Building on the success of the adoptive immunotherapy of cancer

以癌症过继免疫疗法的成功为基础

• 批准号: 7965621
• 负责人: Nicholas Restifo
• 金额: $ 178.23万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7965621
• 关键词: Ablation; Adoptive Cell Transfers; Adoptive Immunotherapy; Adoptive Transfer; Advanced Malignant Neoplasm; Affinity; Allogenic; Animal Model; Antibodies; Antigen Targeting; Antigen-Presenting Cells; Apoptotic; Autoantigens; Automobile Driving; Back; Bacterial Translocation; Biotechnology; CD8B1 gene; Cancer Histology; Cancer Vaccines; Cell Death; Cell Differentiation process; Cell division; Cell surface; Cells; Clinical Trials; Clinical effectiveness; Collaborations; Complementarity Determining Regions; Development; Dose; Employment; Engineering; Environment; Epitopes; Excision; Generations; Genes; Genetic; Goals; HLA-A2 Antigen; Homing; Human; Immune; Immune response; Immune system; Immunosuppressive Agents; Immunotherapy; In Vitro; Inflammatory; Interleukin 2 Receptor Gamma; Interleukin-15; Interleukin-2; Interleukin-7; Lentivirus Vector; Malignant Neoplasms; Mediating; Memory; Modification; Molecular; Mus; Mutate; National Cancer Institute; Pathway interactions; Patients; Phage Display; Population; Process; Proliferating; Property; Protocols documentation; Radiation; Refractory; Research Personnel; Scientist; Shapes; Signal Transduction; Surface; T-Cell Activation; T-Cell Proliferation; T-Lymphocyte; T-Lymphocyte Subsets; TLR4 gene; Testing; Therapeutic; Toll-like receptors; Transgenic Mice; Translating; Treatment Protocols; Tumor Antigens; Vaccine Design; Vaccines; base; chemokine receptor; chemotherapy; cytokine; cytokine therapy; density; design; improved; in vitro Assay; in vitro activity; in vivo; lymph nodes; man; melanoma; mouse model; neoplastic cell; peripheral blood; preclinical study; preconditioning; programs; receptor; response; standard care; success; telomere; tumor

Adoptive immunotherapy for cancer: building on success Nicholas P. Restifo, MD, National Cancer Institute Substantial progress has been made in our understanding of the molecular and cellular bases of T cell mediated anti-tumor responses. T cells are potent effectors of the adaptive anti-tumor immune response. Some target antigens recognized by tumor-reactive CD8+ T cells are non-mutated self-antigens that are also expressed by tumor cells. The molecular signals that modulate T cell activation, function and memory are being elucidated. Both positive and negative signals from co-stimulatory molecules have been shown to shape the anti-tumor response. Cytokines, including those with receptors that contain the common cytokine-receptor gamma chain have been shown to alter the programming of effector CD8+ T cells. Therapeutic cancer vaccines, designed to activate the anti-tumor immune response in vivo are still under development. Adoptive cell transfer (ACT) therapies activate T cells ex vivo prior to the transfer back to patients. Preclinical studies have indicated that immune ablation is an effective preconditioning regimen that can increase T cell responses after adoptive transfer. Adoptive transfer of anti-tumor T cell after non-myeloablative but lymphodepleting systemic chemotherapy can induce clear and reproducible responses in a substantial percentage (50%) of treated patients who have multivisceral, bulky melanoma that is refractory to standard treatments including chemotherapy, radiation and cytokine therapies. The specific mechanisms that contribute to the impact of a lymphodepleting pre-conditioning regimen are now being elucidated. Although it seems counter-intuitive that the efficacy of ACT-based tumor immunotherapy can be improved by the removal of the host immune system, several mechanisms might underlie the augmented efficacy of tumor-reactive T cells in the lymphopenic environment. These factors include the elimination of immunosuppressive cells such as CD4+CD25+ regulatory T (TReg) cells, the depletion of endogenous cells that