PD1-LAG3 Bispecific antibody / Sutro Biopharma - LARVOL DELTA

RELATIVITY-104 Part 2: translational analyses in the programmed death ligand 1 (PD-L1) ≥ 1% and non-squamous (NSQ) non-small cell lung cancer (NSCLC) subgroup (AACR 2026) - "Background: In Part 2 of the phase 2 RELATIVITY-104 study of first-line nivolumab (NIVO) plus relatlimab (RELA) with platinum-doublet chemotherapy (PDCT) vs NIVO + PDCT in patients with metastatic NSCLC, NIVO + RELA + PDCT demonstrated improved clinical benefit, including overall survival, in the prespecified subgroup of tumor PD-L1 expression ≥ 1%, which was further enriched in NSQ tumor histology...Pre- and on-treatment peripheral blood samples were collected for high-dimensional flow cytometry immunophenotyping using a validated 24-marker LAG-3-specific panel that used drug-tolerant, noncompeting clones for LAG-3, PD-1, and CTLA-4... In the RELATIVITY-104 study, the on-treatment immune dynamics of LAG-3+ T cells correlated with the benefit of NIVO + RELA + PDCT vs NIVO + PDCT in patients with PD-L1 expression ≥ 1% and NSQ NSCLC. Immune signatures including progenitor T exhausted signatures associated with improved outcomes with NIVO + RELA + PDCT. These data support..."

IO biomarker • Late-breaking abstract • Lung Cancer • Lung Non-Squamous Non-Small Cell Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • CD4 • CTLA4 • ICOS • PD-L1 • RELA

Non-redundant immune checkpoints direct therapeutic resistance to chemoimmunotherapy in pancreatic ductal adenocarcinoma. (PubMed, Cancer Immunol Res) - "Combinatorial blockade of PD-1, LAG-3, and CTLA-4 along with chemotherapy and anti-CSF1R was necessary to trigger activation of peripheral CD4+ and CD8+ T cells and led to deep, durable, and complete tumor responses, with each immune checkpoint blockade agent contributing to efficacy. Our findings indicate that a comprehensive approach targeting both negative regulatory signals controlling T cell function and the myeloid compartment will be fundamental to unveiling the potential of immunotherapy in PDA."

Journal • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • CCR2 • CD4 • CD8 • CXCR2 • LAG3

Spatial profiling of the metastatic castration resistant prostate cancer tumor microenvironment at the single cell level reveals insights into intrinsic resistance to immunotherapy (SITC 2023) - P3 | "Conclusions Although the TME of mCRPC has appreciable T-cell presence, they lack checkpoint expression of CTLA4/PD1/LAG3...The expression of AR in CD8 T-cells is only present in a minority of patients and may not be a universal mechanism of IO sensitization with AR-targeted therapy. Our data suggest that strategies that increase tumor antigen presentation may increase IO benefit in mCRPC."

Biomarker • IO biomarker • Metastases • Tumor microenvironment • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • CD8 • LAG3

Comprehensive immunophenotyping of solid tumor-infiltrating immune cells reveals the expression characteristics of LAG-3 and its ligands. (PubMed, Front Immunol) - "We determined that these PD-1 LAG-3 CD8 memory T cells exhibited a unique marker profile, with greater expression of activation (CD69, HLA-DR), inhibitory (TIM-3, TIGIT, CTLA-4) and stimulatory (4-1BB, ICOS) markers compared to cells that expressed only PD-1 or LAG-3, or that were negative for both checkpoints...Lastly, we found an inverse relationship between baseline and on-treatment levels of circulating LAG3 transcript-expressing CD8 memory T cells and response to combination PD-1 and CTLA-4 blockade in a clinical trial cohort of melanoma patients profiled by scRNAseq. These results provide insights into the nature of LAG-3- and ligand-expressing immune cells within the TME, and suggest a biological basis for informing mechanistic hypotheses, treatment selection strategies, and combination immunotherapy approaches to support continued development of dual PD-1 and LAG-3 blockade."

Immune cell • IO biomarker • Journal • Melanoma • Oncology • Solid Tumor • CD69 • CD8 • FGL1 • HAVCR2 • ICOS • LAG3 • TIGIT

Quantitative spatial assessment of the tumor-immune microenvironment in the metastatic melanoma lymph node (SITC 2022) - "Pixel-based single cell segmentation and a supervised classifier approach was applied to resolve 10 distinct tumor, stromal and immune cell phenotypes and functional states (e.g. PD1, PDL1, LAG3) in 5.5 million cells...Conclusions Spatial distribution of PD1+ T cells is regionally enriched at the tumor-immune interface among patients that did not experience recurrence following anti-PD1 therapy. The metastatic lymph node represents an ideal tissue landscape to apply cyclic MxIF and study tumor-immune cellular interactions that inform recurrence risk following immunotherapy."

IO biomarker • Melanoma • Oncology • Solid Tumor • LAG3 • PD-L1