Abstract 1727: Tumor associated macrophages and resistance to immune checkpoint blockade: consideration of cancer indications for the clinical development of JTX-8064, an anti-LILRB2/ILT4 monoclonal antibody
Authors: McGrath Lara , Mueller Amy , Rahman Tanzila , Smith Jeffrey , Yore Mark , Stack Edward , O'Malley Kristin , Dunn Andrew , Legendre Kristen , Shenwai Reva , Willer Margaret , Naumovski Allison , Baeck Johan , Umiker Ben 
Published: July 2021

Abstract
Leukocyte immunoglobulin-like receptor B2 (LILRB2; ILT4) is expressed on myeloid cells and inhibits myeloid cell activation through binding Major Histocompatibility class I (MHC-I) molecules. These include Human Leukocyte Antigen-G (HLA-G), which is highly expressed in the tumor microenvironment (TME) of many patients and is known to drive immunosuppressive signaling. JTX-8064 is a highly selective IgG4 monoclonal antibody that binds to LILRB2 and blocks interactions with MHC-I. Cancer types have been identified with the potential for higher likelihood of deriving clinical benefit by JTX-8064 through the analysis of single cell RNAseq and bulk tumor RNAseq from early stage and advanced metastatic tumors, and an evaluation of the TME by immunohistochemistry (IHC). LILRB2 expression was analyzed using over 400,000 single cell transcriptomes from 143 patients across 7 cancer types. We observed that LILRB2 mRNA is highly expressed on tumor-associated macrophages (TAMs). Using these data, we generated an RNA signature of genes highly correlated with LILRB2 on TAMs. This TAM signature was used to score tumors in The Cancer Genome Atlas (TCGA) and other datasets for the infiltration of target cells across many cancer types. Cancer types were ranked using the TAM signature as well as other metrics such as Interferon gamma (IFNg) signatures that represent the levels of cytotoxic immune infiltrate. We also evaluated these signatures in relation to response to immune checkpoint blockade. In a dataset of almost 300 patients treated with a PD-L1 inhibitor, we identified an association between pre-treatment LILRB2 expression and an IFNg signature with patient's response to treatment. Non-responders (SD, PD) compared to responders (CR, PR) had significantly higher intra-tumoral LILRB2 levels relative to the IFNg signature (p &lt;0.01) suggesting LILRB2 may be involved in primary resistance to checkpoint blockade. The data presented provides evidence for the development of JTX-8064 in combination with PD-1(L1) inhibitors. Inhibition of LILRB2 by JTX-8064 on myeloid cells directly increases cell activation, antigen presentation, and secretion of pro-inflammatory cytokines. In Mixed Lymphocyte Reactions (MLRs), JTX-8064 induces indirect T cell activation, proliferation and IFNg secretion by inhibiting LILRB2 on monocyte-derived myeloid cells. The activities of JTX-8064 in cell culture and high LILRB2 expression in non-responding patients with high levels of IFNg signature expression provides a rationale that JTX-8064 may be able to overcome anti-PD-1 primary resistance mechanisms. JTX-8064 is currently in Phase 1 clinical development as a monotherapy and combination with anti-PD-1 inhibitors in settings with both anti-PD-1(L1) naïve and anti-PD-1(L1) experienced patients in specific cancer types.
Citation Format: Lara McGrath, Amy Mueller, Tanzila Rahman, Jeffrey Smith, Mark Yore, Edward Stack, Kristin O'Malley, Andrew Dunn, Kristen Legendre, Reva Shenwai, Margaret Willer, Allison Naumovski, Johan Baeck, Ben Umiker. Tumor associated macrophages and resistance to immune checkpoint blockade: consideration of cancer indications for the clinical development of JTX-8064, an anti-LILRB2/ILT4 monoclonal antibody [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1727.