1080TiP - An investigator-initiated phase I study to assess the safety and tolerability of ex vivo next-generation neoantigen-selected tumor-infiltrating lymphocyte (TIL) therapy in advanced immune checkpoint blockade (ICB) resistant solid tumors (NEXTGENTIL-ACT)

Background

Lymphocytes play a crucial role in cancer immunity and patient survival, representing an attractive treatment option for melanoma and diverse epithelial tumors. Neoantigen-reactive TILs can recognize and kill cancer cells, inducing tumor regression and potentially increasing the efficacy of adoptive cell therapies (ACT). NEXTGENTIL-ACT consists of TIL selected based on identifying somatic non-synonymous mutations or viral neoantigens encoded in tandem minigenes and presented by autologous peripheral B cells.

Trial design

This is an investigator-initiated phase 1, single-center, open-label study assessing the safety, tolerability, and anti-tumor activity of single-dose NEXTGENTIL with high-dose IL-2 (720.000 IU/kg) following non-myeloablative lymphodepleting chemotherapy in adults with confirmed metastatic or unresectable advanced ICB-resistant solid tumors. The NEXTGENTIL product contains a polyclonal autologous lymphocyte population of TILs ranging from 5x108 to 1.11x1011 cells expanded from core tumor biopsies and selected based on neoantigen recognition using a high-throughput personalized screening approach. A bridge treatment during TIL expansion and screening for neoantigen recognition is allowed. The primary objectives are to evaluate the safety, tolerability, feasibility, and initial clinical activity. Four more patients will be included if a maximum of one treatment-limiting toxicity is observed in the first six patients. The preliminary anti-tumor activity will be assessed by RECIST v1.1. Patients must be at least 18 years old, have ECOG 0-1, and have received standard therapy (including ICB when indicated). One target lesion must be accessible for a biopsy/resection that allows TIL generation, and another must meet RECIST criteria. Patients must be medically fit enough to undergo all study procedures and interventions and have adequate cardiovascular and pulmonary functions. Patients with an autoimmune disease requiring immunosuppressive treatments will be excluded.

Clinical trial identification

EudraCT 2020-005778-90 (27.01.2021), NCT05141474.

Editorial acknowledgement

Legal entity responsible for the study

Vall d’Hebron Institute of Oncology.

Funding

Comprehensive Program of Cancer Immunotherapy & Immunology (CAIMI) supported by the BBVA Foundation (grant 89/2017) and Instituto de Salud Carlos III under the “Independent Clinical Investigation” call 2020 (ICI20/00076).

Disclosure

M. Lozano-Rabella: Financial Interests, Personal, Research Funding: ROCHE. I. Braña: Financial Interests, Personal, Advisory Board: Achilles Therapeutics, Bristol Myers Squibb, Cancer Expert Now, eTheRNA Immunotherapies, Merck Serono, Merck Sharp & Dohme (MSD), Rakuten Pharma, Boehringer Ingellheim, PCI Biotech, Guidepoint; Financial Interests, Personal, Invited Speaker: Bristol Myers Squibb, Merck Serono, Merck Sharp & Dohme (MSD), Roche; Financial Interests, Institutional, Local PI: AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, GSK, Gliknik, Incyte, ISA pharmaceuticals, Janssen Oncology, Kura, Merck Serono, Debiopharm, Merck Sharp & Dohme (MSD), Nanobiotix, Novartis, Northern Biologics, Regeneron, Pfizer, Seattle Genetics, Shattuck Labs, VCN Biosciences, Roche, Immutep, MacroGenics, Sanofi, Pharmamar, Odonate Therapeutics, Bicycle Therapeutics, Dragonfly therapeutics, Gilead; Non-Financial Interests, Principal Investigator, Basket of baskets: Cancer Core Europe; Non-Financial Interests, Member, Head and Neck Group: EORTC; Non-Financial Interests, Member: SEOM, ASCO. J. Tabernero: Financial Interests, Personal, Advisory Board, scientific consultancy role: Orion Biotechnology, Array Biopharma, AstraZeneca, Bayer, Boehringer Ingelheim, Chugai, Daiichi Sankyo, F. Hoffmann-La Roche Ltd, Genentech Inc., HalioDX SAS, Ikena Oncology, IQVIA, Lilly, Menarini, Merck Serono, Merus, MSD, Mirati, Neophore, Novartis, Peptomyc, Pfizer, Pierre Fabre, Samsung Bioepis, Sanofi, Seattle Genetics, Servier, Taiho, Tessa Therapeutics, TheraMyc, Hutchinson MediPharma International, Scandion Oncology, Ona Therapeutics, Sotio Biotech, Inspirna Inc, Scorpion Therapeutics, Tolremo Therapeutics; Financial Interests, Personal, Invited Speaker, educational collaboration: Medscape Education, Physicians Education Resource (PER), PeerView Institute for Medical Education, Imedex / HMP; Financial Interests, Personal, Invited Speaker, educacional collaboration: MJH Life Sciences; Financial Interests, Personal, Advisory Board: Cardiff Oncology; Financial Interests, Personal, Stocks/Shares: Oniria Therapeuics; 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, Array Biopharma 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, HalioDX SAS, Hutchinson Medipharma, MedImmune, 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, Principal Investigator, Clinical Trials & Research: AstraZeneca Pharmaceutics LP, Array Biopharma Inc., BeiGene, Boehringer Ingelheim, Debiopharm International SA, Bristol Myers Squibb International Corporation, Celgene International SARL, F. Hoffmann-La Roche Ltd, Genentech Inc., HalioDX SAS, Hutchinson Medipharma, Menarini, Janssen-Cilag International NV, MedImmune, 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, 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, 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, Other, President: Oncology Master Plan – Catalonia Department of Health; Other, Other, Advisory Committee: Advisory Committee on Pharmaceutical Provision Financing under the Spanish National Health System. 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. E. Garralda: Financial Interests, Personal, Advisory Board: Roche, Ellipses Pharma, Boehringer Ingelheim, Janssen Global Services, Seattle Genetics, Alkermes, Thermo Fisher, MabDiscovery, Anaveon, Hengrui, F-Star Therapeutics, Sanofi, Incyte; Financial Interests, Personal, Invited Speaker: MSD, Lilly, Roche, Thermo Fisher, Novartis, Seagen; Financial Interests, Personal, Full or part-time Employment: NEXT Oncology; Financial Interests, Institutional, Funding: Novartis, Roche, Thermo Fisher, AstraZeneca, Taiho; Financial Interests, Institutional, Research Grant: BeiGene, Janssen. All other authors have declared no conflicts of interest.