Type: Oral
Session: 622. Lymphomas: Translational – Non-Genetic: Demystifying the Complexity of the Lymphoma Tumor Microenvironment and Immune Responses
Hematology Disease Topics & Pathways:
Research, Combination therapy, Translational Research, Lymphomas, Non-Hodgkin lymphoma, Drug development, Diseases, Treatment Considerations, Lymphoid Malignancies, Human
Methods: Exploratory biomarker analyses included data from 28 patients with indolent (iNHL, n=9) or aggressive NHL (aNHL, n=19) treated with escalating dose levels of 0.15–14 mg RO7443904, starting after completion of glofitamab step-up dose, on Cycle 2 Day 8 (C2D8), and followed by combination with the fixed target dose of glofitamab (30mg), once every 3 weeks, from C3D1 for up to 12 cycles. Immune profiling of PB by flow cytometry and plasma cytokines analysis by ELLA were performed. Baseline tumor biopsies (n=21) were analyzed by immunohistochemistry/immunofluorescence, bulk mRNA- and targeted DNA-sequencing. To evaluate individual contributions, on-treatment PD changes during the first five cycles of treatment in patients with aNHL were compared to historical glofitamab monotherapy PD data generated in a phase I/II study (NCT03075696).
Results: Compared to glofitamab monotherapy, and in line with the constitutive expression of CD28 on CD4+ and CD8+ T cells, the combination significantly (p<0.01) boosted and sustained CD4+ (1.7-fold) and CD8+ (2.5-fold) T-cell proliferation (Ki67+) in PB, and preferentially increased the differentiation of naïve CD8+ to effector memory (TEM) T cells by 1.5-fold. These effects are similar to what is observed after second-generation chimeric antigen receptor (CAR) T-cell therapies. RO7443904 in combination with glofitamab induced PD changes in PB at all tested doses. Specifically, in a bell-shaped dose-dependent manner, RO7443904 limited the PB expansion of potentially exhausted PD1+ CD8+ TEM cells, which were previously found to expand in a dose-dependent manner following glofitamab monotherapy (Broeske et al, Blood Advances 2022). The optimal PD effects were observed within dose ranges that corresponded to efficacious RO7443904 exposures predicted by pre-clinical humanized mouse models (Sam et al, Blood 2024). Furthermore, within the doses tested, we detected no significant additional cytokine release following RO7443904 alone or in combination with glofitamab, aligning with the clinically observed safety profile.
Complete responses observed with the combination were independent of recurrent mutations identified in pre-treatment biopsies such as KMT2D, TP53, and CREBBP, or cell-of-origin. These responses were not associated with CD19+ B-cell abundance but correlated with a low tumor proliferation index, low infiltration of granulocytic myeloid-derived suppressor cells, and high total and CD28+ T-cell infiltration in pre-treatment biopsies. These trends were observed in aNHL but were more prominent in iNHL.
Conclusions: In this study, we have demonstrated for the first time the MoA of a CD28 costimulatory bispecific (RO7443904) in combination with a T-cell engaging bispecific (glofitamab) in humans. The addition of RO7443904 to glofitamab monotherapy significantly boosted and sustained the proliferation and effector function of T cells. This enhanced response appears to benefit patients with a less immunosuppressive tumor microenvironment and more active T-cell infiltration. Overall, our PD and biomarker findings support the rationale for this combination as an effective off-the-shelf therapy for patients with R/R NHL.
Acknowledgments: This study was sponsored by F. Hoffmann-La Roche Ltd. The authors would like to thank the patients who participated in this trial, their families, and their caregivers. Special thanks also to Iva Lelios, Abu Ali, Kat Reyskens, Isabelle Vogl, Katharina Menzel, Francesca Michielin, and Giuseppe Palladino for their contributions to this work.
Disclosures: Korfi: Roche: Current Employment, Current equity holder in publicly-traded company. Wilson: Roche: Current Employment, Current equity holder in publicly-traded company. Jiang: Roche: Current Employment. Christiansen: Roche: Consultancy. Krishnan: Roche: Current Employment, Current equity holder in publicly-traded company. Jamois: Roche: Current Employment, Current equity holder in publicly-traded company. Blank: Roche: Current Employment. Epp: Roche Diagnostics GmbH: Current Employment. Silva: Roche Diagnostics GmbH: Current Employment. Knuckles: Roche: Current Employment, Current equity holder in publicly-traded company. Hayward: Roche: Consultancy. 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 . Lechner: Roche: Current Employment, Current equity holder in publicly-traded company. Dimier: Roche: Current Employment, Current equity holder in publicly-traded company. Caimi: Abcon Therapeutics: Current holder of stock options in a privately-held company; BMS: Honoraria; Genmab: Research Funding; ADC Therapeutics: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Sobi: Honoraria; Recordati: Honoraria, Research Funding; Novartis: Honoraria; Luminary Therapeutics: Membership on an entity's Board of Directors or advisory committees. Falchi: Genentech, Roche, Genmab, AbbVie, Innate, BeiGene: Research Funding; EvolveImmune: Consultancy; Memorial Sloan Kettering Cancer Center: Current Employment; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Genmab: Consultancy, Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech, Roche, Genmab, Abbvie, Sanofi, EvolveImmune: Honoraria; AbbVie, Genentech, ADC Therapeutics, Seagen, Ipsen: Membership on an entity's Board of Directors or advisory committees; Taylor Francis: Other: Journal Editor; Kaplan: Other: CME Presentation: Projects in Knowledge. Gritti: Ideogen, Takeda: Speakers Bureau; Janssen, Beigene, Kite-Gilead, Roche, Sandoz: Other: Support for attending meetings; Takeda, Abbvie, Roche, Kite-Gilead, Ideogen, Genmab: Membership on an entity's Board of Directors or advisory committees. Morschhauser: AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Epizyme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Chugai: Honoraria; Roche/Genentech: Consultancy, Honoraria, Other: Payment for Expert Testimony, Honoraria for Scientific Lectures; Genmab: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Eisai: Honoraria; Kite/Gilead Sciences: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy. Hutchings: BMS/Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genmab: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Research Funding; Incyte: Research Funding; Janssen/J&J: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding. Dickinson: Roche: Consultancy, Honoraria, Speakers Bureau; Gilead: Consultancy, Honoraria, Speakers Bureau; Adicet Bio: Consultancy, Honoraria; Kite: Consultancy, Honoraria, Speakers Bureau; Genmab: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau. Carlo-Stella: Sanofi, ADC Therapeutics, Celgene/Bristol-Myers Squibb, Karyopharm Therapeutics, Roche, Novartis, Scenic Biotech, Janssen Oncology, Merck Sharp & Dohme, SOBI, AbbVie, Genmab, AstraZeneca: Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics, Roche, Sanofi: Research Funding; Sanofi, ADC Therapeutics: Consultancy; Karyopharm Therapeutics: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Scenic Biotech: Membership on an entity's Board of Directors or advisory committees; SOBI: Honoraria, Membership on an entity's Board of Directors or advisory committees; Humanitas University, Milano (Italy): Current Employment; Merck Sharp & Dohme: Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca, Celgene/Bristol-Myers Squibb, Incyte, Janssen Oncology, Takeda, Novartis, ADC Therapeutics, Roche, Gilead, SOBI, Merck Sharp & Dohme: Honoraria; Genmab: Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Honoraria; ADC Therapeutics: Consultancy, Honoraria, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria; Janssen Oncology: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees.