Custom CARs: Leveraging the Adaptability of Allogeneic CAR Therapies to Address Current Challenges in Relapsed/Refractory DLBCL.
Custom CARs: Leveraging the Adaptability of Allogeneic CAR Therapies to Address Current Challenges in Relapsed/Refractory DLBCL.
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DOI：
10.3389/fimmu.2022.887866
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发表时间：
2022
影响因子：
7.3
通讯作者：
中科院分区：
文献类型：
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细胞疗法已经改变了复发/难治性弥漫性大b细胞淋巴瘤（r/r DLBCL）的治疗方法，这种淋巴瘤通常对补救性化疗反应不佳。最近，在三个不同的试验中，大约40%的r/r DLBCL患者在接受自体嵌合抗原受体（CAR） T细胞（auto-CARs）治疗后1年完全缓解。这些成功促进了auto-CARs在二线环境中的研究，在这些研究中，与自体造血细胞移植（AHCT）相比，axicabtagene ciloleucel和isocabtagene maraleucel均显示出改善的无事件生存。虽然令人鼓舞，但该数据也强调了60%的患者在接受auto-CARs治疗后复发或进展。个体疾病特征和细胞工程的后勤挑战也限制了患者获得auto- car的资格。同种异体CAR - T细胞（同种异体CAR - T细胞）可以解决其中的一些局限性，因为它们可以减轻与auto-CAR相关的延迟，从而减少桥接化疗的需要，并增加侵袭性淋巴瘤患者细胞产品的可用性。通过来自从未接受过细胞毒性化疗的健康供体，同种异体car可以从适应性更好的T细胞中产生。由特定细胞亚群（例如，干细胞记忆或naïve/早期记忆T细胞）制成的同种异体car也可能具有更高的疗效和长期持久性。此外，同种异体car已经成功地从其他类型的细胞中制造出来，包括自然杀伤细胞、γ - δ t细胞和诱导多能干细胞。这些细胞类型可以被改造成靶向病毒抗原，从而能够精确靶向病毒驱动的DLBCL。由于同种异体供体细胞可以分批储存和冷冻保存，它们可以更容易获得，与工程汽车相比，潜在地减少了物流障碍和成本。这可能最终为细胞疗法创造一个更可持续的平台。同种异体car需要解决的挑战包括移植物抗宿主病、同种异体免疫、相对于自体car的潜在持久性降低以及抗原逃逸。简而言之，allo- car的适应性使其成为治疗通过标准化疗、AHCT或auto- car进展的r/r DLBCL患者的理想选择。在这里，我们回顾了已发表的关于使用由不同细胞类型制造的同种异体CAR产品以及即将问世的同种异体CAR技术治疗r/r DLBCL患者的文献。
Cellular therapies have transformed the treatment of relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL), which typically does not respond well to salvage chemotherapy. Recently, approximately 40% of r/r DLBCL patients across three different trials achieved a complete remission at 1 year after receiving treatment with autologous chimeric antigen receptor (CAR) T cells (auto-CARs). These successes have prompted studies of auto-CARs in second-line settings, in which axicabtagene ciloleucel and lisocabtagene maraleucel both showed improved event-free survival over autologous hematopoietic cell transplantation (AHCT). While encouraging, this data also highlights that 60% of patients relapse or progress following treatment with auto-CARs. Individual disease characteristics and logistical challenges of cell engineering also limit patients’ eligibility for auto-CARs. Allogeneic CAR T cells (allo-CARs) may address some of these limitations as they may mitigate delays associated with auto-CARs, thereby reducing the need for bridging chemotherapies and increasing availability of cellular products for patients with aggressive lymphomas. By being sourced from healthy donors who have never been exposed to cytotoxic chemotherapy, allo-CARs can be created from T cells with better fitness. Allo-CARs made from specific cellular subsets (e.g., stem cell memory or naïve/early memory T cells) may also have increased efficacy and long-term persistence. Additionally, allo-CARs have been successfully created from other cell types, including natural killer cells, gamma-delta T-cells and induced pluripotent stem cells. These cell types can be engineered to target viral antigens, enabling precision targeting of virally driven DLBCL. As allogeneic donor cells can be banked and cryopreserved in batches, they can be made more readily available, potentially reducing logistical hurdles and costs compared to engineering auto-CARs. This may ultimately create a more sustainable platform for cell therapies. Challenges with allo-CARs that will need to be addressed include graft versus host disease, alloimmunization, potentially decreased persistence relative to auto-CARs, and antigen escape. In short, the adaptability of allo-CARs makes them ideal for treating patients with r/r DLBCL who have progressed through standard chemotherapy, AHCT, or auto-CARs. Here, we review the published literature on patients with r/r DLBCL treated with allogeneic CAR products manufactured from various cell types as well as forthcoming allogeneic CAR technologies.