Found 13 Presentations For Request "TCR"

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Investigational immunotherapy

1007P - T-cells transgenic for a highly potent PRAME-specific TCR and a chimeric PD1-41BB co-stimulatory receptor represent a promising approach for the treatment of solid tumors

Presentation Number
1007P
Speakers
  • Maja Bürdek (Martinsried (Planegg), Germany)

Abstract

Background

T-cell receptor (TCR)-based immunotherapies have great potential for the safe and efficacious treatment of patients with unmet needs suffering from various types of cancer. However, novel strategies are needed to overcome the inhibitory tumor microenvironment and to enhance the efficacy of TCR-T-cell (TCR-T) therapy in solid tumors. PRAME is a cancer/testis antigen that is highly expressed in various solid tumor indications while its expression in healthy tissues is mainly restricted to the testis.

Methods

The HLA-A2-restricted, PRAME-specific TCR used here was obtained from a non-tolerized T-cell repertoire of a healthy donor using high-throughput TCR isolation and characterization processes. To prevent inhibition of TCR-T function via the PD1-PDL1 axis, the PRAME-TCR was co-expressed with a chimeric PD1-41BB co-stimulatory receptor, consisting of the extracellular domain of PD1 and the intracellular domain of the 41BB co-stimulatory receptor.

Results

Co-expression of PD1-41BB on PRAME-TCR-Ts did not change the favorable preclinical safety profile but led to enhanced TCR-T proliferation and cytokine release after antigen encounter. Under conditions of chronic antigen exposure using HLA-A2/PRAME/PDL1-positive tumor cell lines, TCR-Ts co-expressing PD1-41BB showed increased fitness and cytotoxic anti-tumor activity compared to TCR-Ts carrying the TCR alone. This effect could be confirmed in vivo using an immune-deficient xenograft mouse model. Tumors derived from a melanoma cell line expressing PRAME and high PDL1 levels, partially mimicking the inhibitory TME of solid tumors, were not cleared by TCR-Ts expressing the TCR alone whereas TCR-Ts co-expressing PD1-41BB eradicated the tumors. Furthermore, at the single cell level, in vitro poly-functional cytokine release analysis of TCR-Ts co-expressing PD1-41BB and the PRAME-TCR support the in vivo data.

Conclusions

We showed that co-expression of a chimeric PD1-41BB co-stimulatory receptor enhances in vitro and in vivo PRAME TCR-T functionality and anti-tumor activity, thus representing a highly promising strategy to enhance the efficacy of TCR-T therapies for the treatment of solid cancers.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

M. Bürdek: Financial Interests, Personal, Full or part-time Employment: Medigene Immunotherapies GmbH. I. Fetzer: Financial Interests, Personal, Full or part-time Employment: Medigene Immunotherapies GmbH. N. Sailer: Financial Interests, Personal, Full or part-time Employment: Medigene Immunotherapies GmbH. M. Salvermoser: Financial Interests, Personal, Full or part-time Employment: Medigene Immunotherapies GmbH. D. Brechtefeld: Financial Interests, Personal, Full or part-time Employment: Medigene Immunotherapies GmbH. K. Mutze: Financial Interests, Personal, Full or part-time Employment: Medigene Immunotherapies GmbH. S. Raffegerst: Financial Interests, Personal, Full or part-time Employment: Medigene Immunotherapies GmbH. M. Braun: Financial Interests, Personal, Full or part-time Employment: Medigene Immunotherapies GmbH. R. Goedkoop: Financial Interests, Institutional, Officer: Medigene. S. Wilde: Financial Interests, Personal, Full or part-time Employment: Medigene Immunotherapies GmbH; Financial Interests, Personal, Stocks/Shares: Medigene Immunotherapies GmbH. D. Sommermeyer: Financial Interests, Personal, Full or part-time Employment: Medigene Immunotherapies GmbH.

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Developmental therapeutics

540P - Safety and efficacy from the SURPASS trial with ADP-A2M4CD8, a SPEAR T-cell therapy incorporating a CD8α co-receptor and an affinity optimized TCR targeting MAGE-A4

Presentation Number
540P
Speakers
  • David S. Hong (Houston, United States of America)

Abstract

Background

The ongoing phase 1 SURPASS trial (NCT04044859) evaluates safety and efficacy of next-generation ADP-A2M4CD8 SPEAR T-cells co-expressing the CD8α co-receptor with the engineered T-cell receptor (TCR) targeting MAGE-A4.

