Tumor Vaccines in Autologous Bone Marrow Transplantation

自体骨髓移植中的肿瘤疫苗

• 批准号: 6894248
• 负责人: Ivan M. Borrello
• 金额: $ 13.68万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-06-01 至 2006-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6894248
• 关键词: T cell receptor; antigen presenting cell; autologous transplantation; bone marrow transplantation; colony stimulating factor; genetically modified animals; human subject; human therapy evaluation; laboratory mouse; lymphoma; multiple myeloma; neoplasm /cancer immunology; neoplasm /cancer immunotherapy; neoplasm /cancer vaccine; nonhuman therapy evaluation; patient oriented research

Bone marrow transplantation (BMT) has shown considerable clinical benefit in a variety of hematologic diseases. Nevertheless, a significant percentage of patients will relapse following this procedure. While associated with significant immunosuppression, the BMT setting offers many advantages for the integration of vaccine strategies. Our data show highly efficient transfer of anti-tumor immunity through adoptive transfer, effective anti-tumor responses in the post-BMT prior to full immune reconstitution, and suggest a role of BMT in mediating a delay in tolerance induction. Our first protocol will integrate autologous tumor cells with a GM-CSF-producing bystander cell in the peripheral stem cell transplant setting for multiple myeloma. The trial endpoints will monitor tumor-specific responses to vaccination at various time-points either pre- or post-BMT and determine the correlation of tumor-specific responses with immune reconstitution. Critical to effective responses of GM-CSF vaccines is T cell responsiveness and T cell - antigen presenting cell (APC) interactions. We have shown that T cell tolerance is an early event in tumor progression. Overcoming this barrier offers an attractive opportunity in enhancing vaccine efficacy. The second component of this proposal focuses on the development of future strategies aimed at enhancing the T-cell and antigen presenting cell responsiveness. Integration of these findings into a clinical BMT setting could be easily accomplished and will establish the pre-clinical basis for the next generation of clinical protocols.

骨髓移植(BMT)在多种血液病的治疗中显示出相当大的临床效益。然而，有相当大比例的患者会在这一过程中复发。虽然与显著的免疫抑制相关，但骨髓移植设置为疫苗策略的整合提供了许多优势。我们的数据显示，通过过继转移高效地转移了抗肿瘤免疫，在完全免疫重建之前，骨髓移植后的抗肿瘤反应有效，并提示骨髓移植在介导耐受诱导的延迟中发挥了作用。我们的第一个方案将在多发性骨髓瘤的外周干细胞移植环境中整合自体肿瘤细胞和产生GM-CSF的旁观者细胞。试验终点将监测在骨髓移植前或骨髓移植后的不同时间点接种疫苗的肿瘤特异性反应，并确定肿瘤特异性反应与免疫重建的相关性。GM-CSF疫苗有效应答的关键是T细胞应答和T细胞-抗原提呈细胞(APC)的相互作用。我们已经证明T细胞耐受是肿瘤进展的早期事件。克服这一障碍为提高疫苗效力提供了一个诱人的机会。该提案的第二部分侧重于制定未来的战略，旨在提高T细胞和抗原提呈细胞的反应性。将这些发现整合到临床骨髓移植环境中可以很容易地完成，并将为下一代临床方案奠定临床前基础。