Peter Chockley

Haplo-identical hematopoietic cell transplantation (haploHCT) is an integral treatment paradigm for patients with leukemia. While overall survival (OS) post-haploHCT has steadily improved, relapse-free survival (RFS) remains relatively stagnant. Upon the discovery of killer immunoglobulin-like receptors (KIRs) on natural killer (NK) cells and their cognate human leukocyte antigen (HLA) ligands, algorithms have been developed to enhance graft versus leukemia effects. However, these algorithms fail to yield consistent predictions in patient outcomes. We utilized a combination of in silico protein folding and interactions to determine KIR:HLA reactivity in conjunction with in vitro acoustic force microscopy to measure cell avidity (CA) as a readout for KIR signal strength. CA was determined using monoallelic HLA expressing K562 cell lines, monoallelic KIR Jurkat cells, and peripheral blood NK cells. We extended the CA results and performed standard cytotoxicity assays as well. We discovered that HLA-B*35 interacts with KIR2DS4. We applied the newly discovered interaction to predict outcomes for HCT patients. Stratifying patients based on their HLA-B*35 positivity and donor KIR2DS4 status, we delineated a correlation to survival (P=0.061) when donors only had full-length KIR2DS4. Patients who received a haploHCT and NK cell addback from donors with only full-length KIR2DS4 had a significantly improved RFS (P=0.001) and OS (P=0.016) compared to truncated (KIR1D) and full-length KIR2DS4 donors. This was independently validated in a diverse 10/10 HLA matched European cohort with RFS (P=0.0255) and OS (P=0.0388). Thus, the identified novel KIR2DS4:HLA-B*35 interaction axis predicts patient survival, in both haplo-identical and fully matched, HCT and highlights that our current understanding of the KIR:HLA interactome is incomplete and requires remapping for enhanced therapeutic applications.

LRRC15-CAR T cell phenotypes after repeat stimulation with OS152 osteosarcoma cells

Lrrc15 expression in normal murine tissues by ISH detection

Evaluation of murine tissues post T cell infusion

LRRC15-CAR T cell phenotypes after repeat stimulation with LM7 osteosarcoma cells

LRRC15 expression in human melanoma and melanocyte samples

LRRC15-CAR T cells exhibit transient antitumor activity and enhance survival in a bulky orthotopic limb osteosarcoma model

LRRC15-CAR T cells do not cause weight loss in tumor bearing mice

Tumors from mice with progressive intravenous LM7 lung osteosarcoma have limited LRRC15 expression after treatment with LRRC15-CAR T cells

Pre-infusion healthy donor T cell characteristics for in vivo studies