Methods

First-in-human trial in HLA-A*02 positive patients (pts) with advanced cancers expressing MAGE-A4 antigen. T-cells are obtained by apheresis, transduced with a lentiviral vector containing the engineered TCR and CD8α co-receptor, and expanded in vitro. Prior to infusion, pts receive lymphodepletion with fludarabine 30 mg/m2/day for 4 days and cyclophosphamide 600 mg/m2/day for 3 days. The study consists of a modified 3 + 3 dose escalation design with an expansion cohort. Clinical outcomes (safety and efficacy), product attributes (dose, cell phenotype), and biomarkers (tumor antigen expression, T-cell persistence after transfer, serum cytokines) are evaluated.

Results

As of 05 Apr 2021, 18 pts (10 male, 8 female) were treated with ADP-A2M4CD8 (range 1.0 to 6 billion transduced cells). Median age was 63.5 yrs, median H-score was 255 (range 130 to 300), and primary tumor types included ovarian (n=5), esophagogastric junction (n=4), esophageal (n=2), head and neck (n=2), and 1 pt each with myxoid/round cell liposarcoma, melanoma, non small cell lung cancer, synovial sarcoma, and urothelial cancers. Overall, patients tolerated treatment. Most adverse events were consistent with those experienced by cancer patients undergoing lymphodepletion chemotherapy and cellular therapy. Of the 18 pts treated as of the data cut-off, 2 pts were awaiting first scans and one patient had expired. Of the 15 evaluable pts, 13 had evidence of disease control and there were RECIST responses in several solid tumor types. This trial is ongoing with additional pts awaiting treatment and further tumor assessments.

Conclusions

ADP-A2M4CD8 SPEAR T-cells have shown an acceptable safety profile. Emerging efficacy data remain encouraging with the majority of pts experiencing disease control and RECIST responses in several solid tumor types. A full update will be presented at the conference.

Clinical trial identification

NCT04044859.

Editorial acknowledgement

Writing and editorial support was provided by Gabrielle Knafler, of Excel Scientific Solutions (Fairfield, CT, USA).

Legal entity responsible for the study

Adaptimmune.

Funding

Adaptimmune.

Disclosure

D.S. Hong: Financial Interests, Personal, Research Grant: AbbVie; Financial Interests, Personal, Research Grant: Adaptimmune; Financial Interests, Personal, Research Grant: Adlai Nortye; Financial Interests, Personal, Research Grant: Amgen; Financial Interests, Personal, Research Grant: AstraZeneca; Financial Interests, Personal, Research Grant: Bayer; Financial Interests, Personal, Research Grant: Bristol Myers Squibb; Financial Interests, Personal, Research Grant: Daiichi-Sankyo; Financial Interests, Personal, Research Grant: Eisai; Financial Interests, Personal, Research Grant: Eli Lilly; Financial Interests, Personal, Research Grant: EMD Serono; Financial Interests, Personal, Research Grant: Erasca; Financial Interests, Personal, Research Grant: Fate Therapeutics; Financial Interests, Personal, Research Grant: Genentech; Financial Interests, Personal, Research Grant: Genmab; Financial Interests, Personal, Research Grant: GlaxoSmithKline; Financial Interests, Personal, Research Grant: Ignyta; Financial Interests, Personal, Research Grant: Infinity; Financial Interests, Personal, Research Grant: Kite; Financial Interests, Personal, Research Grant: Kyowa; Financial Interests, Personal, Research Grant: LOXO; Financial Interests, Personal, Research Grant: Merck; Financial Interests, Personal, Research Grant: MedImmune; Financial Interests, Personal, Research Grant: Millenium; Financial Interests, Personal, Research Grant: Mirati; Financial Interests, Personal, Research Grant: miRNA; Financial Interests, Personal, Research Grant: Molecular Templates; Financial Interests, Personal, Research Grant: Mologen; Financial Interests, Personal, Research Grant: Navier; Financial Interests, Personal, Research Grant: NCI-CTEP; Financial Interests, Personal, Research Grant: Novartis; Financial Interests, Personal, Research Grant: Numab; Financial Interests, Personal, Research Grant: Pfizer; Financial Interests, Personal, Research Grant: Seattle Genetics; Financial Interests, Personal, Research Grant: Takeda; Financial Interests, Personal, Research Grant: Turning Point Therapeutics; Financial Interests, Personal, Research Grant: Verstatem; Financial Interests, Personal, Research Grant: VM Oncology; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: AACR; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Amgen; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: ASCO; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: AstraZeneca; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Bayer; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Celgene; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Eli Lilly; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Genentech; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Genmab; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: GlaxoSmithKline; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Janssen; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: LOXO; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: miRNA; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Pfizer; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Philips; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: SITC; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Takeda; Financial Interests, Personal, Ownership Interest: Molecular Match; Financial Interests, Personal, Ownership Interest: OncoResponse; Financial Interests, Personal, Ownership Interest: Presagia Inc; Financial Interests, Personal, Advisory Role: Alpha Insights; Financial Interests, Personal, Advisory Role: Acuta; Financial Interests, Personal, Advisory Role: Amgen; Financial Interests, Personal, Advisory Role: Axiom; Financial Interests, Personal, Advisory Role: Adaptimmune; Financial Interests, Personal, Advisory Role: Baxter; Financial Interests, Personal, Advisory Role: Bayer; Financial Interests, Personal, Advisory Role: Boxer Capital; Financial Interests, Personal, Advisory Role: COG; Financial Interests, Personal, Advisory Role: Ecor1; Financial Interests, Personal, Advisory Role: Genentech; Financial Interests, Personal, Advisory Role: GLG; Financial Interests, Personal, Advisory Role: Group H; Financial Interests, Personal, Advisory Role: Guidepoint; Financial Interests, Personal, Advisory Role: HCW Precision; Financial Interests, Personal, Advisory Role: Infinity; Financial Interests, Personal, Advisory Role: Janssen; Financial Interests, Personal, Advisory Role: Merrimack; Financial Interests, Personal, Advisory Role: Medscape; Financial Interests, Personal, Advisory Role: Numab; Financial Interests, Personal, Advisory Role: Pfizer; Financial Interests, Personal, Advisory Role: Prime Oncology; Financial Interests, Personal, Advisory Role: Seattle Genetics; Financial Interests, Personal, Advisory Role: ST Cube; Financial Interests, Personal, Advisory Role: Takeda; Financial Interests, Personal, Advisory Role: Tavistock; Financial Interests, Personal, Advisory Role: Trieza Therapeutics; Financial Interests, Personal, Advisory Role: WebMD. J.M. Clarke: Financial Interests, Speaker’s Bureau: Merck; Financial Interests, Speaker’s Bureau: AstraZeneca; Financial Interests, Training: BMS; Financial Interests, Other, Consultant: AstraZeneca; Financial Interests, Other, Consultant: Merck; Financial Interests, Other, Consultant: Pfizer; Financial Interests, Other, Consultant: NGM Biopharmaceuticals; Financial Interests, Other, Consultant: Spectrum; Financial Interests, Other, Consultant: Genentech; Financial Interests, Research Grant: Bristol-Myers Squibb; Financial Interests, Research Grant: Genentech; Financial Interests, Research Grant: Spectrum; Financial Interests, Research Grant: Adaptimmune; Financial Interests, Research Grant: Medpacto; Financial Interests, Research Grant: Bayer; Financial Interests, Research Grant: AbbVie; Financial Interests, Research Grant: Moderna; Financial Interests, Research Grant: GlaxoSmithKline; Financial Interests, Research Grant: Array; Financial Interests, Research Grant: AstraZeneca; Financial Interests, Research Grant: Grid Therapeutics; Financial Interests, Research Grant: CBMG; Non-Financial Interests, Member of the Board of Directors: Lung Cancer Initiative of North Carolina. J. Charlson: Financial Interests, Other, Consultant: Deciphera; Financial Interests, Other, Consultant: Adaptimmune; Financial Interests, Advisory Board: Adaptimmune. E. Calvo: Financial Interests, Personal, Advisory Board: Adcendo; Financial Interests, Personal, Advisory Board: Alkermes; Financial Interests, Personal, Advisory Board: Amunix; Financial Interests, Personal, Advisory Board: Anaveon; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Board: BMS; Financial Interests, Personal, Advisory Board: Janssen; Financial Interests, Personal, Advisory Board: MonTa; Financial Interests, Personal, Advisory Board: MSD; Financial Interests, Personal, Advisory Board: Nanobiotix; Financial Interests, Personal, Advisory Board: Nouscom; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Invited Speaker: OncoDNA; Financial