Abstract 179P
Background
cNeT therapy addresses limitations of TIL therapies including the requirement for high dose lymphodepletion and IL-2 which restricts application to fitter patients, and limited understanding of the active component that limits product optimisation and potency assay development. We have initiated trials evaluating cNeT in advanced, heavily pre-treated patients with NSCLC (CHIRON, NCT04032847) or melanoma (THETIS, NCT03997474) utilising lower dose lymphodepletion and IL-2 (1M IU/m2 sc x10d).
Methods
14 patients (8 CHIRON, 6 THETIS) received a single dose of cNeT characterised using cytokine-based antigen-specific assays, flow cytometry and single cell RNA/TCRseq, that were also used to track cNeT post-infusion. These form the safety data set. Median cNeT dose was 18M cells (0.1-287M), with a median clonal reactivity of 16% (0.2-77%).
Results
There were 28 G≥3 treatment-related AEs with lymphopenia and neutropenia the most common. One cNeT related SAE (ICANS) and 3 episodes of cytokine release syndrome (G≤2) were reported with no high-grade toxicities associated with IL-2. 6 patients have died on study, all due to disease progression. With 15-115 wk follow up 7 NSCLC patients have ≥2 restaging scans (1 pending). Best response was PR in 1 (33+wk), SD in 5 (ongoing in 2 at 15+, 26+ wk), and PD in 1, with an overall durable clinical benefit ≥18 wk in 3/7 (43%). The PR showed 57% total tumour reduction at week 24 (investigator reported). Flow cytometry revealed early expansion of CD8+KI67+ T cells previously associated with response to checkpoint inhibitors. Peak expansion of cNeT was seen at d21 coincident with a peak in IL-6. In depth characterisation of the cNeT product using single cell RNA and TCRseq suggests the active component is polyfunctional in nature with reactive T cell clusters bearing signatures of T cell proliferation, IL-2 sensitivity, cytokine secretion and tissue migration.
Conclusions
We demonstrate an encouraging early safety and tolerability profile consistent with further application to a broader patient population along with the potential for deep and durable clinical responses in NSCLC despite low doses of cNeT and reduced dose lymphodepletion and IL-2.
Clinical trial identification
NCT04032847, NCT03997474.
Legal entity responsible for the study
Achilles Therapeutics.
Funding
Achilles Therapeutics.
Disclosure
M.D. Forster: Financial Interests, Personal, Advisory Board: Bayer, Merck, MSD, Novartis, Roche, Takeda, Ultrahuman, Transgene, Ixogen, Immunotep; Financial Interests, Institutional, Research Grant: AstraZeneca, Boehringer Ingelheim, MSD, Merck; Financial Interests, Institutional, Invited Speaker: StarPharma, Roche. J. Cave: Financial Interests, Personal, Other: Novartis, Eli Lilly, Boehringer Ingelheim. A. Greystoke: Financial Interests, Personal, Advisory Board: BMS, AstraZeneca, Boehringer Ingelheim, Takeda, Roche, Novartis; Financial Interests, Personal, Invited Speaker: Merck, MSD, Pfizer, Janssen; Financial Interests, Institutional, Invited Speaker: MSD, Pfizer, AstraZeneca, Novartis, Achilles; Non-Financial Interests, Personal, Advisory Role: National Institue for Health and Clinical Excellence; Other, Personal, Other, Clinical Lead for Cancer (paid position): North East Englad and Yorkshire Genomic Laboratory Hub. R. Plummer: Financial Interests, Personal, Advisory Board: Pierre Faber, Bayer, Novartis, BMS, Cybrexa, Ellipses, CV6 Therapeutics, Astex Therapetics, Sanofi Aventis, Immunocore, Genmab, Medivir, Onexo; Financial Interests, Institutional, Royalties, Royalties relating to rucaparib licencing: Clovis Oncology; Financial Interests, Personal, Other, Honorarium as member of IDMC: SOTIO, Alligator Biosciences; Financial Interests, Personal, Other, Honoraria as member of IDMC: GSK. J. Spicer: Financial Interests, Institutional, Advisory Board: Lilly, AstraZeneca, Boehringer Ingelheim, BMS, Genmab, GSK, RS Oncology, Seattle Genetics, Merck; Financial Interests, Personal, Stocks/Shares, Co-founder: Epsilogen; Financial Interests, Institutional, Invited Speaker: Achilles, Genmab, Roche, Seattle Genetics, Starpharma, Trizell, BergenBio, BMS, IO Biotech, MSD; Non-Financial Interests, Personal, Invited Speaker, National strategy board: Experimental Cancer Medicine Centres; Non-Financial Interests, Personal, Invited Speaker, Steering Committee: British Thoracic Oncology Group. F. Thistlethwaite: Financial Interests, Personal, Advisory Board, honoraria: Bayer; Financial Interests, Personal, Advisory Board, Ad board: BMS, Zelluna; Financial Interests, Personal, Advisory Board, Ad boards: GSK; Financial Interests, Personal, Advisory Board, Adboard/consultancy: Tknife; Financial Interests, Personal, Advisory Board: Adicet, Janssen, EnaraBio, Immatics, Ixaka, Scenic Biotech; Financial Interests, Institutional, Advisory Board: Pfizer; 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 (0.2WTE) 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, 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, Invited Speaker: Pfizer, GenMab, synthon, CytomX, Incyte, Janssen, Adaptimmune, Aveo, BMS, GSK, Roche, AbbVie, Immunocore, Achilles ltd, Agalimmune Ltd, Kymab Ltd, Chugai, Millenium Pharmaceuticals/Takeda, Daiichi Sankyo; Financial Interests, Institutional, Research Grant: Novartis, GSK; Financial Interests, Personal, Invited Speaker: AstraZeneca; Non-Financial Interests, Personal, Other, Panel member for a funding committee (MRC is a UK government NFP organisation): MRC DPFS panel member. S. Turajlic: Financial Interests, Personal, Invited Speaker: IDEA Pharma, Roche, Ventana, MSD, Merck; Financial Interests, Institutional, Funding, Uncommon theme pump priming funds: NIHR; Financial Interests, Institutional, Funding, Digital theme funding: RMH/ICR/BRC/Imperial AHSC/Faculty of Medicine; Financial Interests, Institutional, Funding, Tracking renal cancer evolution in blood: Rosetrees Trust; Financial Interests, Institutional, Funding, Clinical PhD Fellowship over 3 years: CRUK Welcome Trust; Financial Interests, Institutional, Funding, Investigating the relationship between primary melanomas and their metastases: The Robert McAlpine Foundation; Financial Interests, Institutional, Funding, Innovation Grant Award for biomarker development: The Francis Crick Institute; Financial Interests, Institutional, Funding, Developing a novel method of representative tumour in sampling in clinical setting: Ventana; Financial Interests, Institutional, Funding, Mapping clonal evolution in renal cell carcinoma: CRUK training and career development board - clinician scientist fellowship; Financial Interests, Institutional, Funding: Harry J Lloyd Charitable Trust Career Development Award; Financial Interests, Institutional, Funding, Clinical Research Fellowship in melanoma: Andy Quick Charitable fund; Financial Interests, Institutional, Funding, Mechanisms of BRAF resistance: Complete Genomics; Financial Interests, Institutional, Funding, Molecular profiling of non-cutaneous melanoma: CRUK; Financial Interests, Institutional, Funding, Target discovery in acral melanoma: Rosetrees Trust. A. Craig, K. Newton, M. Saggese, S. Quezada, K. Peggs: Financial Interests, Institutional, Full or part-time Employment: Achilles Therapeutics.