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

描述（由申请人提供）：杀伤免疫球蛋白样受体（KIR）识别由HLA等位基因编码的特异性KIR配体（KIR-L），并调节人自然杀伤（NK）细胞的激活和功能。供体NK细胞上KIR受体与受体组织上KIR配体之间的相互作用可影响异基因造血干细胞移植（HSCT）的抗肿瘤效果。在自体HSCT中，个体的KIR等位基因和KIR配体的遗传阵列之间的自体KIR/KIR-L“错配”关系可以增强抗肿瘤作用。因此，我们假设有利的KIR/KIR-L基因型关系（即：KIR/KIR-L错配）可增强NK介导的免疫治疗的功效。我们发现，在一项针对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靶向免疫治疗中获益。为了扩展和证实这一结果，我们的团队正在3个独立的大型（多机构合作组）临床试验中提出验证性KIR/KIR-L分析，每个试验都使用不同形式的已知激活或涉及NK细胞的免疫疗法。对于这些试验中的每一项，我们将确定KIR/KIR-L状态是否与临床应答相关。这些分析将探索表征KIR/KIR-L关系的3种不同算法，并使用几种不同的临床效果/反应指标来评价可能的相关性。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克隆抗体（mAb）的临床获益相关，可能通过抗体依赖性细胞介导的细胞毒性（ADCC）实现。我们将从这3项试验中获得患者FcR等位基因的基因型数据，因为我们假设mAb治疗的疗效可能受到FcR和KIR/KIR-L基因型潜在相互作用的影响。最后，我们假设：a）单一药剂IL 2的一些临床抗肿瘤功效可能是NK介导的;和B）IL 2诱导的抗肿瘤效应的一个组分可能是由于推定的内源性抗肿瘤抗体促进的ADCC活性。这些IL 2诱导的机制也应该通过有利的KIR/KIR-L和FcR基因型来反映。将通过确定KIR/KIR-L和FcR基因型，将基因型与临床结局数据相关联，并评估有利的基因型是否可预测缓解来检验这些假设。如果这种基因分型被证明是有益的临床效果的预测，KIR，KIR-L和FcR基因分型可用作杀伤力筛选试验：1）提高这些免疫治疗方案的疗效，和2）为那些具有不利基因型的个体确定替代/额外的治疗。总体假设：我们假设，KIR/KIR-L数据，独立地和与FcR基因型数据组合，可以识别更可能响应于以下治疗的患者：a）针对淋巴瘤的单药mAb治疗，B）针对肾细胞癌（RCC）的单药IL 2治疗，和c）针对神经母细胞瘤（NBL）的mAb +细胞因子（IL 2 + GM-CSF）治疗。 公共卫生相关性：使用肿瘤反应性单克隆抗体、IL 2及其组合的癌症免疫疗法已显示出临床活性和疗效，并已被批准为几种临床环境中的标准治疗，包括：1）利妥昔单抗单克隆抗体用于治疗某些淋巴瘤的用途，2）IL 2用于转移性肾细胞癌的用途，CH14.18单克隆抗体联合IL 2、GM-CSF治疗高危神经母细胞瘤缓解期患者。尽管在这3种情况下对一些患者有抗肿瘤作用，但许多接受这些治疗的患者会出现免疫介导的毒性，但未显示出临床获益。我们假设，患者从这些治疗中获益的能力应该是可预测的，至少部分是基于某些基因（KIR、KIR-配体和FcR）的遗传，这些基因已知会影响参与单克隆抗体和IL 2应答的免疫细胞的功能。我们将使用来自大型合作组临床试验的数据，在这3种情况下检验这一假设。如果数据验证了这一假设，在这些临床环境中的任何一个，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。

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.