Improving response durability after CAR T cell therapy for multiple myeloma

项目总结/摘要（项目3） 多发性骨髓瘤（MM）是骨髓浆细胞的恶性血液病。虽然MM几乎 现代治疗已显著提高了生存率。最有前途的MM新疗法之一 是靶向B细胞成熟抗原（BCMA）的CAR T细胞。尽管患者的反应率很高， 然而，对于晚期疾病，几乎所有患者在当前一代抗BCMA CAR T治疗后最终都会复发。 细胞该提案进一步推进了预防MM患者在对CAR初始应答后晚期复发的长期目标 T细胞疗法在大多数情况下，BCMA表达在复发时保留，表明抗BCMA免疫应答的丧失。 监测是治疗失败的主要模式。我们和其他人发现， 对于CAR T细胞制造预测临床结果，CAR T细胞偶尔会在晚期增殖 输注后控制疾病进展的时间点，以及骨髓微环境的特征 预测抗BCMA CAR T细胞后的复发风险。该提案提出了预防晚期MM的新方法 CAR T细胞治疗后复发;临床和临床前研究的方法植根于这些先前的研究。 意见。我们将进行一项临床试验，以测试抗BCMA CAR T治疗的安全性和可行性。 由骨髓浸润淋巴细胞（MIL）而不是外周血淋巴细胞制造的细胞 传统上用于CAR T细胞制造。我们假设，军用导弹的弹道导弹寻的能力将 增强骨髓中CAR T细胞的运输和持久性。我们还将在临床前开发两种新方法 以在输注后体内调节CAR T细胞活性。(1)我们将在CAR T中引入修饰的IL-2受体， 细胞，从而能够选择性地输注后体内刺激， 修饰的IL-2配体（orthoIL 2）;我们假设orthoIL 2可以通过维持体内抗-IL-2抗体来预防晚期复发。 BCMA免疫监视。(2)我们将开发编码BCMA的含有mRNA的脂质纳米粒（mRNA- LNP）在免疫抑制性MM外的抗原呈递细胞的背景下呈递BCMA。 我们假设BCMA编码mRNA-LNP可以延长体内抗BCMA免疫， 监测，提供了一种输注后调节CAR T细胞活性的方法， 与已建立的FDA批准的抗BCMA CAR T细胞疗法相结合，具有成本效益。 总的来说，我们提出的研究将产生临床和临床前数据，以支持早期- 阶段临床试验有希望的新方法，以防止复发后，CAR T细胞治疗MM，这是 这是该领域面临的主要临床问题。此外，我们的研究结果可以很容易地转化为其他 癌症类型，包括实体瘤。

PROJECT SUMMARY / ABSTRACT (PROJECT 3) Multiple myeloma (MM) is a hematologic malignancy of bone marrow plasma cells. Even though MM is almost universally fatal, modern therapy has markedly improved survival. Among the most promising new MM therapies are CAR T cells targeting B cell maturation antigen (BCMA). Despite high response rates in patients with advanced disease, however, almost all patients eventually relapse after current-generation anti-BCMA CAR T cells. This proposal furthers a long-term goal to prevent late relapse in MM patients after initial response to CAR T cell therapy. In most cases, BCMA expression is retained at relapse, suggesting loss of anti-BCMA immune surveillance as the primary mode of treatment failure. We and others have found that features of the T cells used for CAR T cell manufacturing predict clinical outcomes, that CAR T cells can occasionally proliferate at late timepoints post-infusion to control progressive disease, and that features of the bone marrow microenvironment predict relapse risk after anti-BCMA CAR T cells. This proposal undertakes new approaches to prevent late MM relapse after CAR T cell therapy; the approache to the clinical and pre-clinical studies is rooted in these prior observations. We will conduct a clinical trial to test the safety and feasibility of therapy with anti-BCMA CAR T cells manufactured from marrow-infiltrating lymphocytes (MIL) rather than the peripheral blood lymphocytes traditionally used in CAR T cell manufacturing. We hypothesize that the BM-homing capability of MILs will enhance trafficking and persistence of CAR T cells in BM. We will also pre-clinically develop two new approaches to modulate CAR T cell activity in vivo post infusion. (1) We will introduce a modified IL-2 receptor into CAR T cells to enable selective post-infusion in vivo stimulation with a pharmacologically administered and orthogonally modified IL-2 ligand (orthoIL2); we hypothesize that orthoIL2 can prevent late relapse by maintaining in vivo anti- BCMA immune surveillance. (2) We will develop BCMA-encoding mRNA-containing lipid nanoparticles (mRNA- LNPs) to present BCMA in the context of antigen-presenting cells outside the immunosuppressive MM microenvironment; we hypothesize that BCMA-encoding mRNA-LNPs can prolong in vivo anti-BCMA immune surveillance, providing an approach to post-infusion modulation of CAR T cell activity that could be rapidly and cost-effectively translated in combination with established, FDA-approved anti-BCMA CAR T cell therapies. Collectively, our proposed studies will generate clinical and pre-clinical data to support the development of early- phase clinical trials promising new approaches to prevent relapse after CAR T cell therapy for MM, which is the primary clinical problem facing the field. In addition, findings from our studies could be readily translated to other cancer types, including solid tumors.