PhI/II Study of CD8-Reduced T Cells for Treatment of MDS or AML IND17305 (12/30/2016)

CD4+T细胞控制着对病毒感染和新生癌症的免疫反应。他们提供了具体的 免疫效应细胞的方向，包括巨噬细胞、B细胞、自然杀伤细胞和CD8+T细胞，以及 赋予适应性免疫系统记忆过去遭遇的能力并快速、 协调、持续的时尚。肿瘤逃脱免疫监视的重大事件是 肿瘤特异性CD4+T细胞的功能性断头，导致抗肿瘤抗体的瘫痪或“衰竭”。 肿瘤效应细胞。在没有CD4+T细胞帮助的情况下，肿瘤特异性CD8+T细胞上调 一种抑制性受体PD-1，不能分泌细胞因子或杀死肿瘤靶点。单克隆 阻断PD-1的抗体为抗肿瘤T细胞“松开刹车”。然而，PD-1封锁攻击了一个 症状而不是逃脱免疫监视的原因：CD4+T细胞的丧失有帮助。确实有 目前还没有已知的方法来逆转患者肿瘤特异性CD4+T细胞的耐受性。幸运的是，CD4+T细胞 来自健康捐赠者的也可以提供同样的指示，以恢复内源性抗肿瘤免疫反应。 这种方法的有效性在最近的一项试验中得到了证明，在该试验中，标准化疗加3剂 不匹配的亲属供者淋巴细胞输注(DLI)产生了80%的完全缓解(CR)和2 一年无病存活率为39%，而目前的治疗方案为43%完全缓解，10%为两年无病 生死存亡。然而，DLI中CD8+T细胞的存在可能与不可接受的毒性有关，如 作为持续的供体细胞植入和致死性移植物抗宿主病(GVHD)。 捐赠者可能会排除家庭捐赠者随后进行异基因干细胞移植的可能性。 约翰霍普金斯大学正在与IND 17305(Cellunova LLC)的赞助商合作开发CD8- 骨髓增生异常综合征患者移植失败后的耗竭、人类白细胞抗原不匹配的非亲缘DLI 去甲基化药物(HMA)或继发性急性髓系白血病患者。标准疗法 包括阿糖胞苷加柔红霉素或伊达阿比星，并在大约20%-50%的患者中诱导CR， 然后成为治疗性异基因干细胞移植的候选者。建议的方法 将GVHD的风险降至最低，并保留了来自家庭的异基因干细胞移植的选择 捐赠者。第一项临床试验将使用标准的3+3设计来确定最大耐受量(MTD) 并为MDS患者队列提供MTD时CR率的估计 HMA不及格。需要监测的主要毒性是CD8耗竭装置的毒性和 供者淋巴细胞。我们预计，非持续性的CD4+T细胞植入将与 在可接受的安全剂量下，淋巴细胞将能够从未刺激的， 在一次分离过程中没有血缘关系的供体。逆转T细胞耗竭和肿瘤特异性反应将 提供将这一新疗法与目前的护理标准进行比较的理由。

CD4+ T cells control the immune response to viral infections and to nascent cancers. They provide specific directions to immunologic effector cells including macrophages, B cells, natural killers, and CD8+ T cells, and endow the adaptive immune system with the capacity to remember past encounters and to respond in a rapid, coordinated, and sustained fashion. The cardinal event in the escape of tumors from immune surveillance is the functional decapitation of tumor-specific CD4+ T cells, resulting in the paralysis, or “exhaustion”, of anti- tumor effector cells. In the absence of CD4+ T cell help, tumor-specific CD8+ T cells upregulate expression of an inhibitory receptor, PD-1, and become unable to secrete cytokines or to kill tumor targets. Monoclonal antibodies that block PD-1 “release the brakes” on anti-tumor T cells. However, PD-1 blockade attacks a symptom and not the cause of the escape from immune surveillance: the loss of CD4+ T cell help. There are no known methods for reversing tolerance in a patient’s tumor specific CD4+ T cells. Fortunately, CD4+ T cells from healthy donors can provide the same instructions to revive the endogenous anti-tumor immune response. The effectiveness of this approach was shown in a recent trial in which standard chemotherapy plus 3 doses of mismatched related donor lymphocyte infusions (DLI) produced a complete remission (CR) in 80% and two- year disease-free survival of 39% compared to current therapy of 43% CR and 10% two-year disease-free survival. However, the presence of CD8+ T cells in the DLI can be associated with unacceptable toxicities such as sustained donor cell engraftment and lethal graft-versus-host disease (GVHD)., and the use of related donors may foreclose the possibility of subsequent allogeneic stem cell transplantation from a family donor. The Johns Hopkins University is collaborating with the sponsor of IND 17305 (Cellunova LLC) to develop CD8- depleted, HLA-mismatched unrelated DLI for patients with myelodysplastic syndrome after failure of hypomethylating agents (HMA) or patients with secondary acute myeloid leukema. Standard therapy comprises cytarabine plus daunorubicin or idarubicin and induces CR in approximately 20-50% of patients, who then become candidates for curative allogeneic stem cell transplantation. The proposed approach minimizes the risk of GVHD and preserves the option of allogeneic stem cell transplantation from a family donor. The first clinical trial will use a standard 3+3 design to establish the maximally tolerated dose (MTD) of donor CD4+ T cells and provide an estimate of the CR rate at the MTD for the cohort of patients with MDS failing HMA. The major toxicities to be monitored are toxicities of the CD8 depletion device and toxicities of the donor lymphocytes. We anticipate that non-sustained engraftment of CD4+ T cells will be associated with an acceptable safety profile at doses of lymphocytes that will be able to be harvested from an unstimulated, unrelated donor in a single apheresis session. Reversal of T cell exhaustion and tumor specific responses will provide the rationale for comparing this novel therapy to the current standard of care.