66O - Association of a blood T cell fitness gene signature with clinical benefit from ImmTAC bispecific T cell engagers

Background

Tebentafusp (tebe), an ImmTAC bispecific (gp100 x CD3), showed OS benefit in metastatic uveal melanoma (mUM). A second ImmTAC, brenetafusp (brene; PRAME x CD3), showed activity in several tumors. Since ImmTAC bispecifics redirect T cells from blood to tumor, we explored whether baseline blood T cell fitness (TCF; ability to renew, proliferate, traffic to tumor as shown for CAR-T, TIL, BiTE) is associated with ImmTAC benefit.

Methods

Bulk RNAseq was conducted on whole blood from 2L+ mUM pts collected prior to tebe (Ph1/2; NCT02570308) or brene (Ph1; NCT04262466). T cell signatures were tested for association with clinical outcomes using KM methods, Cox regression and Fisher’s exact tests.

Results

In 132 pts, a T cell fitness signature (mean of TESPA1, CD28 and GPR183 expression) was strongly associated with tebe clinical benefit (Table). TCF was highly correlated with mean expression of the naïve and stem memory T cell (Tn/scm) genes IL7R, FOXO1 and TCF7 (ρ=0.9, p=2x10^-16). In multivariate analysis, TCF was associated with OS (HR 0.46, 95%CI 0.31-0.70, p

Conclusions

A blood T cell fitness signature that correlated with Tn/scm gene expression was strongly associated with tebe benefit. Association was confirmed with a second ImmTAC in mUM and in cutaneous melanoma (ASCO 2024) and ovarian cancer (ESMO 2024). Tn/scm may be an important determinant of ImmTAC benefit as described for other T cell therapies. The predictive vs prognostic utility of TCF should be tested prospectively.

Clinical trial identification

NCT02570308; NCT04262466.

Editorial acknowledgement

Legal entity responsible for the study

Immunocore Ltd.

Funding

Immunocore.