compete for activating cytokines and the increased function and availability of antigen-presenting cells (APCs) due to the activation of toll-like receptors, specifically the engagement of TLR4 that results from bacterial translocation. Emerging findings from both mouse studies and clinical trials indicate that intrinsic properties related to the differentiation state of the adoptively transferred T cell populations are critical to the success of ACT-based approaches. CD8+ T cell subsets in both mice and humans are characterized by a progressive pathway of CD8+ T cell differentiation. Mouse models indicate that CD8+ T cells that acquired terminal effector properties have increased anti-tumor activity in vitro but are less effective at triggering tumor regression in vivo. Less differentiated, central-memory-like T cells might proliferate and become fully activated in the lymphopenic environment, which is rife with homeostatic cytokines such as IL-7 and IL-15. Evidence in humans indicates that the expression of CD27 and long telomeres by adoptively transferred T cells are associated with clinical effectiveness. Findings in mice emphasize that early effector T cells are more effective than late effector T cells. In humans, standard rapid expansion protocols that employ CD3-specific antibody and high-doses of IL-2 with irradiated allogeneic feeder cell may result in the differentiation of tumor-specific CD8+ T cells to an intermediate and late effector state. Cytokines, acting in concert with signals through the TCR and co-stimulatory molecules, can function as accelerators or brakes for T cell proliferation and differentiation. IL-2 has been shown to be an effective T cell growth factor but has undesirable effects including the ability to decrease the expression of lymph node homing molecules and promote the terminal differentiation of T cells, predisposing them to activation-induced cell death. Other cytokines with a receptor that contains c such as IL-7, IL-15 and IL-21 may be useful in vitro and in vivo as support for the activation or proliferation of tumor-reactive CD8+ T cell populations for ACT. Tumor-specific T cells can be generated by genetically engineering mature peripheral blood T cells in mouse and in man. The affinity of the TCR selected for transduction, the level of transduced TCR expressed on the cell surface and the differentiation state of the transduced T cells used for ACT might critically contribute to the success of trials following TCR transduction. Naturally occurring T cells expressing high affinity TCRs specific for self/tumor antigens might be difficult to obtain owing to intra-thymic deletion, however generation of high affinity TCRs can be performed in vivo in immunized HLA-A2 transgenic mice or in vitro by phage display of TCRs containing degenerate complementarity-determining regions. Integration of retrovirally-delivered sequences requires active division of target cells, a process that also promotes T cell differentiation but lentiviral vectors are less dependent upon active cell division and might be used to transduce high-affinity TCRs into T cells without driving differentiation. Delivery of both the alpha and beta chains of the TCR directs expression of the intact TCR, however, pairing with endogenous TCR alpha and beta chains can occur, thereby reducing the surface density of tumor-specific TCR. Genes other that TCR have been proposed for transduction of tumor-reactive T cells in order to improve their quality and functionality, including co-stimulatory molecules, anti-apoptotic molecules, pro-inflammatory or homeostatic cytokines and chemokine receptors. Transduction with genes encoding TCRs specific for known epitopes allows the concurrent employment of vaccines in order to enhance the anti-tumor response of adoptively transferred T cells. Most importantly, the genetic modification of anti-tumor T cells makes it possible for Immunotherapies to treat virtually any cancer histology.

