The Role of KIR and FcR Genotype in the Efficacy of mAb and IL2 Immunotherapy

KIR 和 FcR 基因型在 mAb 和 IL2 免疫疗法疗效中的作用

• 批准号: 8270774
• 负责人: PAUL M SONDEL
• 金额: $ 33.93万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8270774
• 关键词: Affinity; Algorithms; Alleles; Allogenic; Antibodies; Autologous; Cells; Child; Clinical; Clinical Data; Clinical Research; Clinical Trials Cooperative Group; Control Groups; DNA; Data; Disease; Disease remission; Disease-Free Survival; Eastern Cooperative Oncology Group; Eligibility Determination; Fc Receptor; Follicular Lymphoma; Future; Genes; Genotype; Granulocyte-Macrophage Colony-Stimulating Factor; Hematopoietic Stem Cell Transplantation; Human; IL2 gene; Immune; Immunotherapy; Individual; Inherited; Institution; Interleukin-2; Ligands; Link; Lymphoma; Malignant Neoplasms; Measures; Mediating; Metastatic Renal Cell Cancer; Monoclonal Antibodies; Monoclonal Antibody Ch14.18; Monoclonal Antibody Therapy; Multi-Institutional Clinical Trial; Natural Killer Cells; Neoplasm Antibodies; Neuroblastoma; Outcome; Patients; Phase; Phase III Clinical Trials; Play; Regimen; Renal Cell Carcinoma; Reporting; Research; Role; Sampling; Screening procedure; Self Tolerance; Specificity; Testing; Therapeutic antibodies; Tissues; Toxic effect; Treatment Efficacy; Vaccination; Work; alternative treatment; antibody-dependent cell cytotoxicity; base; cancer immunotherapy; cancer therapy; clinical effect; clinical efficacy; cytokine; experience; high risk; improved; killer immunoglobulin-like receptor; monocyte; neutrophil; phase 2 study; receptor; response; rituximab; standard of care; success; tumor; working group

DESCRIPTION (provided by applicant): Killer Immunoglobulin-like Receptors (KIR) recognize specific KIR ligands (KIR-L) encoded by HLA alleles, and regulate activation and function of human natural killer (NK) cells. The interactions between KIR receptors on donor NK cells and KIR ligands on recipient tissues can influence anti-tumor efficacy of allogeneic hematopoietic stem cell transplantation (HSCT). In autologous HSCT, an autologous KIR/KIR-L "mismatch" relationship between an individual's inherited arrays of KIR alleles and KIR-ligands can augment anti-tumor effects. We thus hypothesized that favorable KIR/KIR-L genotypic relationships (i.e.: KIR/KIR-L mismatch) could augment the efficacy of NK mediated immunotherapy. We found, in a small Phase II immunotherapy trial for neuroblastoma, that patients were more likely to benefit from NK-targeted immunotherapy if they were KIR/KIR-L mismatched. To extend and confirm this result our team is proposing confirmatory KIR/KIR-L analyses in 3 separate large (multi-institution cooperative group) clinical trials, each using a different form of immunotherapy known to activate or involve NK cells. For each of these trials we will determine whether KIR/KIR-L status is associated with clinical response. These analyses will explore 3 separate algorithms for characterizing KIR/KIR-L relationships, and use several distinct measures of clinical effect/response to evaluate possible associations. In addition, other studies have shown that the presence of high affinity Fc Receptor (FcR) alleles is associated with clinical benefit in the use of tumor-reactive monoclonal antibody (mAb), likely via antibody dependent cell-mediated cytotoxicity (ADCC). We will obtain genotype data for patients from these 3 trials for their FcR alleles, as we hypothesize that the efficacy of mAb treatment may be influenced by the potential interaction of both FcR and KIR/KIR-L genotype. Finally, we hypothesize that: a) some of the clinical anti-tumor efficacy of single agent IL2 might be NK mediated; and b) a component of the IL2 induced antitumor effect may be due to ADCC activity facilitated by putative endogenous antitumor antibody. These IL2 induced mechanisms should also be reflected by favorable KIR/KIR-L and FcR genotype. These hypotheses will be tested by determining KIR/KIR-L and FcR genotypes, correlating genotypes with clinical outcome data, and assessing whether favorable genotypes are predictive of response. If this genotyping proves to be predictive of beneficial clinical effect, KIR, KIR-L and FcR genotyping can be used as an eligibility-screening test to: 1) improve the efficacy of these immunotherapy regimens, and 2) identify alternative/additional treatments for those individuals with unfavorable genotypes. Overall Hypothesis: We hypothesize that KIR/KIR-L data, independently and combined with FcR genotype data, can identify patients more likely to respond to: a) single agent mAb therapy for lymphoma, b) single agent IL2 treatment for renal cell carcinoma (RCC), and c) mAb + cytokine (IL2 + GM-CSF) therapy for neuroblastoma (NBL). PUBLIC HEALTH RELEVANCE:: Cancer immunotherapies, using tumor reactive monoclonal antibodies, IL2 and their combination have shown clinical activity and efficacy, and have been approved as the standard of care in several clinical settings, including: 1) the use of the rituximab monoclonal antibody for treatment of certain lymphomas, 2) the use of IL2 for metastatic renal cell carcinoma, and 3) the combination of ch14.18 monoclonal antibody with IL2 and GM-CSF for patients with high-risk neuroblastoma in remission. Despite antitumor effects for some patients in these 3 settings, many patients that receive these treatments experience immune-mediated toxicities but do not show clinical benefit. We hypothesize that a patient's ability to benefit from these treatments should be predictable, at least in part, based o the inheritance of certain genes (KIR, KIR-Ligand, and FcR) that are known to influence the functional capabilities of immune cells involved in monoclonal antibody and IL2 responses. We will test this hypothesis in each of these 3 settings, using data from large cooperative group clinical trials. If the data validate this hypothesis, in any one of these clinical settings, it wold enable this genotyping to be used in the future to determine which patients are most likely to benefit from this treatment, thereby increasing the clinical efficacy of that approach.

