation antigen (BCMA)–directed immunotherapy, including T cells bearing chimeric antigen receptors (CARs) and systemically injected bispecific T cell engagers (TCEs), has shown remarkable clinical activity, and several products have received market approval. However, despite promising results, most patients eventually become refractory and relapse, highlighting the need for alternative strategies. Engineered T cells secreting TCE antibodies (STAb) represent a promising strategy that combines the advantages of adoptive cell therapies and bispecific antibodies. Here, we undertook a comprehensive preclinical study comparing the therapeutic potential of T cells either expressing second-generation anti-BCMA CARs (CAR-T) or secreting BCMAxCD3 TCEs (STAb-T) in a T cell–limiting experimental setting mimicking the conditions found in patients with relapsed/refractory multiple myeloma. STAb-T cells recruited T cell activity at extremely low effector-to-target ratios and were resistant to inhibition mediated by soluble BCMA released from the cell surface, resulting in enhanced cytotoxic responses and prevention of immune escape of multiple myeloma cells in vitro. These advantages led to robust expansion and persistence of STAb-T cells in vivo, generating long-lived memory BCMA-specific responses that could control multiple myeloma progression in xenograft models, outperforming traditional CAR-T cells. These promising preclinical results encourage clinical testing of the BCMA-STAb-T cell approach in relapsed/refractory multiple myeloma.

2022-12-31·OncoImmunology2区 · 医学

Synapse topology and downmodulation events determine the functional outcome of anti-CD19 T cell-redirecting strategies

2区 · 医学

ArticleOA

作者: Roda-Navarro, Pedro ; Aguilar-Sopeña, Óscar ; Segura-Tudela, Alejandro ; Blanco, Belén ; Ramírez-Fernández, Ángel ; Domínguez-Alonso, Carmen ; Díez-Alonso, Laura ; Álvarez-Vallina, Luis

Cancer immunotherapy strategies based on the endogenous secretion of T cell-redirecting bispecific antibodies by engineered T lymphocytes (STAb-T) are emerging as alternative or complementary approaches to those based on chimeric antigen receptors (CAR-T). The antitumor efficacy of bispecific anti-CD19 × anti-CD3 (CD19×CD3) T cell engager (BiTE)-secreting STAb-T cells has been demonstrated in several mouse models of B-cell acute leukemia. Here, we have investigated the spatial topology and downstream signaling of the artificial immunological synapses (IS) that are formed by CAR-T or STAb-T cells. Upon interaction with CD19-positive target cells, STAb-T cells form IS with structure and signal transduction, which more closely resemble those of physiological cognate IS, compared to IS formed by CAR-T cells expressing a second-generation CAR bearing the same CD19-single-chain variable fragment. Importantly, while CD3 is maintained at detectable levels on the surface of STAb-T cells, indicating sustained activation mediated by the secreted BiTE, the anti-CD19 CAR was rapidly downmodulated, which correlated with a more transient downstream signaling. Furthermore, CAR-T cells, but not STAb-T cells, provoke an acute loss of CD19 in target cells. Such differences might represent advantages of the STAb-T strategy over the CAR-T approach and should be carefully considered in order to develop more effective and safer treatments for hematological malignancies.