Nicholas P. Restifo，医学博士，美国国家癌症研究所我们对T细胞介导的抗肿瘤反应的分子和细胞基础的理解已经取得了实质性进展。T细胞是适应性抗肿瘤免疫反应的有效效应器。肿瘤反应性CD8+ T细胞识别的一些靶抗原是非突变的自身抗原，也可由肿瘤细胞表达。调节T细胞活化、功能和记忆的分子信号正在被阐明。来自共刺激分子的积极和消极信号已被证明可以形成抗肿瘤反应。细胞因子，包括那些含有常见细胞因子受体γ链的受体，已被证明可以改变效应CD8+ T细胞的编程。旨在激活体内抗肿瘤免疫反应的治疗性癌症疫苗仍在开发中。过继细胞转移（ACT）疗法在体内激活T细胞，然后再转移回患者体内。临床前研究表明，免疫消融是一种有效的预处理方案，可以增加过继转移后的T细胞反应。在非清髓性但淋巴消耗性全身化疗后，抗肿瘤T细胞过继转移可在相当大比例（50%）的多脏器大体积黑色素瘤患者中诱导明确且可重复的反应，这些患者对包括化疗、放疗和细胞因子治疗在内的标准治疗难以耐受。导致淋巴消耗预处理方案影响的具体机制目前正在阐明。尽管基于act的肿瘤免疫治疗的疗效可以通过去除宿主免疫系统来提高，这似乎是违反直觉的，但有几种机制可能是肿瘤反应性T细胞在淋巴细胞减少环境中增强疗效的基础。这些因素包括免疫抑制细胞（如CD4+CD25+调节性T （TReg）细胞）的消除，竞争激活细胞因子的内源性细胞的消耗，以及由于toll样受体的激活而增加的抗原呈递细胞（APCs）的功能和可用性，特别是由于细菌易位导致的TLR4的参与。小鼠研究和临床试验的新发现表明，与过继转移T细胞群分化状态相关的内在特性对基于act的方法的成功至关重要。小鼠和人类的CD8+ T细胞亚群都具有CD8+ T细胞分化的进行性途径。小鼠模型表明，获得末端效应特性的CD8+ T细胞在体外抗肿瘤活性增强，但在体内触发肿瘤消退的效果较差。分化程度较低的、类似中枢记忆的T细胞可能会在淋巴细胞减少的环境中增殖并被完全激活，淋巴细胞减少的环境中充斥着稳态细胞因子，如IL-7和IL-15。人类的证据表明，过继性转移的T细胞表达CD27和长端粒与临床疗效有关。在小鼠中的发现强调早期效应T细胞比晚期效应T细胞更有效。在人类中，使用cd3特异性抗体和高剂量IL-2与辐照异体饲养细胞的标准快速扩增方案可能导致肿瘤特异性CD8+ T细胞分化到中间和晚期效应状态。细胞因子通过TCR和共刺激分子的信号协同作用，可以作为T细胞增殖和分化的加速器或制动器。IL-2已被证明是一种有效的T细胞生长因子，但也有不良影响，包括能够降低淋巴结归巢分子的表达，促进T细胞的终末分化，使其易于激活诱导的细胞死亡。其他细胞因子的受体含有&amp；#61543；c如IL-7、IL-15和IL-21可能在体外和体内都有用，支持肿瘤反应性CD8+ T细胞群的激活或增殖。肿瘤特异性T细胞可以通过基因工程在小鼠和人的成熟外周血T细胞中产生。选择用于转导的TCR的亲和力，转导的TCR在细胞表面表达的水平以及用于ACT的转导T细胞的分化状态可能对TCR转导后试验的成功至关重要。由于胸腺内缺失，自然产生的表达高亲和力TCRs的T细胞可能难以获得，但是高亲和力TCRs的产生可以在体内免疫HLA-A2转基因小鼠中进行，也可以在体外通过噬菌体展示含有退化互补决定区域的TCRs来进行。逆转录病毒传递序列的整合需要靶细胞的活性分裂，这一过程也促进T细胞分化，但慢病毒载体对活性细胞分裂的依赖性较小，可能用于将高亲和力的tcr转导到T细胞中而不驱动分化。传递TCR的α和β链指导完整TCR的表达，然而，与内源性TCR α配对；和β链可以发生，从而降低肿瘤特异性TCR的表面密度。为了提高肿瘤反应性T细胞的质量和功能，已经提出了TCR以外的基因，包括共刺激分子、抗凋亡分子、促炎或稳态细胞因子和趋化因子受体。编码已知表位特异性TCRs的基因转导允许同时使用疫苗，以增强过继转移T细胞的抗肿瘤反应。最重要的是，抗肿瘤T细胞的基因修饰使得免疫疗法几乎可以治疗任何癌症组织学。