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

University Of Wisconsin-Madison, Madison WI

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Abstract

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).