161P - Fibroblast activation protein (FAP)-CD40 (RO7300490) mediates intratumoral DC maturation and modulation of the tumor microenvironment

Background

Agonistic antibodies to CD40 expressed on antigen presenting cells (APCs), in particular DCs, upregulate tumour antigen-processing and presentation and enhance cross-priming of tumour-specific cytotoxic T-lymphocyte responses. FAP-CD40 (RO7300490) is a second-generation, bispecific CD40 agonist antibody targeted to FAP-expressing tumours to overcome systemic toxicities and broaden the therapeutic index of conventional anti-CD40-agonists.

Methods

The first in human (FIH) study in patients with advanced solid tumours has been concluded and preliminary clinical results have been presented (SITC 2023). Here we present key outcomes of the biomarker analysis. The pharmacodynamic effects in tumour tissue were investigated in-depth in two dedicated biomarker dose expansion cohorts designed to collect tumour biopsies before and after treatment (number of patients enrolled with mandatory biopsy collection: 19 and 24 at 140 mg and 550 mg dose, respectively).

Results

RO7300490 treatment resulted in a remarkable increase of DC-LAMP+ DC density in tumour tissue (DC-LAMP+ DC density log2 fold-change= 2.56, p< 0.01), confirming intratumoral pharmacodynamic activity and proof of mechanism. The increased density of DC-LAMP+ DCs coincided with a reduction of CLEC9A+ classical type 1 DCs (cDC1) (cDC1 density log2 fold-change= -1.23, p= 0.61), supporting the involvement of CD40 agonism in the maturation ofDC subsets in the tumour microenvironment. Moreover, RO7300490 treatment led to a notable increase in intratumor B cell density (B cell density log2 fold-change= 1.84, p< 0.05) and formation of pre-Tertiary Lymphoid Structures (pre-TLS), co-organized in focal micro-neighbourhoods together with DC-LAMP+ DCs. Together, these results provide robust evidence of significant modulation of the tumour microenvironment through FAP-targeted CD40 crosslinking.

Conclusions

In summary, targeting CD40 agonism to the tumour achieved a strong and sustained target engagement and tumour tissue immunomodulation with a favourable safety profile at all tested doses, supporting further studies in combination with other anti-cancer agents in earlier lines of treatment.

Clinical trial identification

WP42627.

Editorial acknowledgement

Legal entity responsible for the study

F. Hoffman-La Roche Ltd.

Funding

F. Hoffman-La Roche Ltd.

Disclosure

I. Melero: Financial Interests, Personal, Advisory Board: Agneus, Alligator Bioscience, AstraZeneca, BMS, BioLineRx, Boehringer Ingelheim, Boston Pharma, CRISPR Therapeutics, CatalYm GmbH, Crescendo Biologics, Curon BIopharmaceutical, EMD Serono, F-Star, Genentech, Genmab, Gossamer Bio, Highlight Therapeutics, Hookipa Pharma, HotSpot Therapeutics, Inc., ImmuneSensor Therapeutics, Inc., Janssen, MSD, Merus N.V., Monopteros Therapeutics, NOXXON Pharma AG, Numab, Phenomic Bio, Pieris Pharmaceuticals GmbH, Pierre Fabre, Roche, Sanofi, Senti Biosciences, Servier, Shattuck Labs, Third Rock Ventures; Financial Interests, Personal, Other, Consultant: Pharma Mar; Financial Interests, Institutional, Coordinating PI: AstraZeneca, Roche, BMS, Genmab, Alligator. B. Reis: Financial Interests, Personal, Full or part-time Employment: F. Hoffman-La Roche Ltd.; Financial Interests, Personal, Stocks/Shares: F. Hoffman-La Roche Ltd.. M.J. Lostes Bardaji: Financial Interests, Personal, Full or part-time Employment: VHIO; Financial Interests, Personal and Institutional, Research Funding: Anaveon AG, Bicycle TX Ltd, BI, GmbH, Catalym GmbH, Roche, Genentech, Genmab B.V., Janssen, Cilag International NV, Janssen, Servier, Medimmune, Merck & Co, Novartis, S.A, SOTIO, SQZ Biotechnologies, Symphogen, Taiho, T-Knife, DIGital, Institute for Canc. I. Spanggaard: Financial Interests, Institutional, Local PI: Roche, Puma Biotechnology, MSD, Genentech, Incyte, AstraZeneca, Orion, Pfizer; Non-Financial Interests, Principal Investigator: Roche, Puma Biotechnology, MSD, Genentech, Incyte, AstraZeneca, Orion, Pfizer. D.H. Lee: Financial Interests, Personal, Advisory Board, honoraria for lectures and consulting: AstraZeneca, Roche; Financial Interests, Personal, Advisory Board, honoraria for lectures: Novartis; Financial Interests, Personal, Invited Speaker, honoraria for lectures: Ono, Pfizer, Takeda, BluePrint Medicine, BC Pharma; Financial Interests, Personal, Advisory Board, honoraria for consulting: ST Cube, BMS, Bayer, AbbVie; Financial Interests, Personal, Advisory Board: Eli Lilly, ChongKeunDang; Financial Interests, Personal, Invited Speaker: Janssen; Financial Interests, Personal, Stocks/Shares: STCube. J. Spicer: Financial Interests, Institutional, Advisory Board, Compensation to my employer for time providing advice: AstraZeneca, BMS, GSK, RS Oncology; Financial Interests, Personal, Stocks/Shares, Co-founder: Epsilogen; Financial Interests, Personal, Stocks/Shares: Avacta; Financial Interests, Institutional, Local PI, Reimbursement for treatment of patients in trial: Achilles, Roche, Trizell, BergenBio, MSD, Gilead, Iovance; Financial Interests, Institutional, Coordinating PI, Reimbursement for treatment of patients in trial: Starpharma, BMS, IO Biotech, RS Oncology; Non-Financial Interests, Leadership Role, National strategy board: Experimental Cancer Medicine Centres; Non-Financial Interests, Member of Board of Directors, Steering Committee: British Thoracic Oncology Group; Non-Financial Interests, Advisory Role, Advice on licensing decisions for MHRA: CHM Expert Advisory Group on Oncology & Haematology; Non-Financial Interests, Advisory Role, Advice on regulatory approvals: CHM Cancer Vaccines Expert Working Group. F. Thistlethwaite: Financial Interests, Personal, Advisory Board, Ad board: BMS; Financial Interests, Personal, Advisory Board, Ad boards: GSK; Financial Interests, Personal, Advisory Board, Adboard/consultancy: T-Knife Therapeutics; Financial Interests, Personal, Advisory Board: Immatics, Scenic Biotech, F-Star, Leucid; 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, 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, 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) 2020-2024: 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; Non-Financial Interests, Advisory Role: ESMO TAT conference scientific advisory board 2025; Non-Financial Interests, 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. S.N. 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Hollebecque: Financial Interests, Personal, Invited Speaker: Servier, Incyte, EISAI, BMS; Financial Interests, Personal, Advisory Board: Basilea, Taiho, Relay Theraeutics, QED Therapeutics, Debiopharm, MSD, Boehringer Ingelheim; Financial Interests, Institutional, Funding: Incyte; Financial Interests, Institutional, Research Grant: AstraZeneca; Non-Financial Interests, Principal Investigator, M19-345 ; M21-404: AbbVie; Non-Financial Interests, Principal Investigator, CO42216; WP42627; CO40939; GO44479; GO42216: Roche; Non-Financial Interests, Principal Investigator, MCLA-158; MCLA-128: Merus; Non-Financial Interests, Principal Investigator, SGNB6A: Seatle Genetics; Non-Financial Interests, Principal Investigator, TAS-120-202: Taiho; Non-Financial Interests, Principal Investigator, Krystal-10: Mirati; Non-Financial Interests, Principal Investigator, ADP-0033: Adaptimmune; Non-Financial Interests, Principal Investigator, ACT16902: Sanofi; Non-Financial Interests, Principal Investigator, C4201002; SGNB6A: Pfizer; Non-Financial Interests, Principal Investigator, RLY-4008: Relay Therapeutics; Non-Financial Interests, Principal Investigator, CC-90011: Celgene/BMS; Non-Financial Interests, Principal Investigator, Loxo-IDH; Loxo-RAS: Loxo/Lilly; Non-Financial Interests, Principal Investigator: AstraZeneca; Non-Financial Interests, Principal Investigator, SN-201 study: Sotio; Non-Financial Interests, Principal Investigator, Tropics-03: Gilead; Non-Financial Interests, Principal Investigator, BI1403: Boehringer Ingelheim; Non-Financial Interests, Principal Investigator, CA120-1001: BMS. N. Rieder: Financial Interests, Personal, Full or part-time Employment: F. Hoffman-La Roche Ltd.; Financial Interests, Personal, Stocks/Shares: F. Hoffman-La Roche Ltd.. P. Schwalie, S. Badillo, N. Kumpesa, C. Rusterholz, O. Cirovic, A. Epp: Financial Interests, Personal, Full or part-time Employment: Roche; Financial Interests, Personal, Stocks/Shares: Roche. A. Thommen: Financial Interests, Personal, Full or part-time Employment: Roche; Financial Interests, Stocks/Shares: Roche. G. Kazantzidis: Financial Interests, Personal, Full or part-time Employment: Roche. V. Moreno Garcia: Financial Interests, Personal, Advisory Board: BMS, Janssen, Roche, Basilea, Bayer, AstraZeneca; Financial Interests, Personal, Full or part-time Employment: START; Financial Interests, Institutional, Local PI, AbbVie, AceaBio, Adaptimmune, ADC Therapeutics, Aduro, Agenus, Amcure, Amgen, Astellas, AstraZeneca, Bayer, BeiGene, BioInvent International AB, BMS, Boehringer Ingelheim, Boston, Celgene, Daiichi Sankyo, Debiopharm, Eisai, e-Terapeutics, Exelixis, Forma Therapeutics, Genmab, GSK, Harpoon, Hutchison, Immutep, Incyte, Inovio, Iovance, Janssen, Kyowa Kirin, Lilly, Loxo, MedSir, Menarini, Merck, Merus, Millennium, MSD, Nanobiotix, Nektar, Novartis, Odonate Therapeutics, Pfizer, PharmaMar, PharmaMar, Principia, PsiOxus, Puma, Regeneron, Rigontec, Roche, Sanofi, Sierra Oncology, Synthon, Taiho, Takeda, Tesaro, Transgene, Turning Point Therapeutics, Upshersmith.: Multiple.