Disclosure

J.J. Sacco: Financial Interests, Institutional, Local PI: Amgen, AstraZeneca, Bristol Myers Squibb, Delcath Systems, Merck, Replimune, Transgene; Financial Interests, Institutional, Research Grant: AstraZeneca, Bristol Myers Squibb, Immunocore; Financial Interests, Institutional, Advisory Board: Bristol Myers Squibb, Delcath Systems, Immunocore, Merck; Other, Congress attendance: Bristol Myers Squibb: Bristol Myers Squibb; Other, Congress attendance: Merck. R.D. Carvajal: Financial Interests, Personal, Advisory Board: Alkermes, Bristol Myers Squibb, Castle Biosciences, Delcath, Eisai, Hengrui, Ideaya, Immunocore, InxMed, Iovance, Merck, Novartis, Oncosec, Pierre Fabre, Puretech Health, Regeneron, Sanofi, TriSalus. O. Hamid: Financial Interests, Personal, Advisory Board: Alkermes, Amgen, BMS, Bactonix, BeiGene, Bioatla, Eisai, GSK, Georgiamune, GigaGen, Grit Bio, IO Biotech, Idera, Immunocore, Incyte, Instil Bio, Iovance, Janssen, KSQ, Merck, Novartis, Obsidian, Pfizer, Roche Genentech, Seagen, Sanofi/Regeneron, Tempus, Vial, Zelluna; Financial Interests, Personal, Invited Speaker: BMS, Immunocore, Novartis, Pfizer, Sanofi/Regeneron; Financial Interests, Personal, Stocks/Shares: Bactonix; Financial Interests, Institutional, Local PI: Aduro, Akeso, Amgen, Arcus, BMS, Bioatla, CytomX, Exelixis, GSK, Idera, Immunocore, Incyte, Iovance, Merck, Merck Serono, Moderna, Nextcure, Novartis, Pfizer, Roche Genentech, Seagen, Sanofi/Regeneron, Torque, Zelluna. P.B. Kirk, F. Peck, K. Ranade: Financial Interests, Personal, Full or part-time Employment: Immunocore. L. Collins: Financial Interests, Personal, Full or part-time Employment: Immunocore; Financial Interests, Personal, Stocks/Shares: Immunocore. M.O. Butler: Financial Interests, Personal, Advisory Board: BMS, Merck, Novartis, Adaptimmune, Instil Bio, Iovance, Sun Pharma, GSK, Sanofi, La Roche Posay, Pfizer, Medison, IDEAYA, Regeneron; Financial Interests, Personal, Invited Speaker: BMS, Merck, Novartis, Sanofi, Pfizer; Financial Interests, Personal, Advisory Board, Safety Review Committee: Adaptimmune; Financial Interests, Institutional, Research Grant, support clinical trial: Merck; Financial Interests, Institutional, Funding, support clinical trial: Takara Bio; Financial Interests, Institutional, Funding, support quality improvement project: Novartis. A.N. Shoushtari: Financial Interests, Personal, Advisory Board: Bristol Myers Squibb, Immunocore, Novartis, Erasca; Financial Interests, Personal, Royalties: UptoDate; Financial Interests, Institutional, Local PI: Bristol Myers Squibb, Immunocore, Pfizer, Novartis, Checkmate Pharmaceuticals, Linnaeus Therapeutics, Foghorn Therapeutics, Prelude Therapeutics, Iovance Biotherapeutics; Financial Interests, Institutional, Coordinating PI: Polaris, Xcovery, Targovax ASA; Non-Financial Interests, Member: ASCO. J.C. Hassel: Financial Interests, Personal, Invited Speaker: BMS, Novartis, Sanofi, MSD, Sunpharma, Amgen, GSK, Pierre Fabre, Immunocore; Financial Interests, Personal, Advisory Board: MSD, Pierre Fabre, Sunpharma, GSK, Onkowissen; Financial Interests, Institutional, Advisory Board: Novartis, BMS, Immunocore, Philogen, Sanofi; Financial Interests, Institutional, Research Grant: BMS, Sunpharma; Financial Interests, Institutional, Local PI: Philogen, Genentech, 4SC, BioNTech, Idera, Iovance, Nektar, Pierre Fabre, Regeneron, Sanofi, Replimune; Financial Interests, Institutional, Coordinating PI: BMS, Immunocore, Novartis, Genmab; Financial Interests, Personal, Steering Committee Member: Immunocore, IO Biotech; Non-Financial Interests, Leadership Role: DeCOG; Non-Financial Interests, Member: ASCO. A.P. Ikeguchi: Financial Interests, Institutional, Research Funding: Dynavax, GSK/Sarah Cannon, Immunocore, Merck, Neon/Therapeutics, Chekmate Pharmaeuticals. L. Hernandez-Aya: Financial Interests, Institutional, Advisory Board: BMS, Castle Bioscience, AstraZeneca, Merck, Amgen, Roche, Regeneron, Novartis, Immunocore, Merck-EMD, Corvus, Polinoma, Genentech, Foghorn; Financial Interests, Institutional, Research Funding: BMS. P. Nathan: Financial Interests, Personal, Advisory Board: BMS, Immunocore, Novartis, Merck, Pfizer, 4SC, IDEAYA; Financial Interests, Institutional, Other, research support: Immunocore; Financial Interests, Personal, Invited Speaker: Novartis, Immunocore; Financial Interests, Institutional, Coordinating PI: BMS, Novartis, Ipsen, Immunocore, Merck, Pfizer; Financial Interests, Personal, Steering Committee Member: 4SC. J.M. Piulats Rodriguez: Financial Interests, Personal, Advisory Board: Janssen, Astellas, Roche, BMS, MSD, BeiGene, VCN, AstraZeneca, Immunocore, Novartis; Financial Interests, Personal and Institutional, Research Grant: BMS, Pfizer, Janssen, BeiGene, Mirati, Immunocore, Regeneron. H. Shaw: Financial Interests, Personal, Invited Speaker: Novartis, ScanCell, MSD, BMS, Eisai, AstraZeneca, Sanofi; Financial Interests, Personal, Advisory Board: Immunocore, Therakos/Mallinkrodt, ScanCell, CDR-Life, Regeneron, MSD; Financial Interests, Personal, Writing Engagement: Sanofi; Financial Interests, Institutional, Coordinating PI: Immunocore, Iovance, IDEAYA, MSD; Financial Interests, Institutional, Local PI: Immunocore, ScanCell, MSD; Financial Interests, Institutional, Steering Committee Member: Immunocore; Financial Interests, Personal, Steering Committee Member: BMS; Financial Interests, Institutional, Funding, Data manager funding: Immunocore; Financial Interests, Institutional, Funding, Immunotherapy