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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Clinical Oncology Study Section (CONC)
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Thurin, Magdalena
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University of Wisconsin Madison
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Morris, Zachary S; Guy, Emily I; Werner, Lauryn R et al. (2018) Tumor-Specific Inhibition of In Situ Vaccination by Distant Untreated Tumor Sites. Cancer Immunol Res 6:825-834
Erbe, Amy K; Wang, Wei; Carmichael, Lakeesha et al. (2018) Neuroblastoma Patients' KIR and KIR-Ligand Genotypes Influence Clinical Outcome for Dinutuximab-based Immunotherapy: A Report from the Children's Oncology Group. Clin Cancer Res 24:189-196
Albertini, Mark R; Yang, Richard K; Ranheim, Erik A et al. (2018) Pilot trial of the hu14.18-IL2 immunocytokine in patients with completely resectable recurrent stage III or stage IV melanoma. Cancer Immunol Immunother 67:1647-1658
Erbe, Amy K; Wang, Wei; Goldberg, Jacob et al. (2017) FCGR Polymorphisms Influence Response to IL2 in Metastatic Renal Cell Carcinoma. Clin Cancer Res 23:2159-2168
Rakhmilevich, Alexander L; Felder, Mildred; Lever, Lauren et al. (2017) Effective Combination of Innate and Adaptive Immunotherapeutic Approaches in a Mouse Melanoma Model. J Immunol 198:1575-1584
Wang, Wei; Erbe, Amy K; Alderson, Kory A et al. (2016) Human NK cells maintain licensing status and are subject to killer immunoglobulin-like receptor (KIR) and KIR-ligand inhibition following ex vivo expansion. Cancer Immunol Immunother 65:1047-59
Erbe, Amy K; Wang, Wei; Gallenberger, Mikayla et al. (2016) Genotyping Single Nucleotide Polymorphisms and Copy Number Variability of the FCGRs Expressed on NK Cells. Methods Mol Biol 1441:43-56
Perez Horta, Zulmarie; Goldberg, Jacob L; Sondel, Paul M (2016) Anti-GD2 mAbs and next-generation mAb-based agents for cancer therapy. Immunotherapy 8:1097-117
Wang, Wei; Erbe, Amy K; Gallenberger, Mikayla et al. (2016) Killer immunoglobulin-like receptor (KIR) and KIR-ligand genotype do not correlate with clinical outcome of renal cell carcinoma patients receiving high-dose IL2. Cancer Immunol Immunother 65:1523-1532
Morris, Zachary S; Guy, Emily I; Francis, David M et al. (2016) In Situ Tumor Vaccination by Combining Local Radiation and Tumor-Specific Antibody or Immunocytokine Treatments. Cancer Res 76:3929-41

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