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: 8450068
• 负责人: PAUL M SONDEL
• 金额: $ 31.89万
• 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/8450068
• 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; 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; screening; standard of care; success; tumor; working group; 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; 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; screening; 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).

描述（由申请人提供）：杀手型免疫球蛋白样受体（KIR）识别由HLA等位基因编码的特定KIR配体（KIR-L），并调节人类天然杀伤（NK）细胞的激活和功能。 KIR受体在供体NK细胞上的相互作用与受体组织上的KIR配体之间的相互作用会影响同种异体造血干细胞移植（HSCT）的抗肿瘤功效。在自体HSCT中，个人的Kir/Kir-l“不匹配”关系之间的遗传阵列KIR等位基因和KIR-ligands之间的关系可以增强反肿瘤效应。因此，我们假设有利的KIR/KIR-L基因型关系（即：KIR/KIR-L不匹配）可以增强NK介导的免疫疗法的疗效。我们发现，在一项针对神经细胞瘤的II期免疫疗法试验中，如果患者患有KIR/KIR-L不匹配，则更有可能受益于NK靶向的免疫疗法。为了扩展和确认这一结果，我们的团队正在提议在3个单独的大型（多机构合作组）临床试验中进行确认的KIR/KIR-L分析，每种试验都使用已知激活或涉及NK细胞的不同形式的免疫疗法。对于这些试验，我们将确定KIR/KIR-L状态是否与临床反应有关。这些分析将探索3种单独的算法来表征KIR/KIR-L关系，并使用几种不同的临床效果/反应度量来评估可能的关联。此外，其他研究表明，高亲和力FC受体（FCR）等位基因的存在与临床益处相关，在使用肿瘤反应性单克隆抗体（MAB）方面，可能是通过抗体依赖性细胞介导的细胞毒性（ADCC）的。我们将从这三个试验的FCR等位基因中获得患者的基因型数据，因为我们假设MAB治疗的功效可能受FCR和KIR/KIR/KIR-L基因型的潜在相互作用的影响。最后，我们假设：a）单个药物IL2的某些临床抗肿瘤功效可能是NK介导的； b）IL2诱导的抗肿瘤作用的成分可能是由于假定的内源性抗肿瘤抗体促进的ADCC活性。这些IL2诱导的机制也应由有利的KIR/KIR-L和FCR基因型反映。这些假设将通过确定KIR/KIR-L和FCR基因型，将基因型与临床结果数据相关联，并评估有利的基因型是否可以预测反应，从而测试这些假设。如果该基因分型被证明可以预测有益的临床效应，则可以将KIR，KIR-L和FCR基因分型用作资格筛查测试，以提高：1）提高这些免疫疗法方案的疗效，2）确定那些患有不利基因型的人的替代/附加治疗方法。总体假设：我们假设KIR/KIR-L数据独立并与FCR基因型数据结合使用，可以识别患者更有可能反应的患者：a）淋巴瘤的单药MAB治疗，b）肾脏细胞癌（RCC）的单药IL2治疗MAB + CINTOKINE（RCC）MAB + CINTOKINE（IL2 + GM-GM-CSF）（NNEURO）（NNEURO）（NNEURO）。