Tumor Vaccines in Autologous Bone Marrow Transplantation

骨髓移植（BMT）已显示出相当大的临床效益，在各种血液病。然而，相当大比例的患者在这种手术后会复发。虽然与显著的免疫抑制相关，但BMT环境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，有效的抗肿瘤免疫转移后，BMT完全免疫重建前的有效的抗肿瘤反应，并建议在介导延迟耐受诱导的BMT的作用。我们的第一个方案将在多发性骨髓瘤的外周血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BMT前或后不同时间点对疫苗接种的肿瘤特异性应答，并确定肿瘤特异性应答与免疫重建的相关性。GM-CSF疫苗的有效应答的关键是T细胞应答性和T细胞-抗原呈递细胞（APC）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有吸引力的机会。该提案的第二部分侧重于开发旨在增强T细胞和抗原呈递细胞反应性的未来策略。将这些发现整合到临床BMT环境中可以很容易地完成，并将为下一代临床方案建立临床前基础。

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.