BMT in Solid Tumors

实体瘤中的 BMT

• 批准号: 10671626
• 负责人: KENNETH R COOKE
• 金额: $ 14.96万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-21 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10671626
• 关键词: Acute; Adolescent and Young Adult; Adoptive Transfer; Age; Alloantigen; Allogeneic Bone Marrow Transplantation; Allogenic; Androgens; Antigens; Blood; Bone Marrow Transplantation; CD8-Positive T-Lymphocytes; Cancer Biology; Cancer Center; Cells; Characteristics; Childhood; Chimerism; Cyclophosphamide; Diagnosis; Disease; Disparity; Dose; Ensure; Failure; Female; Graft-Versus-Tumor Induction; HPV oropharyngeal cancer; Head and Neck Squamous Cell Carcinoma; Hematologic Neoplasms; Hematopoietic; Hematopoietic Neoplasms; Hematopoietic System; Histocompatibility Antigens; Human; Human Papillomavirus; Human papillomavirus 16; Human papillomavirus 18; Immune checkpoint inhibitor; Immune response; Immune system; Immunity; Immunize; Immunologics; Immunosuppression; Immunotherapy; Incidence; Laboratory Study; Maintenance; Major Histocompatibility Complex; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of prostate; Marrow; Mediating; Methods; Minor; Neoplasm Metastasis; Non-Malignant; Outcome; Patient-Focused Outcomes; Patients; Peripheral Blood Stem Cell; Play; Productivity; Prostate; Prostate-Specific Antigen; Radiation therapy; Reaction; Recurrence; Regimen; Relapse; Risk; Role; Safety; Serotyping; Solid Neoplasm; Specificity; T-Lymphocyte; Testosterone; Therapeutic; Therapeutic Index; Tissues; Toxic effect; Translational Research; Tumor Antigens; Tumor Immunity; Tumor Tissue; Vaccinated; Vaccination; Viral Antigens; Virus; WT1 gene; Work; anti-PD-1; antitumor effect; cancer therapy; castration resistant prostate cancer; cell killing; checkpoint inhibition; chemotherapy; childhood sarcoma; chronic graft versus host disease; conditioning; conventional dosing; curative treatments; disorder control; exhaust; first-in-human; graft vs host disease; graft vs leukemia effect; high risk; human disease; immunogenic; improved; improved outcome; indexing; innovation; men; mortality; neoantigens; novel; novel strategies; oral HPV-positive head and neck cancers; patient population; peripheral blood; pilot trial; post implementation; post-transplant; relapse risk; response; sarcoma; sex; success; survivin; tumor; tumor microenvironment; virus related cancer

SUMMARY: Allogeneic blood or marrow transplantation (alloBMT) remains the only curative treatment for many patients with malignant and non-malignant disorders. The primary challenges limiting the success and scope of alloBMT have included: barriers to donor availability, non-relapse mortality (NRM), acute and chronic graft- versus-host disease (GVHD) and relapse of underlying malignancy. Through the implementation of post- transplantation cyclophosphamide (PTCy), translational research initiatives completed at the Johns Hopkins Kimmel Cancer Center have successfully overcome nearly all of these challenges. The administration of PTCy ensures that nearly every patient in need of a BMT will have a suitably matched, related or unrelated, donor. Moreover, when administered following reduced intensity conditioning (RIC) regimens PTCy allows safe, haploidentical (haplo) BMT to be conducted in patients up to a least age 75. Significant reductions in non-relapse mortality (NRM) and chronic GVHD have underscored the risk of relapse as the major challenge facing our patients with malignant conditions. Hence novel strategies to anti-tumor effects post-BMT are desperately needed. Recent breakthroughs in cancer biology and the analysis of anti-tumor immunity conclusively demonstrate that the human immune system plays an active role in the surveillance and treatment of cancer. Patients with cancers that are not responding to chemotherapy or immunotherapy have an immune system that is either exhausted or lifeless. AlloBMT provides a patient with a healthy and functional immune system that when augmented may be capable of responding more productively to immunogenic tumor antigens. Indeed, while donor-derived, tumor responses are known to contribute to disease control after BMT, they are associated with deleterious GVHD. We postulate optimal graft-versus-tumor (GVT) activity needs to be tumor specific / selective. Such activity would be enhanced by the establishment of tolerance to hematopoietic cell antigens (limit GVHD) while harnessing (and augmenting) the response of donor-derived T cells targeting tumor neoantigens (optimize GVL activity). To this end, the central hypothesis of this project is that the efficacy of alloBMT can be improved by developing methods to target donor T cells against antigens selectively or uniquely expressed by tumor tissue. Our PTCy platform is uniquely suited to exploit this scenario, which underscores the innovation of this proposal: to boldly (and safely) broaden the scope of RIC haploBMT as an effective immunotherapy platform for patients with high-risk, poorly responsive solid tumors including sarcomas (Aim 1), castration-resistant prostate cancer (Aim 2) and HPV+ squamous cell cancers of the head and neck (Aim 3) who have no other chance for cure. If successful, the impact of this work will be extremely high; the principle of biasing the donor T cell repertoire toward tumor-specific antigens will open the door for optimizing the role of BMT to treat all human malignancies.

