denotes an abstract that is clinically relevant.
denotes that this is a recommended PHD Trainee Session.
denotes that this is a ticketed session.Session: 622. Lymphomas: Translational – Non-Genetic: Poster II
Hematology Disease Topics & Pathways:
Lymphomas, Non-Hodgkin lymphoma, Diseases, Aggressive lymphoma, Lymphoid Malignancies
Beyond anti-tumor efficacy, GemOx has been shown to modulate the tumor immune environment and to enhance tumor immunogenicity, thus supporting combination with a T-cell-directed therapy such as glofitamab (Liu, et al. Br J Cancer 2010; Mundy-Bosse, et al. Cancer Res 2011).
Here, we present data from a pre-clinical study in stem-cell humanized tumor-bearing mice and from pt samples collected within the STARGLO trial (NCT04408638) to: 1) investigate preclinical anti-tumor activity and combination potential of Glofit-GemOx and 2) evaluate the effect of Glofit-GemOx on T-cell activation in pt samples.
Methods: Humanized NSG mice were subcutaneously injected with human OCl-ly-18 lymphoma cells and randomized into 4 treatment groups at day (D) 18. One group served as a vehicle control. All other groups were administered 30 mg/kg obinutuzumab on D18 plus: 5 mg/kg oxaliplatin and 50 mg/kg gemcitabine on D19 and on D28; or glofitamab 0.15 mg/kg on D21 followed by 0.5 mg/kg on D28; or combination therapy with Glofit-GemOx administered staggered in the first cycle and concomitantly in the second cycle. On D29, intratumor T-cell infiltration was evaluated by flow cytometry in 4 mice/group.
Peripheral blood (PB) collected from a cohort of pts treated with Glofit-GemOx in the STARGLO trial was analyzed by flow cytometry (n=41 pts with pre-glofitamab sample). The analysis includes samples collected before and after glofitamab 2.5mg (C1D8), before glofitamab 10mg (C1D15) and before glofitamab 30mg (C2D1 and C3D1).
Results: In tumor-bearing mice, treatment with glofitamab alone, as well as treatment with GemOx alone, inhibited tumor growth compared to vehicle-treated mice. The highest inhibition of tumor growth was observed with Glofit-GemOx combination compared to vehicle-treated mice. Ex-vivo flow cytometry showed that Glofit-GemOx treatments increased intratumoral T-cell infiltration (CD3+ and CD8+ counts), and marker of proliferation (% of Ki-67+ CD8+), and cytotoxic potential (% of GzB+ CD8+) compared to glofitamab alone or GemOx alone. There were no statistically significant changes in T-cell frequencies, activation, and proliferation in the spleen of treated animals.
In patients treated with Glofit-GemOx immune pharmacodynamics in PB showed activation of T cells during early cycles of glofitamab administration in combination with GemOx. Acute and transient T cell activation, characterized by margination of CD4 and CD8 T cells and increased proportion of CD4 and CD8 T cells expressing CD69 were observed post-treatment after the first glofitamab dose compared to pre-glofitamab sample. Additionally, long term T-cell activation characterized by gradual increase of the proportion of CD4 and CD8 T cells expressing HLA-DR was observed subsequently to glofitamab step-up doses.
Conclusions: This work demonstrates that Glofit-GemOx increased T cell infiltration, proliferation and cytotoxic potential, resulting in greater anti-tumor activity compared to glofitamab alone or GemOx alone in tumor bearing mice. The pharmacodynamic results in the preclinical model are consistent with clinical biomarker data evaluated in PB. In pts treated with Glofit-GemOx within the STARGLO trial, both transient and long-term T cell activation markers were increased during early doses.
Disclosures: Bacac: F. Hoffmann-La Roche Ltd: Current Employment, Current holder of stock options in a privately-held company, Divested equity in a private or publicly-traded company in the past 24 months, Patents & Royalties: Owner of several Roche patents, including glofitamab, Research Funding. Sam: Roche: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties: No royalties from patents Roche patents: PCT/EP2024/056421, WO 2024/094741, WO 2023/232752, WO 2022/253867, WO 2022/189377, WO 2021/198333, WO 2020/260326, WO 2020/127618, WO 2019/175125, WO 2019/175071, WO 2019/122052, WO 2019/122049, WO 2019/086497, WO . Kim: Donga: Research Funding; Sanofi: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding; Kyowa-Kirin: Research Funding; Boryong: Research Funding; BeiGene: Research Funding. Gregory: Merck, BeiGene (to institute, not individual): Research Funding; Roche, Merck: Speakers Bureau; Merck, Amgen, Roche, Novartis, BMS, Clinigen, Gilead, Prelude Therapeutics: Membership on an entity's Board of Directors or advisory committees. Ku: Beigene: Research Funding; Roche, Abbvie: Consultancy; F. Hoffmann-La Roche Ltd, AbbVie: Consultancy; St Vincent's Hospital, Melbourne: Current Employment. Herter: Roche Glycart AG: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties. Klein: F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties. Umana: Roche Glycart AG: Current Employment; F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company. Simko: Genentech, Inc.: Current Employment; Roche Holding AG: Current equity holder in publicly-traded company; Apple, Inc.: Current equity holder in publicly-traded company. Orellana-Noia: Genentech, Inc.: Current Employment; F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company. Lundberg: F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company, Current holder of stock options in a privately-held company, Patents & Royalties. Bottos: F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in private company, Current holder of stock options in a privately-held company, Ended employment in the past 24 months.
OffLabel Disclosure: All study therapy constituted investigational or off-label use.Glofitamab (Columvi) is a bispecific CD20-directed CD3 T-cell engager indicated for the treatment of adult patients with relapsed or refractory DLBCL, NOS or large B-cell lymphoma arising from FL, after two or more lines of systemic therapy.Rituximab (Rituxan) is a CD20-directed cytolytic antibody indicated for the treatment of adult pts with: relapsed or refractory, low grade or follicular, CD20-positive, B-cell NHL as a single agent; previously untreated follicular, CD20-positive, B-cell NHL in combination with first-line chemotherapy (chemo) and, in pts achieving a CR or PR to a rituximab product in combination with chemo, as single-agent maintenance therapy; non-progressing (including stable disease), low-grade, CD20Âpositive, B-cell NHL as a single agent after first-line CVP chemo; previously untreated diffuse large B-cell, CD20-positive, NHL in combination with CHOP or other anthracycline-based chemo regimens; previously untreated and previously treated CD20-positive CLL in combination with fludarabine and cyclophosphamide.
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