Session: 622. Lymphomas: Translational–Non-Genetic: Poster II
Hematology Disease Topics & Pathways:
adult, Antibody Therapy, clinical trials, Research, Biological therapies, assays, Translational Research, Bispecific Antibody Therapy, Lymphomas, non-Hodgkin lymphoma, Clinical Research, immune mechanism, Diseases, indolent lymphoma, aggressive lymphoma, Immunotherapy, Therapies, Lymphoid Malignancies, Biological Processes, Technology and Procedures, Study Population, Human, profiling, Minimal Residual Disease , molecular testing
Methods: Data to date were obtained from patients on dose escalation cohorts that received 0.5-1000 mg under fixed or dose titration schemes (n=40). Immune profiling of peripheral blood was performed by flow cytometry. Plasma biomarker evaluation included measurement of cytokines by MSD, complement activation markers by ELISA, and ctDNA-MRD by PhasED-Seq (Foresight Dx). Tumor biomarkers were assessed in baseline and on-treatment tissue through immunohistochemistry.
Results: Imvotamab biologic activity was observed starting at the 10 mg dose, as evidenced by transient elevations in plasma cytokines, which occurred over multiple sequential infusions, peaking within 2-12 hours post-infusion and returning to baseline by 24 hours. Maximal cytokine levels were observed after Cycle 1 Day 1 in the majority of patients, including those that received dose titration. In contrast to bispecific IgG T cell engagers, imvotamab induced consistently higher levels of IFNγ relative to inflammatory cytokines such as IL-6 and TNFα. However, patients with cytokine release syndrome (CRS) exhibited a poly-cytokine profile, where elevated levels of multiple cytokines in addition to IFNγ were also observed. The timing of poly-cytokine response corresponded with the onset and duration of CRS.
Complement activation factors Bb, C3a, C4a, and sC5b9 transiently increased ~2-5 fold on average in plasma of nearly all patients tested, with peak values detected immediately after the first dose. Circulating B cells were depleted by the end of Cycle 1 in majority of patients with measurable B cells at baseline. In peripheral blood, imvotamab infusion resulted in rapid and transient T cell activation that coincided with T cell margination. There was a trend for higher frequency of activated CD69+ T cells and greater margination at 24 hours following intermediate 100 and 300 mg vs. higher 600 and 1000 mg plateau doses. Notably, patients with progressive disease did not show significant T cell activation. Patients with complete response had marked elevations of T cells at later cycles; these patients also had higher baseline T cell counts vs. others (median: 910 vs. 590 cells/ul). The proportion of PD1+ T cells on-treatment was ~2-fold lower in responders vs. non-responders.
Paired tumor biopsies showed increase of intratumoral CD3+ T cells on-treatment regardless of response. At baseline, some complete responders had low CD20 expression, as indicated by CD20 H-scores < 30. Finally, ctDNA analysis in a subset of patients showed greater depth of decrease in responders vs. non-responders, with sustained MRD responses seen in samples > 1 year from patients with complete response.
Conclusions: Acute pharmacodynamic changes confirm TDCC and CDC MOA for imvotamab in patients. The repeatable IFNγ-dominant cytokine profile is consistent with its ability to induce a more physiologic stimulation that can preserve or strengthen T cell effector function, without overstimulating undesired inflammatory cytokines related to CRS. Overall, the data support the use of dose titration as a safe and efficacious drug administration scheme and suggest a model whereby an optimal number of sufficiently activated and functional T cells may be required to elicit strong and durable clinical responses. Updated analyses will be presented at the meeting.
Disclosures: Hernandez: IGM Biosciences, Inc.: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties: WO2022109023A1; Teiko Bio: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees. So: IGM Biosciences, Inc.: Current Employment, Current equity holder in publicly-traded company. Logronio: IGM Biosciences, Inc.: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties: WO2022109023A1. Kotturi: IGM Biosciences, Inc.: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties: WO2022109023A1. Armand: GenMab: Consultancy; Tessa Therapeutics: Consultancy; ADC Therapeutics: Consultancy; Kite Pharma: Research Funding; IGM Biosciences: Research Funding; Roche/Genentech: Consultancy, Research Funding; Adaptive Biotechnologies: Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Merck: Consultancy, Honoraria, Research Funding; C4 Therapeutics: Consultancy; Enterome: Consultancy; Regeneron: Consultancy; Epizyme: Consultancy; AstraZeneca: Consultancy. Cheah: Novartis: Consultancy, Honoraria; Beigene: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria; Eli Lilly and Company: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Merck Sharp & Dohme: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding. Gopal: Merck, I-Mab bio, IgM Bio, Takeda, Gilead, Astra-Zeneca, Agios, Janssen, BMS, SeaGen, Teva, Genmab: Research Funding; Incyte, Kite, Morphosys/Incyte, ADCT, Acrotech, Merck, Karyopharm, Servier, Beigene, Cellectar, Janssen, SeaGen, Epizyme, I-Mab bio, Gilead, Genentech, Lilly, Caribou, Fresenius-Kabi: Consultancy, Honoraria. Flinn: Takeda: Consultancy; MorphoSys: Consultancy, Research Funding; Roche: Consultancy, Research Funding; 2seventy bio: Research Funding; Triphase Research & Development Corp: Research Funding; Tessa Therapeutics: Research Funding; Biopath: Research Funding; Servier Pharmaceuticals: Consultancy; Janssen: Consultancy, Research Funding; Forty Seven: Research Funding; Forma Therapeutics: Research Funding; Unum Therapeutics: Research Funding; Bristol Myers Squibb: Research Funding; Fate Therapeutics: Research Funding; TG Therapeutics: Consultancy, Research Funding; Millenium Pharmaceuticals: Research Funding; Novartis: Consultancy, Research Funding; ArQule: Research Funding; Agios: Research Funding; Celgene: Research Funding; Trillium Therapeutics: Research Funding; Seattle Genetics: Research Funding; Constellation Pharmaceuticals: Research Funding; Nurix Therapeutics: Consultancy, Research Funding; Kite Pharma: Consultancy, Research Funding; TCR2 Therapeutics: Research Funding; Vincerx Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Acerta Pharma: Research Funding; Pharmacyclics: Consultancy, Research Funding; Portola Pharmaceuticals: Research Funding; Curis: Research Funding; Infinity Pharmaceuticals: Research Funding; Loxo@Lilly: Research Funding; Myeloid Therapeutics: Research Funding; Verastem: Consultancy, Research Funding; CALIBR: Research Funding; CALGB: Research Funding; Incyte: Research Funding; IGM Biosciences: Research Funding; Rhizen Pharmaceuticals: Research Funding; Merck: Research Funding; Secura Bio: Consultancy; Xencor: Consultancy; Pfizer: Research Funding; City of Hope National Medical Center: Research Funding; Epizyme: Research Funding; CTI Biopharma: Research Funding; InnoCare Pharma: Consultancy, Research Funding; Iksuda Therapeutics: Consultancy; Hutchison MediPharma: Consultancy; Gilead Sciences: Research Funding; Genmab: Consultancy; Genentech: Consultancy, Research Funding; Century Therapeutics: Consultancy; AstraZeneca: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding. Gregory: Roche, BMS: Honoraria; Roche: Speakers Bureau; BeiGene, Merck, AbbVie, Janssen: Research Funding; Roche, Novartis: Other: Travel/ Accommodations/ Expenses; Janssen: Other: Expert testimony; Roche, Novartis, BMS, Janssen: Consultancy. Matasar: Karyopharm: Consultancy; Rocket Medical: Consultancy, Research Funding; Merck: Consultancy, Current equity holder in private company; TG Therapeutics: Consultancy; Juno Therapeutics: Consultancy; Genentech, Inc.: Consultancy, Honoraria, Research Funding; F. Hoffmann-La Roche Ltd.: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy; Bayer: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Honoraria, Research Funding; AstraZeneca: Consultancy; Teva: Consultancy; Takeda: Consultancy, Honoraria; Epizyme: Consultancy, Honoraria; IMV Therapeutics: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria, Research Funding; ImmunoVaccine Technologies: Honoraria, Research Funding; ADC Therapeutics: Consultancy, Honoraria; Janssen: Honoraria, Research Funding; IGM Biosciences: Research Funding; Pharmacyclics: Honoraria, Research Funding. Nastoupil: BMS, Caribou Biosciences, Epizyme, Genentech, Gilead/Kite, Genmab, Janssen, IGM Biosciences, Novartis, Takeda: Research Funding; ADC Therapeutics, BMS, Caribou Biosciences, Epizyme, Genentech/Roche, Gilead/Kite, Genmab, Janssen, MEI, Morphosys, Novartis, Takeda: Honoraria; Genentech/Roche, MEI, Takeda: Other: DSMC. Diefenbach: Kite: Consultancy; Incyte: Research Funding; IMAB: Consultancy; Gilead: Current equity holder in publicly-traded company; Genmab: Consultancy; Genentech/Roche: Consultancy, Research Funding; FATE Therapeutics: Research Funding; Celgene: Consultancy; BMS: Consultancy, Research Funding; Merck: Consultancy, Research Funding; MEI Pharma: Research Funding; MorphoSys: Consultancy, Research Funding; Seattle Genetics: Research Funding. Yoon: Kyowa Kirin: Research Funding; Astellas Pharma: Consultancy; Tikaros: Consultancy; Yuhan Pharmaceutical: Research Funding; Roche-Genetech: Research Funding; Takeda: Consultancy; Janssen Pharmaceutical: Consultancy; Celgene: Consultancy; Chugai Pharmaceutical: Consultancy; Novartis: Consultancy; Amgen: Consultancy. Ku: Genor BioPharma: Consultancy; Roche: Consultancy; St Vincent's Hospital: Current Employment; Antengene: Consultancy. Qazi: IGM Biosciences, Inc.: Current Employment, Current equity holder in publicly-traded company. Leabman: IGM Biosciences, Inc.: Current Employment, Current equity holder in publicly-traded company. Sison: IGM Biosciences, Inc.: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties: WO2022109023A1. Keyt: IGM Biosciences: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties. Takimoto: IGM Biosciences, Inc.: Current Employment, Current equity holder in publicly-traded company. Manley: IGM Biosciences, Inc.: Current Employment, Current equity holder in publicly-traded company. Budde: Merck: Research Funding; Amgen: Research Funding; Amgen: Research Funding; AstraZeneca: Research Funding; Mustang Therapeutics: Research Funding; Ziopharm: Other: DMSC member for a phase 1 clinical; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; BeiGene: Membership on an entity's Board of Directors or advisory committees.
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