Interests, Personal, Invited Speaker: PharmaMar; Financial Interests, Personal, Invited Speaker: Roche/Genentech; Financial Interests, Personal, Advisory Board: Servier; Financial Interests, Personal, Advisory Board: TargImmune; Financial Interests, Personal, Advisory Board: T-knife; Financial Interests, Personal, Advisory Board: Chugai; Financial Interests, Personal, Other, Director, Clinical Research: START Madrid Group; Financial Interests, Personal, Full or part-time Employment: HM Hospitales Group; Financial Interests, Personal, Full or part-time Employment: START Madrid - CIOCC (Centro Integral Oncológico Clara Campal); Financial Interests, Personal, Ownership Interest: START; Financial Interests, Personal, Ownership Interest: Oncoart Associated; Financial Interests, Personal, Ownership Interest: International Cancer Consultants; Financial Interests, Institutional, Funding: Achilles; Financial Interests, Personal, Other, Steering Committee Member: BeiGene; Financial Interests, Personal, Other, Steering Committee Member: MedSIR; Non-Financial Interests, Personal, Officer, Steering Committee Member: EORTC IDMC; Non-Financial Interests, Personal, Member of the Board of Directors: INTHEOS (Investigational Therapeutics in Oncological Sciences) Foundation; Non-Financial Interests, Personal, Advisory Role: PsiOxus; Non-Financial Interests, Personal, Advisory Role: Amcure; Non-Financial Interests, Personal, Member: ASCO; Non-Financial Interests, Personal, Member: ESMO; Non-Financial Interests, Personal, Member: SEOM; Non-Financial Interests, Personal, Member: EORTC. V. Boni: Financial Interests, Personal, Speaker’s Bureau: Lilly; Financial Interests, Personal, Other, Consultant: Puma; Financial Interests, Personal, Other, Consultant: Cytomx; Financial Interests, Personal, Other, Consultant: Loxo Oncology; Financial Interests, Personal, Other, Consultant: Amunix; Financial Interests, Personal, Other, Consultant: Ideaya; Financial Interests, Institutional, Research Grant: Abbvie; Financial Interests, Institutional, Research Grant: ACEO; Financial Interests, Institutional, Research Grant: Adaptaimmune; Financial Interests, Institutional, Research Grant: Amcure; Financial Interests, Institutional, Research Grant: AMGEN; Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Institutional, Research Grant: BMS; Financial Interests, Institutional, Research Grant: Cytomx; Financial Interests, Institutional, Research Grant: GSK; Financial Interests, Institutional, Research Grant: Genentech/Roche; Financial Interests, Institutional, Research Grant: H3; Financial Interests, Institutional, Research Grant: Incyte; Financial Interests, Institutional, Research Grant: Janssen; Financial Interests, Institutional, Research Grant: Kura; Financial Interests, Institutional, Research Grant: Lilly; Financial Interests, Institutional, Research Grant: Loxo; Financial Interests, Institutional, Research Grant: Nektar; Financial Interests, Institutional, Research Grant: Macrogenics; Financial Interests, Institutional, Research Grant: Menarini; Financial Interests, Institutional, Research Grant: Merck; Financial Interests, Institutional, Research Grant: Merus; Financial Interests, Institutional, Research Grant: Nanobiotix; Financial Interests, Institutional, Research Grant: Novartis; Financial Interests, Institutional, Research Grant: Pfizer; Financial Interests, Institutional, Research Grant: PharmaMar; Financial Interests, Institutional, Research Grant: Principia; Financial Interests, Institutional, Research Grant: PUMA; Financial Interests, Institutional, Research Grant: Sanofi; Financial Interests, Institutional, Research Grant: Taiho; Financial Interests, Institutional, Research Grant: Tesaro; Financial Interests, Institutional, Research Grant: BeiGene; Financial Interests, Institutional, Research Grant: Transgene; Financial Interests, Institutional, Research Grant: Takeda; Financial Interests, Institutional, Research Grant: Incyte; Financial Interests, Institutional, Research Grant: Innovio; Financial Interests, Institutional, Research Grant: MSD; Financial Interests, Institutional, Research Grant: PsiOxus; Financial Interests, Institutional, Research Grant: Seattle Genetics; Financial Interests, Institutional, Research Grant: Mersana; Financial Interests, Institutional, Research Grant: GSK; Financial Interests, Institutional, Research Grant: Daiichi; Financial Interests, Institutional, Research Grant: Astellas; Financial Interests, Institutional, Research Grant: ORCA; Financial Interests, Institutional, Research Grant: Boston Therapeutics; Financial Interests, Institutional, Research Grant: Dynavax; Financial Interests, Institutional, Research Grant: DebioPharm; Financial Interests, Institutional, Research Grant: Boehringen Ingelheim; Financial Interests, Institutional, Research Grant: Regeneron; Financial Interests, Institutional, Research Grant: Millenium; Financial Interests, Institutional, Research Grant: Synthon; Financial Interests, Institutional, Research Grant: Spectrum; Financial Interests, Institutional, Research Grant: Rigontec; Financial Interests, Institutional, Research Grant: Zenith; Financial Interests, Personal, Member of the Board of Directors: Puma; Financial Interests, Personal, Member of the Board of Directors: Cytomx; Financial Interests, Personal, Member of the Board of Directors: Ideaya. J. Zugazagoitia: Financial Interests, Speaker’s Bureau: BMS; Financial Interests, Speaker’s Bureau: Roche; Financial Interests, Speaker’s Bureau: AstraZeneca; Financial Interests, Speaker’s Bureau: Pfizer; Financial Interests, Speaker’s Bureau: NanoString; Financial Interests, Research Grant: AstraZeneca. G.R. Blumenschein Jr.: Financial Interests, Personal, Research Grant: Amgen, Bayer, Adaptimmune, Elelixis, Daiichi Sankyo, GlaxoSmithKline, Immatics, Immunocore, Incyte, Kite Pharma, Macrogenics, Torque, AstraZeneca, Bristol-Myers Squibb, Celgene, Genentech, MedImmune, Merck, Novartis, Roche, Xcovery, Tmunity Therapeutics; Financial Interests, Personal, Other, Consulting Fees: Abbvie, Adicet, Amgen, Ariad, Bayer, Clovis Oncology, AstraZeneca, Bristol-Myers Squibb, Celgene, Daiichi Sankyo, Instil Bio, Genentech, Gilead, Lilly, Janssen, MedImmune, Merck, Novartis, Roche, Tyme Oncology, Xcovery, Virogin Biotech; Financial Interests, Personal, Other, Participation on a Data Safety Monitoring Board or Advisory Board: Virogin Biotech, Maverick therapeutics; Financial Interests, Personal, Stocks/Shares: Virogin Biotech; Non-Financial Interests, Personal, Other, Immediate family member employment: Johnson & Johnson/Janssen; Financial Interests, Personal, Research Grant: Regeneron, Beigene, Repertoire Immune Medicines, Verastem; Financial Interests, Personal, Other, Consulting Fees: Maverick Therapeutics. Q. Lin: Financial Interests, Personal, Full or part-time Employment: Adaptimmune. H. Danesi: Financial Interests, Personal, Full or part-time Employment: Adaptimmune. E. Norry: Financial Interests, Full or part-time Employment: Adaptimmune. All other authors have declared no conflicts of interest.

