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，也可以产生产生成熟细胞的祖细胞。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，这些癌细胞对癌症药物和辐射比CSC更敏感。因此，一些CSC在治疗中存活，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，所有癌症及其CSC都通过表达“不要吃我”的信号（称为CD 47）来保护自己，该信号可以防止先天免疫系统巨噬细胞吃掉并杀死它们。我们开发了一种新的疗法（抗CD 47阻断抗体），使巨噬细胞能够消除CSC和它们产生的肿瘤。这种CIRM赠款系统-管理https://grants.cirm.ca.gov/applicant/grant_app/print/3385抗CD 47抗体消除人类癌症干细胞时，患者癌症在小鼠中生长。在资助这项提案时，我们将满足FDA/MHRA的要求，将这种抗体纳入临床试验，在动物模型中显示抗体是安全的和耐受性良好的，并且我们可以按照MHRA/FDA的规格生产用于人类的抗体。我们建议进行抗CD 47抗体的初步临床研究，在患有急性髓性白血病（AML）或单独的多种实体瘤的患者中进行的人类I期临床试验，这些患者不再是常规疗法的候选者或没有进一步的标准疗法。我们的I期临床试验的主要目的是评估抗CD 47抗体的安全性和耐受性。这些试验旨在确定最多42名AML患者和最多70名实体瘤患者接受抗CD 47抗体的最大耐受剂量和最佳给药方案。虽然将对患者进行停止疾病进展的临床评价，但由于晚期疾病和患者数量少，并且因为不知道如何最佳地施用抗体，因此在I期试验中这种临床应答是罕见的。后续进展至II期临床试验将涉及向更多患者给予最佳给药方案。这些II期试验对于评估抗CD 47抗体延迟疾病进展或引起临床应答（包括完全缓解）的能力至关重要。除了作为独立疗法外，抗CD 47抗体在临床前癌症模型中显示出与批准的抗癌疗法组合以显著根除疾病的前景。因此，我们未来的临床计划包括在IB/II期研究中使用目前批准的产生部分应答的癌症治疗剂测试抗CD 47抗体。最终，我们希望抗CD 47抗体治疗将在没有显著毒性的情况下提供持久的临床应答。

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.