Clinical Investigation of a Humanized Anti-CD47 Antibody in Targeting Cancer Stem Cells in Acute Myelodi Leukaemia (and Solid Tumours).

大多数正常组织由少量干细胞维持，这些干细胞既可以自我更新以维持干细胞数量，也可以产生生成成熟细胞的祖细胞。我们已经证明，正常干细胞可以积累突变，导致祖细胞自我更新失控，形成癌症干细胞(CSC)。CSC使肿瘤由癌细胞组成，这些癌细胞比CSC对抗癌药物和辐射更敏感。因此，一些CSC在治疗后存活下来，并生长和扩散。我们试图找到包括所有CSC作为靶点的治疗方法。我们发现，所有的癌症及其CSC都通过表达一种名为CD47的信号来保护自己，这种信号可以防止天生免疫系统的巨噬细胞吞噬并杀死它们。我们已经开发出一种新的治疗方法(抗CD47封闭抗体)，使巨噬细胞能够消除CSC及其产生的肿瘤。当病人的癌症在小鼠体内生长时，这种CIRM授予系统管理https://grants.cirm.ca.gov/applicant/grant_app/print/3385抗CD47抗体消除人类癌症干细胞。在为这项提议提供资金时，我们将已经满足FDA/MHRA的要求，将这种抗体投入临床试验，在动物模型中显示该抗体是安全的和耐受性良好的，我们可以根据MHRA/FDA的规范制造它用于人类给药。在此，我们建议在急性髓系白血病(AML)患者或不再适合常规治疗或没有进一步标准治疗的多种实体肿瘤患者中进行平行的人类第一阶段临床试验的初步临床研究。我们第一阶段临床试验的主要目标是评估抗CD47抗体的安全性和耐受性。这些试验旨在确定42名AML患者和70名实体瘤患者服用抗CD47抗体的最大耐受量和最佳剂量方案。虽然将对患者进行临床评估以阻止疾病进展，但由于疾病晚期和患者数量较少，而且还不知道如何以最佳方式给药抗体，这种临床反应在I期试验中很少见。随后进行的第二阶段临床试验将涉及对更多的患者进行最佳剂量方案的管理。这些第二阶段试验对于评估抗CD47抗体延缓疾病进展或引起临床反应(包括完全缓解)的能力至关重要。除了作为一种单独的治疗方法，抗CD47抗体还在临床前癌症模型中显示出与经批准的抗癌疗法相结合的前景，以显著根除疾病。因此，我们未来的临床计划包括在IB/II期研究中用目前批准的产生部分反应的癌症治疗药物测试抗CD47抗体。最终，我们希望抗CD47抗体治疗将在没有显著毒性的情况下提供持久的临床反应。

Most normal tissues are maintained by a small number of stem cells that can both self-renew to maintain stem cell numbers, and also give rise to progenitors that make mature cells. We have shown that normal stem cells can accumulate mutations that cause progenitors to self-renew out of control, forming cancer stem cells (CSC). CSC make tumors composed of cancer cells, which are more sensitive to cancer drugs and radiation than the CSC. As a result, some CSC survive therapy, and grow and spread. We sought to find therapies that include all CSC as targets. We found that all cancers and their CSC protect themselves by expressing a 'don't eat me' signal, called CD47, that prevents the innate immune system macrophages from eating and killing them. We have developed a novel therapy (anti-CD47 blocking antibody) that enables macrophages to eliminate both the CSC and the tumors they produce. This CIRM Grants System - Administration https://grants.cirm.ca.gov/applicant/grant_app/print/3385 anti-CD47 antibody eliminates human cancer stem cells when patient cancers are grown in mice. At the time of funding of this proposal, we will have fulfilled FDA/MHRA requirements to take this antibody into clinical trials, showing in animal models that the antibody is safe and well-tolerated, and that we can manufacture it to MHRA/FDA specifications for administration to humans.Here, we propose the initial clinical investigation of the anti-CD47 antibody with parallel first-in-human Phase 1 clinical trials in patients with either Acute Myelogenous Leukemia (AML) or separately a diversity of solid tumors, who are no longer candidates for conventional therapies or for whom there are no further standard therapies. The primary objectives of our Phase I clinical trials are to assess the safety and tolerability of anti-CD47 antibody. The trials are designed to determine the maximum tolerated dose and optimal dosing regimen of anti-CD47 antibody given to up to 42 patients with AML and up to 70 patients with solid tumors. While patients will be clinically evaluated for halting of disease progression, such clinical responses are rare in Phase I trials due to the advanced illness and small numbers of patients, and because it is not known how to optimally administer the antibody. Subsequent progression to Phase II clinical trials will involve administration of an optimal dosing regimen to larger numbers of patients. These Phase II trials will be critical for evaluating the ability of anti-CD47 antibody to either delay disease progression or cause clinical responses, including complete remission. In addition to its use as a stand-alone therapy, anti-CD47 antibody has shown promise in preclinical cancer models in combination with approved anti-cancer therapeutics to dramatically eradicate disease. Thus, our future clinical plans include testing anti-CD47 antibody in Phase IB/II studies with currently approved cancer therapeutics that produce partial responses. Ultimately, we hope anti-CD47 antibody therapy will provide durable clinical responses in the absence of significant toxicity.