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Haematological malignancies

853P - PRAME expression and ImmTAC TCR bispecific sensitivity in acute myeloid leukaemia in the presence and absence of the hypomethylating agent decitabine

Presentation Number
853P
Speakers
  • Camille Britton-Rivet (Abingdon-on-Thames, United Kingdom)

Abstract

Background

ImmTAC molecules are high affinity TCR-anti-CD3 bispecific fusion proteins currently being tested in solid tumour trials, with the gp100-directed ImmTAC tebentafusp demonstrating survival benefit in metastatic uveal melanoma (1). The cancer testis antigen PRAME is expressed in multiple cancer types including malignant haematological cells and can be increased by treatment with hypomethylating agents (HMA), which are used clinically in AML (2). These findings prompted us to test leukaemia cell sensitivity to PRAME-directed ImmTAC in vitro and its potential regulation by HMA.

Methods

Public bulk and single-cell RNAseq datasets were analysed for PRAME expression and extended by in-house analyses. Cancer cell lines, healthy donor PBMC, and the hypomethylating agent decitabine were sourced commercially, and a PRAME-specific ImmTAC was used for IFNg, Granzyme B and killing assays.

Results

Multiple AML cohorts identified 24-29% frequency of detectable PRAME transcripts across all disease subtypes by bulk RNAseq, and scRNAseq analyses confirmed expression in AML blasts. ImmTAC induced robust T cell activation towards multiple PRAME+ haem cancer cell lines (2xAML, 1xHL, 1xCLL), and subsequent ImmTAC-dependent killing of AML cells was confirmed by Annexin V stain. Treatment of PRAMEneg AML cells with clinically relevant levels of decitabine (300nM) induced sustained expression of both PRAME transcript and protein, and PRAME upregulation in response to HMA therapy was confirmed in AML patient samples. Notably, decitabine turned unresponsive AML cells into efficient mediators of PRAME ImmTAC-dependent T cell activation (IFNg EC50 137 pM) and killing activity (Granzyme B EC50 113 pM).

Conclusions

These results demonstrate that PRAME ImmTAC can redirect T cells against PRAME+ AML cells. HMA treatment augments PRAME expression in PRAMEneg AML lines, resulting in robust ImmTAC-dependent T cell activation. This preclinical study suggests that a PRAME-directed ImmTAC may have anti-cancer activity in AML patients.1. Piperno-Neumann et al. AACR 2021 Abstract #5342; 2. Atanackovic et al. Am. J. Hematol. 86:918-922, 2011.

Legal entity responsible for the study

Immunocore Holdings PLC.

Funding

Immunocore FIMM.

Disclosure

C. Britton-Rivet, J. Houghton, R. Khanolkar, M. Patel, T. Aleksic, A. Benlahrech, D.M. Gascoyne: Financial Interests, Full or part-time Employment: Immunocore. All other authors have declared no conflicts of interest.

