Immunization of Stem Cell Transplant Donors with Myeloma

利用干细胞移植物的潜在抗肿瘤作用仍然是一个有吸引力的概念。增强移植物抗肿瘤反应而不加重移植物抗宿主病（GVHD）的一种策略是选择性靶向针对限定的肿瘤特异性抗原的免疫应答。这可以通过在过继转移给受体之前，通过主动免疫在干细胞移植（SCT）供体中引发抗肿瘤免疫应答来实现。先前在人SCT中的工作表明，可以发生对临床上重要的病毒抗原的体液和较小程度的细胞抗原特异性免疫从免疫供体转移到受体，这应该有利于转移供体肿瘤抗原特异性免疫的努力。此外，通过高剂量预处理方案在许多患者中可实现的最小残留疾病负担为测试过继免疫治疗的累加效应提供了最佳临床环境。最后，也许也是最令人信服的是，人们可以预测，与患者相比，健康供体对肿瘤抗原的免疫接种将更容易实现，患者可能因潜在疾病或细胞毒性治疗而免疫功能低下，或两者兼而有之。然而，安全性考虑将要求肿瘤疫苗高度精制，由明确定义的抗原组成，并且靶向抗原是真正的肿瘤特异性的。基于我们在两个小鼠模型系统中的临床前研究，我们在多发性骨髓瘤的疾病适应症中开创了这种策略，这为这种方法提供了理论基础。经FDA批准，一名患有难治性骨髓瘤（M蛋白3.9 g/dl，50%骨髓浆细胞增多症）的女性的HLA匹配的兄弟接受了两次皮下注射。在骨髓收获前以一周的间隔免疫骨髓瘤Id-KLH（Lancet 345：1016 - 20，1995）。T细胞免疫转移的证明是通过回收从受体血液中产生的CD4+、供体来源的、独特型特异性T细胞系来提供的。基于上述研究的单个患者的令人鼓舞的结果，与阿肯色州大学（作为临床移植中心）合作，根据批准的FDA IND，在多发性骨髓瘤中开展了骨髓供体免疫的临床试验。本临床方案和未来的临床方案旨在探索接受者的加强免疫是否可以改善转移的独特型特异性应答的效力和持续时间，并将支持以下两个具体的子目标。迄今为止，该方案已招募了另外五对供体-受体。在DETI开设一个专门的SCT单位的同时，与Michael Bishop，M.D.联合开发了一个完全基于DETI的新的试点临床方案。以取代现有的协议。这一新方案将两项补充纳入供体疫苗接种策略，旨在进一步优化T细胞免疫从供体到受体的转移。首先，将使用非清髓性预处理方案，与稍微减弱的GVHD预防相关，GVHD预防是供体肿瘤抗原特异性T细胞转移的潜在障碍。第二，干细胞来源将是用G-CSF动员的血液，而不是骨髓。由于同种异体移植物中T细胞的比例较大，使用外周血作为转移元件可能会潜在地增强肿瘤免疫的转移。该项目的长期目标是将高度富集的独特型特异性T细胞群体从供体转移到受体（例如肿瘤特异性DLI）。在未来几年中，将探索体外扩增引发的供体T细胞的方法，以及体外引发供体T细胞独特型的方法，后者作为接种健康供体的潜在替代方法。(This项目以前与ID Z01 SC 009397 M相关。）

Exploiting the potential anti-tumor effect of stem cell grafts remains an attractive concept. One strategy for enhancing graft vs. tumor reactions without aggravating graft vs. host disease (GVHD) would be to selectively target an immune response against a defined tumor specific antigen. This could be accomplished by eliciting an anti-tumor immune response in stem cell transplant (SCT) donors by active immunization, prior to adoptive transfer to the recipient. Previous work in human SCT, demonstrating that the transfer of humoral, and to a lesser extent cellular, antigen-specific immunity to clinically important viral antigens from immune donors to recipients can occur, should favor efforts to transfer donor tumor antigen-specific immunity. In addition, the minimal residual disease burden achievable in many patients by high dose conditioning regimens provides an optimal clinical setting to test the additive effect of adoptive immunotherapy. Finally, and perhaps most compelling, one would predict that immunization of a healthy donor against a tumor antigen would be more easily accomplished, compared with the patient, who may be immunocompromised from the underlying disease or cytotoxic treatment, or both. However, safety considerations would mandate that the tumor vaccine be highly refined, consisting of a well-defined antigen, and that the targeted antigen be truly tumor-specific. Based on our preclinical studies in two murine model systems which provided the rationale for this approach, we pioneered this strategy in the disease indication of multiple myeloma. With FDA approval, the HLA-matched brother of a woman with refractory myeloma (M-protein 3.9 g/dl, 50% marrow plasmacytosis) received two s.c. immunizations of myeloma Id-KLH at one week intervals before marrow harvest (Lancet 345:1016-20, 1995). The demonstration of transfer of T-cell immunity was provided by the recovery of a CD4+, donor-derived, idiotype-specific T-cell line generated from the recipient's blood. Building on the encouraging results from the single patient studied above, a clinical trial of marrow donor immunization in multiple myeloma was opened under an approved FDA IND in collaboration with the University of Arkansas (as the clinical transplantation site). This and future clinical protocols have been designed to explore whether a booster immunization of the recipient might improve the potency and duration of the transferred idiotype-specific response and will support the two specific subaims below. To date, five additional donor-recipient pairs have been enrolled on this protocol. Coincident with the opening of a dedicated SCT unit in the DETI, a new pilot clinical protocol, based entirely within the DETI, has been developed jointly with Michael Bishop, M.D. to replace the existing protocol. This new protocol incorporates two additions to the strategy of donor vaccination which are designed to further optimize the transfer of T-cell immunity from donor to recipient. First, a non-myeloablative conditioning regimen will be used, associated with somewhat attenuated GVHD prophylaxis, which is a potential barrier to transfer of donor tumor antigen-specific T cells. Second, instead of marrow, the stem cell source will be blood mobilized with G-CSF. Because of the larger proportion of T cells in the allograft, the use of peripheral blood as the transfer element could potentially enhance the transfer of tumor immunity. The longterm goal of this project is to transfer highly enriched populations of idiotype-specific T cells from donor to recipient (e.g. tumor-specific DLI). In future years, methods of expansion of primed, donor T cells in vitro will be explored, as well as priming of donor T cells to idiotype in vitro, the latter as a potential alternative to vaccinating healthy donors. (This project was formerly associated with ID Z01 SC 009397 M.)