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

CD 4 + T细胞控制对病毒感染和新生癌症的免疫反应。他们提供具体的 免疫效应细胞包括巨噬细胞、B细胞、自然杀伤细胞和CD 8 + T细胞，以及 赋予适应性免疫系统记住过去遭遇的能力， 协调和持续的方式。肿瘤逃脱免疫监视的主要事件是 肿瘤特异性CD 4 + T细胞的功能性断头，导致抗-CD 4 + T细胞的麻痹或“耗尽”， 肿瘤效应细胞在没有CD 4 + T细胞帮助的情况下，肿瘤特异性CD 8 + T细胞上调了CD 8 + T细胞的表达。 抑制性受体PD-1，并变得不能分泌细胞因子或杀死肿瘤靶点。单克隆 阻断PD-1的抗体在抗肿瘤T细胞上“释放刹车”。然而，PD-1封锁攻击 症状，而不是逃避免疫监视的原因：CD 4 + T细胞的损失帮助。有 没有已知的逆转患者肿瘤特异性CD 4 + T细胞耐受性的方法。幸运的是，CD 4 + T细胞 可以提供相同的指令以恢复内源性抗肿瘤免疫应答。 最近的一项试验显示了这种方法的有效性，在该试验中，标准化疗加3剂 不匹配的相关供体淋巴细胞输注（DLI）在80%和20%的患者中产生完全缓解（CR）。 1年无病生存率为39%，而当前治疗的CR率为43%，2年无病生存率为10% 生存然而，DLI中CD 8 + T细胞的存在可能与不可接受的毒性相关，例如 如持续的供体细胞植入和致命的移植物抗宿主病（GVHD）。和使用有关的 供者可能排除来自家庭供者的后续同种异体干细胞移植的可能性。 约翰霍普金斯大学正在与IND 17305（Cellunova LLC）的申办者合作开发CD 8- 骨髓增生异常综合征患者在治疗失败后， 低甲基化剂（HMA）或继发性急性髓性白血病患者。标准疗法 包括阿糖胞苷加柔红霉素或伊达比星，并在约20-50%的患者中诱导CR， 这些人将成为治疗性异基因干细胞移植的候选人。所提出的方法 最大限度地减少GVHD的风险，并保留来自家族的异基因干细胞移植的选择 供体第一个临床试验将使用标准的3+3设计来确定最大耐受剂量（MTD）。 供体CD 4 + T细胞，并提供MDS患者队列MTD时的CR率估计值 失败的HMA待监测的主要毒性是CD 8耗竭装置的毒性和CD 8耗竭装置的毒性。 供体淋巴细胞我们预期，CD 4 + T细胞的非持续植入将与 在能够从未刺激的， 一个无关的捐赠者在一个单一的单采阶段。T细胞耗竭和肿瘤特异性应答的恢复将 提供了将这种新疗法与当前标准治疗进行比较的依据。

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.