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Basic science

17P - PD-1 and LAG-3 immune checkpoints constitutive activators exhibit differential expression phenotypes

Presentation Number
17P
Speakers
  • Luisa Chocarro (Pamplona, Spain)

Abstract

Background

The lack of PD-1 or LAG-3 mutants with constitutive inhibitory activities prevents a systematic approach to dissect all the intracellular events regulated by PD- 1 and LAG-3 that establish a strong T cell dysfunctionality in patients with intrinsic resistance to PD-1 therapies. It is thought that PD-1 and LAG-3 form a supramolecular complex together with TCR components in order to exert their inhibitory activity over TCR signal transduction. So far, no PD-1 and LAG-3 mutants with constitutive signalling activities have been described. Here we have constructed molecules that provide an initial TCR-dependent signal in T cells that lead to a sustained inhibitory activity of PD-1 and LAG-3.

Methods

To construct molecules with constitutive PD-1 and LAG-3 signaling activities in T cells, we replaced their immunoglobulin domains with a sequence encoding a single chain antibody that binds CD3. These fusion genes were cloned into the pDUAL lentivector expression system, which coexpress antibiotic resistance for selection of cells lines. When expressed in T cells, the engagement with CD3 will trigger a TCR signal in neighbouring T cells, and these molecules will then transmit either PD-1 or LAG-3 signals. To test their expression, human T cells were transduced with lentivectors expressing these constructs singly or in combination and their phenotypes were characterized by flow cytometry analysis.

Results

Both constructs showed differential phenotypes and expression levels within different surface and intracellular molecules compared with their WT and CD3 activator controls, such as CD3, CD4, CD27, CD28, CD69, CD62L, CD45RA, PD1, LAG3, TIM-3, CTLA-4, KIR2DL1/S1/S3/S5, IFNg, IFNa/b, IL-12/IL-13, IL-4, IL-2 and IL-17A, among others.

Conclusions

These results showed that these molecules had functional PD-1 and LAG-3 constitutive inhibitory signalling in T cells leading T cell dysfunctionality. This will allow to study the reasons behind the intrinsic resistance to PD-1 blockade.

Legal entity responsible for the study

Navarrabiomed, Instituto de Investigaciones Sanitarias de Navarra (IdiSNA), Universidad Pública de Navarra.

Funding

This work was supported and funded by the Spanish Association against Cancer (AECC, PROYE16001ESCO), Instituto de Salud Carlos III (ISCIII, FIS. PI17/02119), Biomedicine Project grant from the Department of Health of the Government of Navarre (BMED 050-2019).

Disclosure

All authors have declared no conflicts of interest.

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Translational research (agnostic)

1773P - Anti-PD1-induced acute interstitial pneumonitis is characterized by alveolar infiltration of PD-1+CD38+TIGIT+ cytotoxic effector CD8+ T cells and CD206+ inflammatory macrophages

Presentation Number
1773P
Speakers
  • François-Xavier Danlos (Villejuif, France)

Abstract

Background

Among immune related adverse events associated with anti PD-1 antibody, acute interstitial pneumonitis (AIP) is frequent and can be lethal. We analyzed alveolar immune infiltrates from bronchoalveolar lavages (BAL) of patients with AIP related to ICB.

Methods

Fresh BAL samples from patients with anti-PD-1 induced AIP were collected. Cells were analyzed by flow cytometry (BD, LSRFortessa X20®), mass cytometry (CyTOF, Fluidigm, Helios®), and single-cell RNA and TCR sequencing (scRNAseq, 10x genomics, chromium®).

Results

Ten BAL from patients with anti-PD-1-induced AIP were explored for analysis of cellular alveolar infiltration, by flow cytometry (n=7), CyTOF (n=6) and scRNAseq (n=2). Immune infiltrates were characterized by predominance of CD3+ T lymphocytes (68%, +/- 24%SD), and mostly CD8+ T cells (64% +/- 26%SD). These were mainly CD8+ effector and effector memory (TEM) T cells, which expressed predominantly CD27+CD28loCD38+CD69+KLRG1-PD-1+TIGIT+. Single-cell RNAseq analyzes showed that those CD8+ T cells expressed high levels of GZMH, GZMA, CST7, CTSW, NKG7, CCL4, CCL5, CD27, PDCD1, TIGIT, CD69 and ITGAE genes. They also expressed transcription factors IKZF6, ZNF683, TOX but not TCF7, EOMES or TBX21. Analysis of the TCR repertoire of those CD8+ T cells revealed oligoclonal expansion. CD14+CD163+CD1c- macrophages, partially double positive for CD206 and CCR2, were the main population among CD11c+ HLA-DR+ cells. CD206+ macrophages represented one third of total immune cells. They were positive for CD64, CD40 and partially for CD86 and PD-L1. Single-cell RNAseq of these cells found high levels of expression for MRC1, CD163, LILRB2, FCN1, S100A8, S100A9, CXCL9 and CXCL10 genes.

