561P - Liquid biopsy tracking of immunotherapy-induced T cell dynamics in MSS colorectal and endometrial tumors

Background

Immune checkpoint inhibition (ICI) shows high response rates in MSI colorectal (CRC) and endometrial cancer (EC) but has low efficacy in MSS tumors. The presence of T cells in tumors correlates with response to ICI. Profiling of the T cell receptor (TCR) provides evidence of anti-tumor T cell activity and is used to track T cell clones longitudinally. We present spatio-temporal T cell clonal tracking in blood and matched biopsies as a correlate of ICI efficacy in patients with refractory MSS/MSI CRC and EC treated with single dose tremelimumab (Trem) followed by Durvalumab (Dur) or Dur as monotherapy.

Methods

The SERPENTINE trial includes patients with advanced MSS/MSI CRC/EC that progressed during/after standard therapy with measurable disease per RECIST 1.1, ECOG ≤1, treated with Dur 1500mg plus Trem 300mg at Week 0, followed by Dur 1500 mg Q4W. The patient response was correlated with TCR dynamics (3-4 time points) based on ultra-deep TCR sequencing (OS-TCR, Omniscope Inc) of T cells in the blood. T cell clonotype infiltration was tracked in matched longitudinal biopsies profiled with paired TCR and single-cell RNA sequencing from freshly processed specimens.

Results

TCR profiling was performed for 15 CRC/EC patients. 14 patients showed progressive disease (PD) and 1 patient a partial response (PR). Despite the lack of response, we detected strong amplification of T cell clones in all patients after ICI therapy in blood, pointing to a successful activation of T cells. However, while PD patients showed moderate expansion of existing and new clonotypes, we detected a strong amplification of specifically newly induced clones with sequence similarities in the PR patient. Expanded clones of PD patients were mostly absent from the matched tumor biopsy, while they infiltrated the tumor of the PR patient after ICI. These tumor infiltrating clones were mostly CD4 and CD8 T cells with follicular helper and pre-exhausted phenotypes, respectively.

Conclusions

Deep T cell repertoire profiling detects dynamic expansion of circulating T cells with quantitative and qualitative difference related to ICI response. Liquid biopsy immune cell tracking is a powerful tool to quantify the efficacy of ICI in real time.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

AstraZeneca PLC.

Funding

AstraZeneca PLC.

