Adoptive Immunotherapy for Multiple Myeloma Using Educated T Cells

自体干细胞移植治疗多发性骨髓瘤（MM）可有效减少细胞数量，但患者随后复发。一个有希望的研究领域是开发癌症疫苗，其教育宿主免疫选择性靶向和消除MM细胞，并可用于根除自体干细胞移植后的残留疾病。我们已经开发了一种癌症疫苗，其中树突状细胞（DC）融合到自体肿瘤细胞，导致呈现具有引起广泛抗肿瘤应答的能力的多种肿瘤抗原。在晚期MM患者的临床试验中，自体DC/MM融合疫苗接种在大多数患者中诱导了抗肿瘤免疫，疾病稳定范围为10周至36个月。在一项正在进行的MM患者试验中，接受DC/肿瘤融合疫苗接种联合干细胞移植，我们已经证明了骨髓瘤反应性T细胞的显着扩增，并伴随着疫苗接种后移植后残留疾病的根除。为了克服限制疫苗应答的内在免疫抑制环境和调节性T细胞，我们正在开发将过继性免疫疗法与MM反应性T细胞克隆结合的策略。一种方法是在干细胞收集之前使用疫苗接种，使得受教育的淋巴细胞在移植时输注，并通过移植后疫苗接种在体内进一步扩增。或者，过继性免疫疗法可以通过离体产生具有活化表型的MM特异性T细胞来进一步优化。我们已经发现，在用DC/MM融合疫苗离体刺激后，CD 3/CD 28的连接导致活化的肿瘤反应性T细胞的急剧扩增，同时使调节性T细胞的存在最小化。我们的假设是，将移植介导的细胞减少和调节性T细胞耗竭与活化的肿瘤反应性淋巴细胞的输注和DC/MM融合物的加强疫苗接种相结合，为MM的优化细胞免疫治疗提供了理想的平台。为了解决这一假设，具体目的是：1）评估DC/MM联合疫苗接种和体内过继转移的毒性、细胞和体液抗肿瘤免疫以及临床应答。 致敏T细胞; 2）使用DC/MM融合物和抗-CD 3/CD 28离体的顺序刺激优化骨髓瘤特异性T细胞的离体扩增的策略;和3）确定与移植前和移植后用DC/MM融合物疫苗接种联合施用的离体产生和扩增的骨髓瘤特异性T细胞的毒性、免疫应答和临床效果。

Autologous stem cell transplantation for multiple myeloma (MM) results in effective cytoreduction but patients subsequently relapse. A promising area of investigation is the development of cancer vaccines that educate host immunity to selectively target and eliminate MM cells and can be used to eradicate residual disease following autologous stem cell transplantation. We have developed a cancer vaccine in which dendritic cells (DC) are fused to autologous tumor cells resulting in the presentation of multiple tumor antigens with the capacity to elicit a broad anti-tumor response. In a clinical trial of patients with advanced MM, vaccination with autologous DC/MM fusions induced anti-tumor immunity in a majority of patients, and disease stabilization ranging from 10 weeks to 36 months. In an ongoing trial of MM patients undergoing DC/tumor fusion vaccination in conjunction with stem cell transplantation, we have demonstrated a marked expansion of myeloma reactive T cells with the concomitant eradication of post-transplant residual disease following vaccination. To overcome the intrinsic immunosuppressive environment and regulatory T ceils that limit vaccine response, we are developing strategies to incorporate adoptive immunotherapy with MM reactive T cell clones. One approach is the use of vaccination prior to stem cell collection such that educated lymphocytes are infused at the time of transplant and further expanded in vivo by post-transplant vaccination. Alternatively, adoptive immunotherapy may be further optimized by ex-vivo generation of MM specific T cells with an activated phenotype. We have found that ligation of CD3/CD28 following ex vivo stimulation with DC/MM fusion vaccine results in the dramatic expansion of activated tumor reactive T cells while minimizing the presence of regulatory T cells. Our hypothesis is that combining transplant mediated cytoreduction and regulatory T cell depletion with the infusion of activated tumor reactive lymphocytes and boosting vaccination with DC/MM fusions offers the ideal platfomn for optimized cellular immunotherapy in MM. To address this hypothesis the Specific Aims are: 1) To evaluate toxicity, cellular and humoral antitumor immunity, and clinical response of a combined DC/MM vaccination and adoptive transfer of in vivo primed T cells; 2) To optimize strategies for the ex vivo expansion of myeloma specific T cells using sequential stimulation with DC/MM fusions and anti-CD3/CD28 ex vivo; and 3) To define the toxicity, immunologic response and clinical effect of ex vivo generated and expanded myeloma specific T cells administered in conjunction with pre and post-transplant vaccination with DC/MM fusions.