GM-CSF secreting tumor cell vaccines to enhance post-transplant anti-CLL immunity

GM-CSF分泌肿瘤细胞疫苗增强移植后抗CLL免疫力

• 批准号: 7394132
• 负责人: Catherine Ju-Ying Wu
• 金额: $ 37.84万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7394132
• 关键词: Acute; Adjuvant; Allogenic; Antibodies; Antibody Formation; Antigens; Autoimmune Responses; Autologous; Autologous Tumor Cell; B-Lymphocytes; Binding; Biological Assay; Biopsy; Cancer Vaccines; Cell Line; Cells; Characteristics; Chronic; Chronic Lymphocytic Leukemia; Clinical; Complement; Condition; Custom; Delayed Hypersensitivity; Development; Disease Progression; Distant; Donor Lymphocyte Infusion; Engineering; Enrollment; Flow Cytometry; Foundations; Generations; Goals; Granulocyte-Macrophage Colony-Stimulating Factor; Hematopoietic Stem Cell Transplantation; Immune; Immune response; Immune system; Immunity; Immunization; Immunoblotting; Immunologic Monitoring; K562 Cells; Lead; Measures; Mediating; Minor Histocompatibility Antigens; Monitor; Neoplasm Metastasis; Patients; Phase I Clinical Trials; Plasma; Protein Microchips; Protocols documentation; Range; Rate; Reaction; Reagent; Recruitment Activity; Safety; Site; Skin; Solid; Source; Surface; T-Lymphocyte; Testing; Therapeutic; Time; Toxic effect; Transplant Recipients; Transplantation; Tumor Antigens; Tumor Immunity; Vaccination; Vaccine Production; Vaccines; base; chemotherapy; cytotoxic; in vitro Assay; innovation; leukemia; neoplastic cell; novel; reconstitution; response; tumor; tumor eradication

DESCRIPTION (provided by applicant): Chronic lymphocytic leukemia (CLL) is susceptible to immune-mediated destruction as demonstrated by observations of the graft-versus-leukemia (GvL) effect after hematopoietic stem cell transplantation and donor lymphocyte infusion (DLI). Our preliminary studies demonstrate that DLI-treated CLL patients who developed GvL without apparent GvHD developed potent polyclonal B cell responses directed against antigens that are highly expressed in CLL and that mostly had perfect sequence identity between host and donor (and hence are not minor histocompatibility antigens). From these observations, we hypothesize that anti-CLL immunity can be further boosted by immunizing post-transplant patients with leukemia antigens combined with an adjuvant. Several unique characteristics of CLL support the rationale of developing this innovative therapeutic approach. Advanced CLL patients typically have high levels of circulating tumor, and thus tumor for vaccine generation is readily harvestable. As CLL patients are inherently immune-deficient, anti-tumor immunity is likely to be more effective after reconstitution of normal donor-derived immunity through allogeneic transplant. Finally, the potentially slow rate of disease progression in CLL patients should allow sufficient time for the development of immunity following transplant combined with several rounds of vaccination. Thus, we are actively recruiting patients to a newly opened phase I trial, in which we will administer irradiated autologous tumor cells as the source of leukemia antigens in combination with irradiated bystander cells expressing GM-CSF to patients with CLL following nonmyeloablative transplant. Studies at the DFCI have shown that local secretion of GM-CSF in the presence of irradiated tumor cells at the vaccination site can lead to destruction of tumor cells at distant sites of metastasis, reflecting development of anti-tumor B and T cell immunity. A recently engineered bystander cell line (called GM-K562 cells) will be used for this trial to secrete high and reproducible levels of GM-CSF at the site of vaccination, thus providing a consistent clinical reagent. In Aim 1, we describe the primary objective of the trial, which is to evaluate safety, toxicity and feasibility of the proposed treatment approach. As we anticipate the toxicity to be low based on previous GM- CSF trials, we will monitor the immunological effects of the vaccine by utilizing a set of assays that we have developed to measure antigen-specific B (Aim 2) and T cell (Aim 3) immunity against CLL-associated antigens. Novel aspects of this trial thus include: 1) vaccination of post-transplant patients with reconstituted immune systems; 2) use of a novel engineered reagent for secretion of GM-CSF; 3) detailed monitoring of anti-CLL immunity using a panel of CLL-associated antigens that we identified as targets of GvL; 4) reduced intensity transplant as a platform for generating effective tumor immunity under acceptable conditions of toxicity. The studies will thus test an important hypothesis, provide a solid basis for further trials of tumor-based vaccines for CLL and further our long-term goal of generating curative, non-toxic immune-based treatment for CLL.

描述（由申请方提供）：慢性淋巴细胞白血病（CLL）对免疫介导的破坏敏感，如造血干细胞移植和供体淋巴细胞输注（DLI）后移植物抗白血病（GvL）效应观察所示。我们的初步研究表明，发生GvL而无明显GvHD的DLI治疗的CLL患者发生了针对CLL中高度表达的抗原的有效多克隆B细胞应答，这些抗原在宿主和供体之间大多具有完美的序列同一性（因此不是次要的组织相容性抗原）。根据这些观察结果，我们假设可以通过用白血病抗原与佐剂联合免疫移植后患者来进一步增强抗CLL免疫力。CLL的几个独特特征支持开发这种创新治疗方法的基本原理。晚期CLL患者通常具有高水平的循环肿瘤，因此用于疫苗生成的肿瘤是容易收获的。由于CLL患者具有先天性免疫缺陷，因此通过同种异体移植重建正常供体来源的免疫后，抗肿瘤免疫可能更有效。最后，CLL患者疾病进展的潜在缓慢速率应允许在移植结合几轮疫苗接种后有足够的时间产生免疫力。因此，我们正在积极招募患者参加一项新开放的I期试验，在该试验中，我们将给予经辐照的自体肿瘤细胞作为白血病抗原的来源，并联合经辐照的表达GM-CSF的旁观者细胞治疗非清髓性移植后的CLL患者。DFCI的研究表明，在疫苗接种部位存在经照射的肿瘤细胞的情况下，局部分泌GM-CSF可导致远处转移部位的肿瘤细胞破坏，反映了抗肿瘤B和T细胞免疫的发展。本试验将使用最近工程化的旁观者细胞系（称为GM-K562细胞），在接种部位分泌高水平且可重现的GM-CSF，从而提供一致的临床试剂。在目的1中，我们描述了试验的主要目的，即评价所提出的治疗方法的安全性、毒性和可行性。由于我们基于先前的GM-CSF试验预期毒性较低，因此我们将通过利用我们开发的一组测定来监测疫苗的免疫学效应，所述测定用于测量针对CLL相关抗原的抗原特异性B（Aim 2）和T细胞（Aim 3）免疫。因此，该试验的新方面包括：1）用重建的免疫系统对移植后患者进行疫苗接种; 2）使用新型工程化试剂分泌GM-CSF; 3）使用我们鉴定为GvL靶标的一组CLL相关抗原详细监测抗CLL免疫; 4）降低强度的移植作为在可接受的毒性条件下产生有效肿瘤免疫的平台。因此，这些研究将测试一个重要的假设，为进一步试验基于肿瘤的CLL疫苗提供坚实的基础，并进一步实现我们的长期目标，即为CLL产生治愈性，无毒的免疫治疗。