Conclusions

Alveolar immune infiltrates in patients with anti-PD1 induced AIP were characterized by a predominance and oligoclonal expansion of cytotoxic resident memory CD8+ T cells. Macrophages exhibited characteristics of cells derived from circulating monocytes and not from resident alveolar macrophages. Those results should help the diagnosis and treatment of lung toxicities induced by anti-PD-1 immunotherapies.

Legal entity responsible for the study

Gustave Roussy.

Funding

Fondation Gustave Roussy, Fondation Malakoff Médéric.

Disclosure

J-C. Soria: Financial Interests, Personal, Stocks/Shares: AstraZeneca; Financial Interests, Personal, Stocks/Shares: Gritstone Oncology; Financial Interests, Personal, Stocks/Shares: Relay Therapeutics; Non-Financial Interests, Personal, Member of the Board of Directors: Hookipa Pharmaceuticals; Non-Financial Interests, Personal, Full or part-time Employment, Sept 2017 to Dec 2019: AstraZeneca. L. Zitvogel: Non-Financial Interests, Personal, Member of the Board of Directors: Transgene; Non-Financial Interests, Personal, Advisory Board: Transgene; Non-Financial Interests, Personal, Advisory Board: Lytix Biopharma; Non-Financial Interests, Personal, Advisory Board: EpiVax; Non-Financial Interests, Personal, Advisory Board: NeoVax; Non-Financial Interests, Personal, Advisory Board: Vedanta; Non-Financial Interests, Institutional, Other, Research contracts: BMS; Non-Financial Interests, Institutional, Other, Research contracts: Incyte; Non-Financial Interests, Institutional, Other, Research contracts: GSK; Non-Financial Interests, Institutional, Other, Research contracts: Transgene; Non-Financial Interests, Institutional, Other, Research contracts: Innovate Biopharma; Non-Financial Interests, Institutional, Other, Research contracts: Pilege; Non-Financial Interests, Institutional, Other, Research contracts: Kaleido; Financial Interests, Personal, Leadership Role: everImmune. A. Marabelle: Financial Interests, Personal and Institutional, Research Grant: Merus; Financial Interests, Personal and Institutional, Research Grant: BMS; Financial Interests, Personal and Institutional, Research Grant: Boehringer Ingelheim; Financial Interests, Personal and Institutional, Research Grant: Transgene; Financial Interests, Personal and Institutional, Research Grant: Fondation MSD Avenir; Financial Interests, Personal and Institutional, Research Grant: Sanofi; Financial Interests, Personal, Stocks/Shares: Pegascy SAS; Financial Interests, Personal, Stocks/Shares: Centessa Pharmaceuticals; Financial Interests, Personal, Stocks/Shares: HiFiBio; Financial Interests, Personal, Stocks/Shares: Shattuck Labs; Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Personal, Invited Speaker: BMS; Financial Interests, Personal, Invited Speaker: MSD; Financial Interests, Personal, Invited Speaker: Merk Serono; Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Personal, Invited Speaker: Amgen; Financial Interests, Personal, Invited Speaker: Sanofi; Financial Interests, Personal, Invited Speaker: Servier. All other authors have declared no conflicts of interest.

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Investigational immunotherapy

1008P - cytoTIL15: A novel TIL therapy for melanoma with superior potency and enhanced persistence without IL2 to improve safety & efficacy and expand patient eligibility

Presentation Number
1008P
Speakers
  • Mithun Khattar (Cambridge, United States of America)

Abstract

Background

Tumor-infiltrating lymphocyte (TIL) therapy is at the cusp of approval for heavily pretreated patients with solid tumor malignancies. TIL therapy currently requires IL2 for in vivo maintenance of TILs, significantly limiting its application due to patient safety and eligibility hurdles. cytoTIL15 is a TIL product engineered with regulatable membrane bound IL15 (mbIL15) designed via our cytoDRiVE® platform. Armoring TILs with endogenous mbIL15 has several advantages over systemic IL2. Unlike IL2, IL15 does not increase immunosuppressive regulatory T-cells and drives T-cell differentiation towards a stem-cell memory phenotype associated with long-term persistence.

