17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023.

Abstract

Introduction: T cells normally recognize bacterial proteins originating from the gut microbiome, including some that cross-react with normal host B cell-specific proteins. A peptide-based strategy designed to activate and expand such pre-existing memory CD8+ T cells recognizing and driving anti-tumor activity against B cell malignancies was developed. EO2463 includes 4 synthetically produced peptides corresponding to cytotoxic CD8 HLA-A2 restricted epitopes which exhibit molecular mimicry with the B cell antigens CD20, CD22, CD37, and CD268 (BAFF-receptor), as well as a helper CD4 peptide, UCP2, derived from hTERT. Memory CD8+ T cell clones can be detected in the peripheral blood of healthy donors recognizing the EO2463 mimic peptides; in vitro, such cells can kill target T2 cells loaded with mimic or human counterpart peptides. Methods: This first-in-human trial include HLA-A2+ patients (pts) with follicular lymphoma (FL) and marginal zone lymphoma (MZL). In the safety lead-in dose-finding part, EO2463 is administered subcutaneously every other week (w) × 4, followed by monthly administrations for a max of 12 months. After 6 w of EO2463 monotherapy, oral lenalidomide (20 mg/day for 21/28 days up to 12 cycles) is added, and if no complete remission (CR) at w 19, rituximab (375 mg/m2 IV, weekly × 4, followed by q4 w infusions × 4) is also added. The peptide-dose is evaluated in a 3-by-3 safety design, starting at 150 μg/peptide, max escalation to 300 μg. Results: Pts in the 1st (150 μg dose; 3 pts) and 2nd (300 μg dose; 3 pts) cohorts received EO2463 monotherapy without related grade ≥3 adverse events. Three more pts are being enrolled at the 300 μg dose, prior to starting expansion cohorts. Among the initial 6 pts, 5 had FL and 1 MZL; median number of prior therapies was 1 (range 1–4). Objective response rate 67%, including 50% CR (at w18, w18, w42), and 17% partial remission (at w18; ongoing treatment). On EO2463 monotherapy (at w6), 3 stable disease (including one metabolic response in 5 of 6 target lesions), 2 indeterminate responses (increased FDG uptake, no size change), 1 progressive disease. Combination therapy toxicity; grade 3 thrombocytopenia, rash, anemia, atrial fibrillation, bronchitis and sepsis (all n = 1); in addition, grade 4 neutropenia (n = 2). Expansion of specific CD8+ T cells against the mimic peptides and targeted B cell proteins was detected in 4/6 pts, including in 2 pts with no measurable B cells at baseline (prior anti-CD20). Immune response was maintained even following addition of rituximab. In vitro expanded EO2463 specific CD8+ T cells from pts with immune response can kill malignant HLA-A2 B cell lines. Conclusions: EO2463 is well tolerated as monotherapy, and without additional safety signals when combined with lenalidomide and rituximab. We find evidence of on-target immune activation, and preliminary complete response rate is encouraging. Expanded data to be presented. NCT04669171. Keywords: Combination Therapies, Immunotherapy, Indolent non-Hodgkin lymphoma Conflicts of interests pertinent to the abstract. A. A. Pinto Consultant or advisory role: Scientific Advisory Boards (F. Hoffmann-La Roche AG, Merck Sharp and Dohme, Incyte-Italy) Honoraria: Speaking engagements – Educational Lectures (F. Hoffmann-La Roche AG, Incyte –Italy, Merck Sharp and Dohme, Servier Affaires Medicales, BMS-CELGENE) Other remuneration: Speaker's Bureau: Incyte-Italy, F. Hoffmann-La Roche AG S. D. Smith Consultant or advisory role: ADC Therapeutics, Astrazeneca, Beigene, Epizyme, Karyopharm, KITE pharma, Incyte, Numab Therapeutics, AG Abbvie, Coherus Biosciences, advisory board (spouse): Genentech Research funding: ADC Therapeutics, Astrazeneca, Ayala (spouse), Bayer, Beigene, Bristol Myers Squibb (spouse), De Novo Biopharma, Enterome, Genentech, Ignyta (spouse), Incyte Corporation, Kymera Therapeutics, Merck Sharp and Dohme Corp., MorphoSys, Nanjing Pharmaceuticals Co., Ltd., Portola Pharmaceuticals, Viracta Therapeutics L. Arcaini Consultant or advisory role: Roche, Janssen-Cilag, Verastem, Incyte, EUSA Pharma, Celgene/Bristol Myers Squibb, Kite/Gilead, ADC Therapeutics Research funding: Gilead Sciences Other remuneration: Speakers’ Bureau: EUSA Pharma, Novartis R. Merryman Consultant or advisory role: Genmab, Adaptive Biotechnologies, Bristol Myers Squibb, Abbvie, Inteillia, Epizyme, Alphasights Research funding: Merck, Bristol Myers Squibb, Genmab, Genentech/Roche S. Ansel Research funding: Bristol Myers Squibb, SeaGen, Takeda, Regeneron, AstraZeneca, Pfizer, Affimed and ADC Therapeutics. P. Armand Consultant or advisory role: Merck, BMS, ADC Therapeutics, Tessa, GenMab, Enterome, Regeneron, Epizyme, Astra Zeneca, Genentech, Xencor, ATB Therapeutics Honoraria: Merck Research funding: Kite, Merck, BMS, Adaptive, Genentech, IGM P. L. Zinzani Consultant or advisory role: Secura Bio, Celltrion, Gilead, Janssen-Cilag, BMS, Servier, Sandoz, MSD, AstraZeneca, Takeda, Roche, Eusa Pharma, Kyowa Kirin, Novartis, ADC Therap., Incyte, Beigene Other remuneration: Speaker's Bureau: Celltrion, Gilead, Janssen-Cilag, BMS, Servier, MSD, AstraZeneca, Takeda, Roche, Eusa Pharma, Kyowa Kirin, Novartis, Incyte, Beigene