Disclosure

H. Heyn: Financial Interests, Personal and Institutional, Ownership Interest: Omniscope Inc. J.L. Melero: Financial Interests, Full or part-time Employment: Omniscope Inc. I. Baraibar Argota: Financial Interests, Personal, Invited Speaker: Sanofi; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Amgen, Merck, Sanofi, Servier. M. Grzelak: Financial Interests, Full or part-time Employment: Omniscope Inc. C. Garcia Duran: Financial Interests, Institutional, Invited Speaker: MSD, AstraZeneca, GSK; Financial Interests, Institutional, Other, Educative activity: EISAI; Financial Interests, Personal, Other, Travel expenses: GSK, AstraZeneca. J.F. Grau Béjar: Financial Interests, Speaker’s Bureau: GSK plc, AstraZeneca plc; Financial Interests, Other, travel & accomodation expenses: GSK plc, AstraZeneca plc. L. Fariñas Madrid: Financial Interests, Personal, Advisory Board: GSK; Financial Interests, Institutional, Invited Speaker: AstraZeneca, MSD, PHARMAND; Financial Interests, Personal, Invited Speaker: EISAI, GSK. A. Rotem: Financial Interests, Institutional, Stocks/Shares: AstraZeneca plc; Financial Interests, Institutional, Full or part-time Employment: AstraZeneca plc. P. Casbas-Hernandez: Financial Interests, Personal, Full or part-time Employment: AstraZeneca. A. Gros: Financial Interests, Personal, Advisory Board: Achilles Therapeutics, Singula Bio, Pact Pharma, Inc., BioNTech; Financial Interests, Personal, Other, Consulting: Instil Bio; Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Personal, Other, Consultant: Genetech; Financial Interests, Personal, Royalties: Intima Bioscience, Inc., Intelia Therapeutics, Inc., Tailored Therapeutics, LLC, Cellular Biomedicine Group, Inc., Geneius Biotechnology, Inc.; Financial Interests, Institutional, Research Grant: Novartis, Roche, Merck KGaA; Financial Interests, Institutional, Other, Project in collaboration: RootPath; Non-Financial Interests, Member: American Association for Cancer Research, SITC, EACR. J. Tabernero: Financial Interests, Personal, Advisory Board, scientific consultancy role: Orion Biotechnology, AstraZeneca, Boehringer Ingelheim, Chugai, Daichii Sankyo, F. Hoffmann-La Roche Ltd, Genentech Inc., Ikena Oncology, Lilly, Menarini, Merck Serono, Merus, MSD, Mirati, Neophore, Novartis, Peptomyc, Pfizer, Pierre Fabre, Samsung Bioepis, Sanofi, Seattle Genetics, Servier, Taiho, Scandion Oncology, Ona Therapeutics, Sotio Biotech, Inspirna Inc, Scorpion Therapeutics, Tolremo Therapeutics, CARSgen Therapeutics, hC Bioscience Inc, Takeda Pharmaceuticals International AG, Alentis Therapeutics, Immodulon Therapeutics; Financial Interests, Personal, Invited Speaker, educational collaboration: Medscape Education, Physicians Education Resource (PER), PeerView Institute for Medical Education, Imedex / HMP; Financial Interests, Personal, Advisory Board: Cardiff Oncology, Aveo Oncology; Financial Interests, Personal, Stocks/Shares: Oniria Therapeuics, 1TRIALSP, Alentis Therapeutics, Pangaea Oncology; Financial Interests, Institutional, Research Grant, ACRCelerate: Colorectal Cancer Stratified: Fundación Científica de la Asociación Española Contra el Cáncer; Financial Interests, Institutional, Research Grant, OPTIMISTICC: Opportunity to Investigate the Microbiome’s Impact on Science and Treatment In Colorectal Cancer: Cancer Research UK; Financial Interests, Institutional, Funding, Clinical Trials & Research: Amgen Inc, AstraZeneca Pharmaceuticals LP, Bristol-Myers Squibb International Corporation, Celgene International SARL, Debiopharm International SA, F. Hoffmann-La Roche Ltd, Genentech Inc, Janssen-Cilag International NV, Merck Health KGAA, Merck, Sharp & Dohme de España, SA, Novartis Farmacéutica SA, PharmaMar SA, Sanofi-Aventis Recherche & Développement, Servier, Taiho Pharma USA, Inc, BeiGene, Boehringer Ingelheim, Menarini, Merus N V, Pfizer, Mirati; Non-Financial Interests, Member of Board of Directors, Board of Directors: Cancer Core Europe, Spanish Association Against Cancer -AECC; Non-Financial Interests, Member of Board of Directors, General Assembly: Horizon Europe Cancer Mission; Non-Financial Interests, Leadership Role, External Scientific Committee: Institute for Health Research INCLIVA – Clinical Hospital of Valencia, IdiSNA –Universidad de Navarra; Non-Financial Interests, Leadership Role, Scientific Advisory Board: Spanish National Cancer Research Centre (CNIO); Non-Financial Interests, Advisory Role, International Scientific Evaluation Committee: Bosch Health Campus (BHC); Non-Financial Interests, Advisory Role, Review Board: National Decade Against Cancer (NCT) - German Consortium for Translational Cancer Research (DKTK); Non-Financial Interests, Advisory Role, Scientific Advisory Board: Karolinska Comprehensive Cancer Centre; Non-Financial