nurse pilot project funding - JWP: MSD; Non-Financial Interests, Advisory Role, Non-remunerated advisory role: NovalGen; Non-Financial Interests, Advisory Role: iOnctura, Agenus. D. Davar: Financial Interests, Personal, Advisory Board: ACM Bio, Ascendis, Clinical Care Options (CCO), Gerson Lehrman Group (GLG), Immunitas, Medical Learning Group (MLG), Replimmune, Trisalus, Xilio Therapeutics; Financial Interests, Personal, Stocks/Shares: Zola; Financial Interests, Institutional, Other, US Patent 63/124,231, “Compositions and Methods for Treating Cancer”, Dec 11, 2020: None; Financial Interests, Institutional, Royalties, US Patent 63/208,719, “Compositions and Methods For Responsiveness to Immune Checkpoint Inhibitors (ICI), Increasing Effectiveness of ICI and Treating Cancer”, June 9, 2021: None; Financial Interests, Institutional, Coordinating PI: Arcus, Immunocore, Merck, Regeneron Pharmaceuticals Inc., Tesaro/GSK. M.R. Middleton: Financial Interests, Personal, Advisory Board: Alkermes, Boehringer Ingelheim, Bristol Myers Squibb; Financial Interests, Personal, Other: Immunocore, Infinitopes, GRAIL. F. Thistlethwaite: Financial Interests, Personal, Advisory Board, Ad board: BMS; Financial Interests, Personal, Advisory Board, Ad boards: GSK; Financial Interests, Personal, Advisory Board, Ad board/consultancy: T-Knife Therapeutics; Financial Interests, Personal, Advisory Board: Janssen, Immatics, Ixaka, Scenic Biotech, F-Star, Leucid; Financial Interests, Personal, Invited Speaker: Kite Gilead; Financial Interests, Personal, Other, Occasional individual consulting: Guidepoint; Financial Interests, Institutional, Other, iMATCH is a 12 partner consortium funded by not for profit Innovate UK (UK government body) partners include commercial, clinical and academic institutes. I am director and my salary (0.1WTE) 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, Officer, Clinical lead for this 10 partner consortium of clinical academic and commercial partners. My salary is partly supported (approx. 0.05WTE) through this by a grant paid by Innovate UK (a NFP government body) to my institution (The Christie NHS foundation trust a NFP UK hospital): Sample; Financial Interests, Institutional, Local PI, NCT02890069: Novartis; Financial Interests, Institutional, Research Grant, Sarcoma pathways project and CAR-T PROMs study: GSK; Financial Interests, Institutional, Local PI, NCT02493751: Pfizer; Financial Interests, Institutional, Local PI, NCT03245736, NCT02988817, NCT02552121, NCT02001623, NCT05180474: GenMab; Financial Interests, Institutional, Local PI, NCT02277717: Synthon; Financial Interests, Institutional, Local PI, NCT03013491: CytomX; Financial Interests, Institutional, Local PI, NCT03314935: Incyte; Financial Interests, Institutional, Local PI, NCT02908906 and CAR-T referrals project: Janssen; Financial Interests, Institutional, Local PI, NCT03132792, NCT04044768,: Adaptimmune; Financial Interests, Institutional, Local PI, NCT03400332: BMS; Financial Interests, Institutional, Local PI, NCT04262466, NCT03973333, NCT03515551: Immunocore; Financial Interests, Institutional, Local PI, EudraCT 2018-001005-85, 2018-003446-16: Achilles ltd; Financial Interests, Institutional, Local PI: Agalimmune Ltd; Financial Interests, Institutional, Local PI, NCT02834247: Millenium Pharmaceuticals/Takeda; Financial Interests, Institutional, Local PI, NCT02690350: Daiichi Sankyo; Financial Interests, Institutional, Local PI, NCT04839991: Crescendo; Financial Interests, Institutional, Local PI, NCT05104515: Oxford Vacmedix Ltd; Financial Interests, Institutional, Local PI, NCT05278975: RS Oncology LLC; Financial Interests, Institutional, Coordinating PI, NCT03697824, NCT03391778: GSK; Financial Interests, Institutional, Coordinating PI, NCT04140500, NCT04857138, NCT04826003: Roche; Financial Interests, Personal, Coordinating PI, NCT05008913, NCT04949425, NCT0331509, NCT03313557: AstraZeneca; Financial Interests, Institutional, Coordinating PI, NCT03829501: Kymab Ltd/Sanofi; Financial Interests, Institutional, Coordinating PI, EudraCT 2019-003329-11: Chugai; Financial Interests, Institutional, Coordinating PI, NCT05430555: T-Knife Therapeutics; Financial Interests, Institutional, Coordinating PI, NCT03621982: ADCT Therapeutics; Financial Interests, Institutional, Research Grant, IRAS Project ID: 227414: Novartis; Financial Interests, Institutional, Coordinating PI, ITIL-306-202: Instil Bio; Financial Interests, Institutional, Funding, CAR-T referrals project: Gilead, Autolus; Financial Interests, Institutional, Local PI, NCT04763083: Novalgen; Financial Interests, Institutional, Local PI, NCT05714553: Nucana; Non-Financial Interests, Other, Panel member for a funding committee (MRC is a UK government NFP organisation): MRC DPFS panel member; Non-Financial Interests, 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, 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, Advisory Role, Funding panel member for CRUK (not-for profit charity). Role is not compensated: CRUK New Agents Committee Member; Non-Financial Interests, 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, Leadership Role: ESMO Congress 2024 Experimental Immunotherapy Track Chair. T. Sato: Financial Interests, Institutional, Advisory Board: Immunocore, Castle Biosciences; Financial Interests, Institutional, Research Funding: Immunocore, Verastem, IDEAYA, TriSalus, BMS. All other authors have declared no conflicts of interest.