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。 恶性和非恶性疾病患者。限制成功和范围的主要挑战 alloBMT包括：供体可用性障碍、非复发死亡率（NRM）、急性和慢性移植物- 抗宿主病（GVHD）和潜在恶性肿瘤复发。通过实施后 移植环磷酰胺（PTCy），在约翰霍普金斯完成的转化研究计划 Kimmel癌症中心成功地克服了几乎所有这些挑战。PTCy的给药 确保几乎每一个需要骨髓移植的病人都有一个合适的匹配的，相关的或不相关的供体。 此外，当在降低强度预处理（RIC）方案后施用时，PTCy允许安全， 在最小年龄75岁的患者中进行单倍相合（haplo）BMT。非复发率显著降低 死亡率（NRM）和慢性GVHD强调复发的风险是我们面临的主要挑战。 恶性肿瘤患者。因此，BMT后抗肿瘤作用的新策略迫切需要 needed.癌症生物学的最新突破和抗肿瘤免疫的分析 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。 对化疗或免疫疗法无反应的癌症患者的免疫系统 不是精疲力竭就是毫无生气AlloBMT为患者提供健康和功能性免疫系统， 当增强时，能够更有效地应答免疫原性肿瘤抗原。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 有害的GVHD我们假设最佳的移植物抗肿瘤（GVT）活性需要是肿瘤特异性的。 选择性的这种活性将通过建立对造血细胞抗原的耐受性而增强（限制性免疫）。 GVHD），同时利用（和增强）靶向肿瘤新抗原的供体来源的T细胞的应答 （优化GVL活性）。为此，该项目的中心假设是，alloBMT的功效可以被 通过开发靶向供体T细胞对抗抗原的方法来改进，所述抗原选择性地或独特地由 肿瘤组织我们的PTCy平台非常适合利用这种情况，这强调了 这一建议：大胆（安全）地扩大RIC haploBMT作为有效免疫治疗平台的范围 对于高风险、反应差的实体瘤患者，包括肉瘤（Aim 1），去势抵抗性 前列腺癌（目标2）和HPV+头颈部鳞状细胞癌（目标3）， 治愈的机会如果成功，这项工作的影响将是极高的;偏向捐助者T的原则 针对肿瘤特异性抗原的细胞库将为优化BMT的作用打开大门， 恶性肿瘤。