Interests, Advisory Role, International Review Committee (IRC): Oncode Institute; Non-Financial Interests, Advisory Role, Scientific Advisory Board (SAB): Oslo University Hospital Comprehensive Cancer Centre (OUH CCC); Non-Financial Interests, Leadership Role, Governance Advisory Committee: European Organization for Research and Treatment of Cancer -EORTC; Non-Financial Interests, Leadership Role, Vice Chairman: World Innovative Networking (WIN) Consortium in Personalized Cancer Medicine; Non-Financial Interests, Other, Coordinating PI & Steering Committee Member. Clinical Trials & Research: Array Biopharma Inc., AstraZeneca Pharmaceutical LP, Boehringer Ingelheim, MedImmune, Menarini, Merck Healthcare KGAA, Merck, Sharp & Dohme de España SA, Pfizer, Servier; Non-Financial Interests, Principal Investigator, Clinical Trials & Research: Array Biopharma Inc., AstraZeneca Pharmaceutics LP, BeiGene, Boehringer Ingelheim, Bristol-Myers Squibb International Corporation, Celgene International SARL, Debiopharm International SA, F. Hoffmann-La Roche Ltd, Genentech Inc., HalioDX SAS, Hutchinson Medipharma, Janssen-Cilag International NV, MedImmune, Menarini, Merck Healthcare KGAA, Merck, Sharp & Dohme de España SA, Merus NV, Mirati, Novartis Farmacéutica SA, Pfizer, Sanofi-Aventis Recherche & Développement, Servier, Taiho Pharma USA Inc; Non-Financial Interests, Other, Steering Committee Member. Clinical Trials & Research: Debiopharm International SA, F. Hoffmann-La Roche Ltd, Genentech Inc., HalioDX SAS, Hutchinson Medipharma, Janssen-Cilag International NV, Merus NV, Taiho Pharma USA Inc; Non-Financial Interests, Other, Coordinating PI. Clinical Trials & Research: Mirati; Non-Financial Interests, Member: AACR, ASCO, EACR, EORTC, SEOM; Other, President: Oncology Master Plan – Catalonia Department of Health; Other, Advisory Committee: Advisory Committee on Pharmaceutical Provision Financing under the Spanish National Health System. A. Oaknin: Financial Interests, Personal, Advisory Board: Roche, PharmaMar, Clovis Oncology, Tesaro Inc., ImmunoGen, Genmab, Mersana Therapeutics, GSK, Deciphera Pharmaceuticals, AstraZeneca; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: AstraZeneca, Roche, PharmaMar. J.N. Sachica: Financial Interests, Advisory Board: Omniscope Inc. N. Borcherding: Financial Interests, Full or part-time Employment: Omniscope Inc. M.E. Elez Fernandez: Financial Interests, Personal, Advisory Board: Hoffman La - Roche, Servier, Amgen, Merck Serono, Sanofi, Bayer, Pierre Fabre, MSD, Takeda, Boehringer Ingelheim, Cure Teq AG, Repare Therapeutics Inc., RIN Institute Inc., Janssen; Financial Interests, Personal, Invited Speaker: Organon, Novartis, Pfizer, BMS, Lilly, Medscape; Financial Interests, Personal, Other, Educational training: Seagen International GmbH; Financial Interests, Institutional, Funding: Hoffmann-La Roche Ltd, Sanofi Aventis Recherche & Développement, Amgen Inc., Boehringer Ingelheim, Novartis Farmacéutica SA, Bristol-Myers Squibb International Corporation, BeiGene, HalioDX SAS, Janssen-Cilag SA, Merck Health KGAA, Merck Sharp & Dohme de España SA, PharmaMar SA, Servier, Taiho Pharma USA Inc, Hutchison MediPharma International, Menarini, Merus NV, Pfizer, Mirati, Array Biopharma Inc, AstraZeneca Pharmaceuticals LP, Celgene International SARL, Debiopharm International SA, Genentech Inc, MedImmune, Abbvie Deutschland Gmbh & Co KG, Bayer Pharma AG, Bioncotech Therapeutics, S.L., Biontech Rna Pharmacuticals GMBH, Biontech Small Molecules GMBH, Boehringer Ingelheim de España S.A., Daiichi Sankyo, Inc, Gercor, Hutchinson Medipharma Limited, Iovance Biotherapeutics, Inc., Janssen Research & Development, Menarini Ricerche SPA, Merck, Sharp & Dohme De España S.A., Nouscom SRL., Pledpharma AB, Redx Pharma PLC, Scandion Oncology, Seattle Genetics Inc., Sotio A.S., Wntresearch AB; Non-Financial Interests, Other, Coordinator of the SEOM +MIR Section of Residents and Young Assistants: Sociedad Española de Oncología Médica (SEOM); Non-Financial Interests, Other, Speaker of the ESMO Academy: European Society for Medical Oncology (ESMO); Non-Financial Interests, Other, Volunteer member of the ASCO Annual Meeting Scientific Program Committee: Developmental Therapeutics – Immunotherapy: American Society of Clinical Oncology (ASCO); Non-Financial Interests, Leadership Role, Member of the Scientific Program Committee and Developmental Therapeutics-Immunotherapy Track Leader, 2023-2024 term: American Society for Clinical Oncology (ASCO); Non-Financial Interests, Other, Member of the Scientific Committee 2024: European Society for Medical Oncology (ESMO); Other, Travel, Accommodations, Expenses: Roche, Merck Serono, Sanofi, Amgen, Array BioPharma, Servier, Bristol-Myers Squibb. All other authors have declared no conflicts of interest.