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）仍然是许多人的唯一治疗方法 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，非释放死亡率（NRM），急性和慢性移植的障碍 - 与宿主病（GVHD）和潜在恶性肿瘤的复发。通过实施后 移植环磷酰胺（PTCY），在约翰·霍普金斯（Johns Hopkins）完成的转化研究计划 金梅尔癌症中心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的患者都有适当匹配，相关或无关的捐助者。 此外，当降低强度调节（RIC）方案后进行给药时，PTCY可以安全， 在75岁以下的患者中进行单倍体（Haplo）BMT。 死亡率（NRM）和慢性GVHD强调了复发的风险，这是我们面临的主要挑战 恶性疾病的患者。因此，在BMT之后抗肿瘤效应的新颖策略拼命 需要。癌症生物学的最新突破和抗肿瘤免疫的分析 证明人免疫系统在癌症的监测和治疗中起着积极作用。 对化学疗法或免疫疗法反应不反应的癌症患者具有免疫系统 要么精疲力尽或毫无生气。 AlloBMT为患者提供健康且功能性的免疫系统 当增强时，可能能够对免疫原性肿瘤抗原做出更有效的反应。的确， 虽然已知供体衍生的肿瘤反应会导致BMT后疾病控制，但它们与之相关 与有害的GVHD。我们假设最佳的移植物与肿瘤（GVT）活性需要特定于肿瘤 / 选择性。通过建立对造血细胞抗原的耐受性，将增强这种活性（极限 GVHD）利用（和增强）靶向肿瘤新抗原的供体衍生的T细胞的响应 （优化GVL活动）。为此，该项目的核心假设是Allobmt的功效可以是 通过开发靶向供体T细胞针对抗原有选择性或由唯一表达的方法改进 肿瘤组织。我们的PTCY平台非常适合利用这种情况，这强调了创新 该建议：大胆（并安全地）扩大RIC HaplobMT的范围，作为有效的免疫疗法平台 对于高风险，反应良好的实体瘤的患者，包括肉瘤（AIM 1），castration抗性 前列腺癌（AIM 2）和HPV+ HPV+鳞状细胞癌（AIM 3） 治愈的机会。如果成功，这项工作的影响将极高。偏向供体的原则 细胞曲目针对肿瘤特异性抗原将为优化BMT的作用打开大门 恶性肿瘤。