Abstract 58P
Background
Engineered to activate a patient’s own immune response, T Cell Engagers (TCEs) are uniquely positioned to mediate T cell directed efficacy through targeted engagement of a tumour antigen. Despite their attractive properties TCE therapies have yet to lead in the treatment of solid tumours with limiting factors that include adverse toxicity profiles. This systematic review and meta-analysis explores the role of TCE structure, bioavailability, and mechanism of action to better understand TCE-mediated toxicity.
Methods
Papers were sourced from MEDLINE, Cochrane Library, CINHL, EMBASE, Web of Knowledge, Scopus. The Cochrane Collaboration Risk of Bias Tool v13 was used to evaluate publication bias. Prevalence data from the identified primary studies was pooled using an inverse variance method with a restricted maximum-likelihood (REML) estimator and the Freeman-Tukey double arcsine transformation to determine toxicity prevalence and confidence intervals.
Results
A total of 1136 publications were identified of which 71 were selected for review. Toxicity profiles from 16 TCEs, comprising 9 different ligands that utilised the CD3, CD40, CD28 or CD64 signalling pathways were characterised in this study. Toxicity type and severity were associated with the ligand, potency to induce T-cell response and treatment duration. Toxicity was independent of a patient’s primary tumour type, patient gender, ethnicity, and age. Whilst Cytokine release syndrome (CRS) was reported as the predominant toxicity for many TCEs, this was not always the case. For instance, patients treated with MDX-H210 (EpCAM containing ligand), exhibited gastrointestinal (GI) and liver toxicity prevalence of 31% (CI 0 – 0.95) compared to CRS that was prevalent at 18% (CI 0 – 0.67). TCEs containing NY-ESO-1 predominantly elicited haematological toxicities (prevalence 0.97 (CI 0.54 – 1).
Conclusions
This study highlights the importance of recognising toxicities other than CRS and acknowledges that each TCE favours a particular toxicity profile. A tailored approach to the management of TCEs should be based on the tumour-associated ligand, TCE structure and propensity to activate certain downstream T cell mediated pathways.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The Christie NHS Trust.
Funding
Has not received any funding.
Disclosure
F. Thistlethwaite: Financial Interests, Personal, Advisory Board, Adboard/consultancy: T-Knife Therapeutics; Financial Interests, Personal, Advisory Board: Immatics, Scenic Biotech, F-Star; Financial Interests, Personal, Invited Speaker: Kite Gilead; Financial Interests, Personal, Other, Occasional individual consulting: Guidepoint; Financial Interests, Personal, Advisory Board, Advisory board meeting Feb 2023: CytomX; Financial Interests, Personal, Advisory Board, Advisory board Feb 2024: Grey Wolf Therapeutics; Financial Interests, Personal, Invited Speaker, Video interview speaking as an expert on emerging IO therapies (not speaking on behalf of ESMO): AstraZeneca; Financial Interests, Institutional, Other, iMATCH is a consortium funded by not for profit Innovate UK (UK government body) partners include clinical and academic institutes. I am director and my salary (0.2WTE) is supported through this work as a grant to my institution (The Christie NHS foundation trust - not for profit NHS hospital) from IUK: iMATCH director; Financial Interests, Institutional, Invited Speaker, NCT02890069: Novartis; Financial Interests, Institutional, Research Grant, Sarcoma pathways project and CAR-T PROMs study: GSK; Financial Interests, Institutional, Invited Speaker, NCT02493751: Pfizer; Financial Interests, Institutional, Invited Speaker, NCT03245736, NCT02988817, NCT02552121, NCT02001623, NCT05180474: GenMab; Financial Interests, Institutional, Invited Speaker, NCT03013491: CytomX; Financial Interests, Institutional, Invited Speaker, NCT03314935: Incyte; Financial Interests, Institutional, Invited Speaker, NCT02908906 and CAR-T referrals project: Janssen; Financial Interests, Institutional, Invited Speaker, NCT03132792, NCT04044768,: Adaptimmune; Financial Interests, Institutional, Invited Speaker, NCT03400332: BMS; Financial Interests, Institutional, Invited Speaker, NCT04262466, NCT03973333, NCT03515551: Immunocore; Financial Interests, Institutional, Invited Speaker, EudraCT Number: 2018-001005-85, 2018-003446-16: Achilles ltd; Financial Interests, Institutional, Invited Speaker: Agalimmune Ltd; Financial Interests, Institutional, Invited Speaker, NCT04839991: Crescendo; Financial Interests, Institutional, Invited Speaker, NCT05104515: Oxford Vacmedix Ltd; Financial Interests, Institutional, Invited Speaker, NCT05278975: RS Oncology LLC; Financial Interests, Institutional, Invited Speaker, NCT03697824, NCT03391778: GSK; Financial Interests, Institutional, Invited Speaker, NCT04140500, NCT04857138, NCT04826003: Roche; Financial Interests, Personal, Invited Speaker, NCT05008913, NCT04949425, NCT03315091, NCT03313557: AstraZeneca; Financial Interests, Institutional, Invited Speaker, NCT03829501: Kymab Ltd/Sanofi; Financial Interests, Institutional, Invited Speaker, EUDRACT ID No: 2019-003329-11: Chugai; Financial Interests, Institutional, Invited Speaker, NCT05430555: T-Knife Therapeutics; Financial Interests, Institutional, Invited Speaker, NCT03621982: ADCT Therapeutics; Financial Interests, Institutional, Research Grant, IRAS Project ID: 227414: Novartis; Financial Interests, Institutional, Invited Speaker, ITIL-306-202: Instil Bio; Financial Interests, Institutional, Funding, CAR-T referrals project: Gilead, Autolus; Financial Interests, Institutional, Invited Speaker, NCT04763083: Novalgen; Financial Interests, Institutional, Invited Speaker, NCT05714553: Nucana; Non-Financial Interests, Personal, Other, Panel member for a funding committee (MRC is a UK government NFP organisation) 2020-2024: MRC DPFS panel member; Non-Financial Interests, Personal, Advisory Role, Sarcoma UK is a not-for-profit charity. I act as an advisor on their Research Strategy Committee. This role is not compensated: Sarcoma UK; Non-Financial Interests, Personal, Leadership Role, Funding is from not-for-profit government bodies. Role is not compensated.: Chair of the Independent Steering Committee for NIHR Blood & Transplant Research Unit, Oxford; Non-Financial Interests, Personal, Advisory Role, Funding panel member for CRUK (not-for profit charity). Role is not compensated: CRUK New Agents Committee Member; Non-Financial Interests, Personal, Leadership Role, Chair of Cell therapy subgroup. MRC is a not-for-profit organisation. Role is not compensated.: MRC Advanced Therapies Task Group; Non-Financial Interests, Personal, Leadership Role: ESMO Congress 2024 Experimental Immunotherapy Track Chair; Non-Financial Interests, Personal, Advisory Role: ESMO TAT conference scientific advisory board 2025; Non-Financial Interests, Personal, Advisory Role, Target Ovarian Cancer is a not-for-profit charity. I am Chair of their Scientific Advisory board. This role is not compensated: Target Ovarian Cancer. All other authors have declared no conflicts of interest.