摘要：同种异体血液或骨髓移植 (alloBMT) 仍然是许多患者的唯一治疗方法 患有恶性和非恶性疾病的患者。限制成功和范围的主要挑战 alloBMT 包括：供体可用性的障碍、非复发死亡率 (NRM)、急性和慢性移植物 抗宿主病（GVHD）和潜在恶性肿瘤的复发。通过实施后 移植环磷酰胺 (PTCy)，约翰·霍普金斯大学完成的转化研究计划 金梅尔癌症中心已经成功克服了几乎所有这些挑战。 PTCy 的管理 确保几乎每个需要 BMT 的患者都会有一个适当匹配的、相关或不相关的捐赠者。 此外，当按照降低强度调节 (RIC) 方案进行 PTCy 治疗时，可以安全、 对年龄不低于 75 岁的患者进行单倍相合 (haplo) BMT。显着降低不复发率 死亡率（NRM）和慢性 GVHD 强调了复发风险是我们面临的主要挑战 患有恶性疾病的患者。因此，迫切需要寻找 BMT 后抗肿瘤效果的新策略。 需要。癌症生物学最新突破及抗肿瘤免疫解析 证明人类免疫系统在癌症的监测和治疗中发挥着积极作用。 对化疗或免疫疗法没有反应的癌症患者的免疫系统 要么精疲力尽，要么毫无生气。 AlloBMT 为患者提供健康且功能齐全的免疫系统 当增强时可能能够更有效地响应免疫原性肿瘤抗原。的确， 虽然已知供体来源的肿瘤反应有助于 BMT 后的疾病控制，但它们与 具有有害的 GVHD。我们假设最佳的移植物抗肿瘤（GVT）活性需要具有肿瘤特异性/ 有选择性的。通过建立对造血细胞抗原的耐受性（限制 GVHD），同时利用（并增强）供体来源的 T 细胞针对肿瘤新抗原的反应 （优化 GVL 活性）。为此，该项目的中心假设是alloBMT的功效可以 通过开发针对供体 T 细胞选择性或独特表达的抗原的方法来改进 肿瘤组织。我们的 PTCy 平台非常适合利用这种场景，这强调了创新 该提案：大胆（且安全）地扩大 RIC haploBMT 作为有效免疫治疗平台的范围 适用于患有高风险、反应不佳的实体瘤（包括肉瘤）（目标 1）、去势抵抗的患者 前列腺癌（目标 2）和 HPV+ 头颈鳞状细胞癌（目标 3）且没有其他疾病 治愈的机会。如果成功，这项工作的影响将非常大；供体T偏向原则 针对肿瘤特异性抗原的细胞库将为优化 BMT 治疗所有人类的作用打开大门 恶性肿瘤。