描述(申请人提供)：杀伤免疫球蛋白样受体识别由人类白细胞抗原等位基因编码的特异性免疫球蛋白样受体配体(L)，并调节人类自然杀伤(NK)细胞的激活和功能。供者NK细胞上的KIR受体与受体组织上的KIR配体之间的相互作用影响异基因造血干细胞移植(HSCT)的抗肿瘤效果。在自体造血干细胞移植中，个体遗传的KIR等位基因阵列和KIR配体之间的自体KIR/KIR-L“不匹配”关系可以增强抗肿瘤效果。因此，我们假设良好的KIR/KIR-L基因型关系(即：KIR/KIR-L错配)可以增强NK介导的免疫治疗的疗效。我们发现，在神经母细胞瘤的小型II期免疫治疗试验中，如果KIR/KIR-L不匹配，患者更有可能从NK靶向免疫治疗中受益。为了扩展和确认这一结果，我们的团队提议在3个单独的大型(多机构合作小组)临床试验中进行验证性的KIR/KIR-L分析，每个试验都使用一种已知的激活或涉及NK细胞的不同形式的免疫疗法。对于每一项试验，我们将确定KIR/KIR-L状态是否与临床反应相关。这些分析将探索三种不同的算法来表征KIR/KIR-L关系，并使用几种不同的临床效果/反应衡量标准来评估可能的关联。此外，其他研究表明，高亲和力Fc受体(FCR)等位基因的存在与使用肿瘤反应性单抗(MAb)的临床益处有关，可能是通过抗体依赖的细胞介导的细胞毒性(ADCC)。我们将从这3个试验中获得患者的fcr等位基因的基因型数据，因为我们假设单抗治疗的疗效可能受到fcr和kir/kir-L基因型潜在交互作用的影响。最后，我们假设：a)单药IL2的部分临床抗肿瘤作用可能是由NK介导的；b)IL2诱导的抗肿瘤作用的一部分可能是由于内源性抗肿瘤抗体促进了ADCC的活性。这些IL-2诱导机制也应反映在良好的KIR/KIR-L和FCR型上。这些假说将通过确定KIR/KIR-L和FCR型，将基因型与临床结果数据相关联，以及评估有利的基因型是否预测疗效来检验。如果这种基因分型被证明可以预测有益的临床效果，KIR、KIR-L和FCR基因分型可以作为一种合格的筛选试验：1)提高这些免疫治疗方案的有效性，2)为那些基因不良的个体确定替代/额外的治疗方法。总体假设：我们假设KIR/KIR-L的数据，独立地结合FCR型数据，可以确定患者更有可能对：a)单药单抗治疗淋巴瘤，b)单药IL2治疗肾癌，以及c)单抗+细胞因子(IL2+GM-CSF)治疗神经母细胞瘤(NBL)。 公共卫生相关性：使用肿瘤反应性单抗、IL2及其组合的癌症免疫疗法已显示出临床活性和疗效，并已被批准作为多种临床环境下的标准护理，包括：1)使用利妥昔单抗治疗某些淋巴瘤；2)使用IL2治疗转移性肾癌；3)将ch14.18单抗与IL2和GM-CSF联合用于高危神经母细胞瘤缓解期患者。尽管在这三种情况下，一些患者有抗肿瘤作用，但许多接受这些治疗的患者经历了免疫介导的毒性，但没有显示出临床益处。我们假设，患者从这些治疗中获益的能力应该是可预测的，至少部分基于某些基因(KIR、KIR配体和FCR)的遗传，这些基因已知会影响参与单抗和IL2反应的免疫细胞的功能能力。我们将使用来自大型合作小组临床试验的数据，在这三个环境中的每一个环境中检验这一假设。如果数据证实了这一假设，在这些临床环境中的任何一种，它将使这种基因分型在未来用于确定哪些患者最有可能从这种治疗中受益，从而提高该方法的临床疗效。