Abstract 2796: Translating combined PD1 and LAG3 inhibition from preclinical models to patients with refractory, DNA replication repair deficient (RRD) glioblastoma: An IRRDC study

Abstract Background and Aims: Glioblastoma driven by DNA Replication Repair Deficiency (RRD) account for 10% of all high-grade glioma in children and young adults, harbour high tumor mutation burden (TMB) and can respond to anti-PD1 immune-checkpoint inhibition (ICI). However, not all respond, and the majority ultimately progress, highlighting the need for combinatorial therapies for sustained immune-surveillance. Methods: We performed transcriptomic analyses of human RRD-glioblastoma specimens for immune checkpoint expression, and accordingly, tested combined ICI in immunocompetent murine models. Based on these preclinical data, we treated refractory patients using a combination of anti-PD1+anti-LAG3 through single-patient trial/compassionate access. Complimentary immuno-genomic biomarker analyses including circulating tumor DNA (ctDNA) were performed to investigate mechanisms and track responses. Results: Human RRD-glioblastoma (n=80) demonstrated high LAG3 expression, providing a strong rationale for therapeutic targeting. We tested combined anti-PD1+anti-LAG3 inhibition in three immunocompetent RRD-glioblastoma murine models. In the anti-PD1-responsive (Nestin-CreMSH2LoxP/LoxP-POLES459F/+) model, anti-PD1+anti-LAG3 resulted in universal tumor response and superior survival to ICI-monotherapy. In the anti-PD1 resistant models (Mlh1-/-/NestinCre+/Trp53LoxP/LoxP and therapy-induced hypermutant ENU/Trp53-/- gliomas), anti-PD1+antiLAG3 improved survival, overcoming the lack of response to ICI-monotherapy. Biologically, high LAG3 expression and immune-exhaustion observed in CD8 T-cells after treatment with anti-PD1 was ablated following the addition of anti-LAG3. Serially transplanted, post-anti-PD1 treated tumors showed response, confirming, in-vivo, that resistance to anti-PD1 could be abrogated by anti-PD1+anti-LAG3. Seven children with refractory RRD-glioblastoma who had progressed after anti-PD1 treatment were treated using anti-PD1+anti-LAG3, resulting in objective radiological responses and prolonged ongoing survival. Tolerability was better than a previous study of combined CTLA4 and PD1 inhibition for similar patients. Paired immuno-genomic tumor analyses, serial blood flow-cytometry, T-cell receptor clonotype, and CSF ctDNA analyses provided novel insights into the mechanisms of immunological invigoration and first-in-human, radiological responses. Conclusions: LAG3 is an effective target in refractory RRD-glioblastoma. Combined inhibition with anti-PD1 inhibition demonstrated radiological response, prolonged survival and manageable toxicities in patients, and unearthered mechanisms of immune-responses. The combination will now be tested in biomarker-driven clinical trials in RRD-glioblastoma and other immune-inflamed solid tumors. Citation Format: Anirban Das, Vienna Mazzoli, Owen Crump, Olha Kos, Nuno M. Nunes, Lucie Stengs, Amanda Li, Adrian Levine, Yoshiko Nakano, Hope Friedman, Katharine O'Flaherty, Alexander Stein, Gadi Abebe-Campino, Annika Bronsema, Vanessa Bianchi, Melissa Edwards, Stergios Zacharoulis, Birgit Ertl-Wagner, Daniel A. Morgenstern, Trevor J. Pugh, Pamela Ohashi, Eric Bouffet, Cynthia E. Hawkins, Peter B. Dirks, Uri Y. Tabori. Translating combined PD1 and LAG3 inhibition from preclinical models to patients with refractory, DNA replication repair deficient (RRD) glioblastoma: An IRRDC study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2796.