项与 CD1a-STAb T cells(Onechain Immunotherapeutics) 相关的新闻（医药）

2024-03-23

·生物制药小编

同靶点的双抗为什么要结合CAR-T

随着近日FDA专家会的一致性意见，BCMA-CAR-T推至更前线治疗方案的概率也越来越高，但现阶段的BCMA-CAR-T治疗仍然有很高的复发概率，而这个时候使用CAR-T再次治疗可能会因为免疫排斥或抗CAR抗体等原因而使得情况更为复杂。来自西班牙的Luis Álvarez-Vallina团队认为他们找到了一劳永逸的解决方案。相关研究成果发表在Science子刊Science Translational Medicine上。他们认为核心问题在于效率上。可溶性BCMA阻碍了CAR-T的效率BCMA是BCMA-CAR-T的靶标，它几乎只在浆细胞上表达，在恶性B细胞上过度表达，将BCMA作为CAR-T靶点开发似乎是相当理想的。问题是当肿瘤负荷过高的情况下，会存在高水平的可溶性BCMA，而这可能会让细胞表面的BCMA密度下降。而当BCMA以可溶性形式存在于血液或其他体液中时，它可能与CAR-T细胞上的BCMA特异性CAR竞争结合其配体，从而减少CAR-T细胞对肿瘤细胞表面BCMA的有效识别和攻击。尽管BCMA双抗似乎不受这一问题的影响，但是现阶段上市的BCMA/CD3双抗的作用时间可能相对较短，不像CAR-T细胞可以在体内持续存在并长期杀伤肿瘤细胞。一旦停止治疗，它们就不能产生记忆性抗肿瘤反应。Luis Álvarez-Vallina团队决定利用这两种策略的优势，设计出一款能够长期分泌BCMA双抗的T细胞疗法。STAb-T的优势其实该团队之前就有试图将开发手段用在T-ALL上（T细胞急性淋巴细胞白血病），因为对于T-ALL那样的T细胞肿瘤，T细胞自身产生癌变会导致CAR-T“自杀”，采用分泌CD1a的TCE抗体或许能为这一问题提供解决方案。而在这项研究中，他们的团队基于相似的机理设计了一种串联抗BCMA x CD3双特异性抗体（BCMA-TCE），然后他们用慢病毒载体将其转导到原代T细胞中以产生STAb-T细胞。为了测试StAb-T细胞的有效性，研究人员将它们的细胞毒性与BCMA+或BCMA-靶细胞以不同的效应靶(E:T)细胞比例（有效T细胞和无效T细胞的比值）共培养的BCMA CAR-T细胞进行比较。而BCMA CAR-T细胞仅在较高比例下(每个靶细胞超过1个效应细胞，E:T = 1:1)显示出≥80%的细胞毒性，而即使在最低比例下(1:10)，STAb-T细胞也诱导出≥80%的特异性细胞毒性。这些结果在临床相关环境中得到证实，分别使用来自MM或浆细胞白血病患者的骨髓细胞或外周血单核细胞进行体外分析。在这两种情况下，STAb-T细胞明显比CAR-T细胞更有效，在所有E:T比率下消除了70%以上的靶细胞，而CAR-T细胞在最高E:T比率下溶解了30%的细胞。这意味着STAb-T可能只需要较低的剂量就能达到CAR-T相似的效果。STAb-T疗法的另外一个好处还是能招募那些产生旁观者效应的T细胞。因为TCE本身能结合那些尚未被激活的T细胞，而CAR-T细胞并不能招募那些旁观的T细胞。规避可溶性BCMA问题为了评估STAb T细胞是否可以抵消sBCMA（可溶性BCMA）的作用，研究人员还在sBCMA浓度增加的情况下将CAR-T和STAb-T细胞与靶细胞共培养。尽管STAb-T细胞的细胞毒性在所有浓度下都保持在100%，但CAR-T细胞的活性以剂量依赖的方式下降。最后，研究人员作者在用两种不同剂量的CAR-T和STAb-T细胞(标准剂量为5 x10^6或治疗极限剂量(TLD)为3x10^6)治疗的MM异种移植小鼠模型中评估了STAb-T细胞在体内的疗效。在最高剂量下，STAb-T细胞治疗组的所有小鼠（n= 6）无肿瘤，在CAR-T细胞治疗组中只有两只小鼠无肿瘤。当小鼠在TLD接受治疗时，在STAb治疗组中只有一只小鼠在第5周和第6周显示出一些肿瘤负荷，而用CAR-T细胞治疗的所有小鼠从第3周开始显示出疾病进展。而在接受STAb-T细胞的小鼠中几乎检测不到sBCMA，而在两个CAR-T细胞组中都观察到了sBCMA，其中以用TLD治疗的小鼠尤为显著。而对治疗小鼠骨髓和脾脏中恢复的CD4+和CD8+细胞比例的分析显示，STAb-T细胞中CD4+记忆细胞的比例远高于CAR-T细胞，研究人员将其归因于分泌的BCMA-TCE的旁观者效应。参考来源：Díez-Alonso L, Falgas A, Arroyo-Ródenas J, Romencín PA, Martínez A, Gómez-Rosel M, Blanco B, Jiménez-Reinoso A, Mayado A, Pérez-Pons A, Aguilar-Sopeña Ó, Ramírez-Fernández Á, Segura-Tudela A, Perez-Amill L, Tapia-Galisteo A, Domínguez-Alonso C, Rubio-Pérez L, Jara M, Solé F, Hangiu O, Almagro L, Albitre Á, Penela P, Sanz L, Anguita E, Valeri A, García-Ortiz A, Río P, Juan M, Martínez-López J, Roda-Navarro P, Martín-Antonio B, Orfao A, Menéndez P, Bueno C, Álvarez-Vallina L. Engineered T cells secreting anti-BCMA T cell engagers control multiple myeloma and promote immune memory in vivo. Sci Transl Med. 2024 Feb 14;16(734):eadg7962. doi: 10.1126/scitranslmed.adg7962. Epub 2024 Feb 14.

免疫疗法细胞疗法

100 项与 CD1a-STAb T cells(Onechain Immunotherapeutics) 相关的药物交易

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