BMT in Solid Tumors

摘要：异基因血液或骨髓移植(AllBMT)仍然是许多疾病的唯一治愈方法。 有恶性和非恶性疾病的患者。限制成功和范围的主要挑战 异基因骨髓移植包括：供者可获得性障碍，无复发死亡率(NRM)，急性和慢性移植物- 抗宿主病(GVHD)和潜在恶性肿瘤的复发。通过实施员额-- 移植环磷酰胺(PTCy)，在约翰霍普金斯大学完成的翻译研究倡议 坎摩尔癌症中心已经成功地克服了几乎所有这些挑战。PTCy的给药情况 确保几乎每个需要骨髓移植的患者都有合适的匹配的、相关的或不相关的捐赠者。 此外，当在降低强度调节(RIC)方案之后给药时，PTCy允许安全， 对年龄不低于75岁的患者进行半相合(Haplo)骨髓移植。非复发率大幅下降 死亡率(NRM)和慢性移植物抗宿主病(GVHD)强调了复发的风险是我们面临的主要挑战 患有恶性疾病的患者。因此，骨髓移植后抗肿瘤作用的新策略亟待解决 需要的。肿瘤生物学最新突破与抗肿瘤免疫分析综述 证明人类免疫系统在癌症监测和治疗中发挥积极作用。 对化疗或免疫治疗无效的癌症患者的免疫系统 要么筋疲力尽，要么死气沉沉。AllBMT为患者提供了健康和功能正常的免疫系统 当增强时，可能能够更有效地对免疫原性肿瘤抗原做出反应。的确， 虽然已知供者来源的肿瘤反应有助于骨髓移植后的疾病控制，但它们是相关的 患有有害的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。 有选择性的。这种活性将通过建立对造血细胞抗原的耐受性来增强(限制 GVHD)，同时利用(和增强)供者来源的T细胞针对肿瘤新抗原的反应 (优化GVL活动)。为此，该项目的中心假设是，allBMT的疗效可以是 通过开发针对供体T细胞选择性或唯一表达的抗原的方法进行了改进 肿瘤组织。我们的PTCy平台非常适合利用这一场景，这突显了 这一建议：大胆(和安全地)扩大RIC单倍体骨髓移植的范围，作为一个有效的免疫治疗平台 对于包括肉瘤(AIM 1)在内的高危、反应差的实体肿瘤患者，耐阉割 前列腺癌(目标2)和头颈部HPV阳性鳞状细胞癌(目标3)，没有其他 治愈的机会。如果成功，这项工作的影响将是非常高的；偏袒捐赠者T的原则 肿瘤特异性抗原的细胞库将为优化骨髓移植治疗全人类的作用打开大门 恶性肿瘤。

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.