Tumor Vaccines in Autologous Bone Marrow Transplantation

骨髓移植（BMT）在多种血液病中显示出相当大的临床疗效。然而，很大比例的患者会在手术后复发。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，通过过继性转移，抗肿瘤免疫的高效转移，在完全免疫重建之前，BMT后有效的抗肿瘤反应，并提示BMT在介导耐受诱导延迟中的作用。我们的第一个方案是将自体肿瘤细胞与产生gm - csf的旁观者细胞整合在多发性骨髓瘤的外周干细胞移植环境中。试验终点将监测bmt前后不同时间点对疫苗接种的肿瘤特异性反应，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）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。本建议的第二个组成部分侧重于旨在增强t细胞和抗原提呈细胞反应性的未来策略的发展。将这些发现整合到临床BMT设置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.