Methods

cytoTIL15 uses Obsidian’s cytoDRiVE® platform, which consists of a carbonic anhydrase 2 (CA2) derived drug responsive domain that enables regulated expression of mbIL15 under control of acetazolamide (ACZ), an FDA-approved orally bioavailable small molecule ligand. We use a proprietary process for high efficiency transduction of TILs with regulatable mbIL15 and expansion without IL2, after which TILs can be cryopreserved or used fresh in downstream in vitro and in vivo assays.

Results

Our process achieved robust expression of ACZ-regulatable mbIL15 on TILs that expand in the absence of IL2 to levels required for clinical manufacturing. Upon administration in NSG mice, cytoTIL15 exhibited significantly higher expansion and persistence compared to conventional TILs treated with clinically analogous IL2 dosing. cytoTIL15 have a CD8+ effector T-cell biased immunophenotypic profile distinct from conventional TILs, while maintaining a diverse TCR repertoire and tumor reactivity with robust IFNg production. In addition, cytoTIL15 demonstrated significantly higher tumor cytotoxicity in vitro in the absence of exogenous IL2 in comparison to conventional TILs, indicative of superior potency.

Conclusions

cytoTIL15 is a more potent and persistent TIL product that does not require infusion of IL2, thereby enhancing the safety and durable efficacy of TIL therapy for patients with metastatic melanoma and other solid tumor malignancies.

Legal entity responsible for the study

Obsidian Therapeutics.

Funding

Obsidian Therapeutics.

Disclosure

M. Khattar: Financial Interests, Institutional, Stocks/Shares: Obsidian Therapeutics. R. Burga: Financial Interests, Institutional, Stocks/Shares: Obsidian Therapeutics. K. Pedro: Financial Interests, Institutional, Stocks/Shares: Obsidian Therapeutics. C. Foley: Financial Interests, Institutional, Stocks/Shares: Obsidian Therapeutics. S. Lajoie: Financial Interests, Institutional, Stocks/Shares: Obsidian Therapeutics. A.V. Ocando: Financial Interests, Institutional, Stocks/Shares: Obsidian therapeutics. J. Tremblay: Financial Interests, Institutional, Stocks/Shares: Obsidian Therapeutics. D. Thornton: Financial Interests, Institutional, Stocks/Shares: Obsidian Therapeutics. S. Tam: Financial Interests, Institutional, Stocks/Shares: Obsidian Therapeutics. F. Nabulsi: Financial Interests, Institutional, Stocks/Shares: Obsidian Therapeutics. C. Vallaster: Financial Interests, Institutional, Stocks/Shares: Obsidian Therapeutics. S. Saha: Financial Interests, Institutional, Stocks/Shares: Obsidian Therapeutics. G. Wilmes: Financial Interests, Institutional, Stocks/Shares: Obsidian Therapeutics. G. Helmlinger: Financial Interests, Institutional, Stocks/Shares: Obsidian Therapeutics. J. Tchaicha: Financial Interests, Institutional, Stocks/Shares: Obsidian Therapeutics. D. Sethi: Financial Interests, Institutional, Stocks/Shares: Obsidian Therapeutics. M. Ols: Financial Interests, Institutional, Stocks/Shares: Obsidian Therapeutics. G. Vanasse: Financial Interests, Institutional, Stocks/Shares: Obsidian Therapeutics. S. Subramanian: Financial Interests, Institutional, Stocks/Shares: Obsidian Therapeutics. J. ter Meulen: Financial Interests, Institutional, Stocks/Shares: Obsidian Therapeutics.

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Investigational immunotherapy

1009P - Current strategies of cell and gene therapy for solid tumors: Preliminary results of the joint international ESMO and EBMT Cell Therapy and Immunobiology Working Party questionnaire-based survey

Presentation Number
1009P
Speakers
  • Patrizia Comoli (Pavia, Italy)

Abstract

Background

Among novel strategies for treatment of solid tumors (ST), cell and/or gene therapy (CT/GT) products are increasingly under investigation, also based on encouraging results observed in lymphoid cancers with industry-manufactured CAR-T-cells. Available information on ongoing studies in ST is limited, due to the variety of programs and infrastructures involved in advanced therapy medicinal products (ATMPs) manufacturing and delivery.

Methods

This study aimed to describe the current landscape of CT/GT developments for treatment of ST from Jan 2018 to Dec 2020 by means of a web-based questionnaire circulated within the ESMO and EBMT centers.

Results

147 questionnaires were returned from 53 countries, 22% of the respondents were involved in CT/GT trials during the study period and 16% indicated their intention to start a CT/GT program. The majority of the active centers treated only adults (88%), while a minority exclusively or partially treated children (12%); 50% of the centers treated 1-5 pts, while a quarter enrolled more than 20 pts. Almost half of the studies were dedicated to melanoma or lung cancer; GI tract tumors, bone sarcomas, head & neck and gynecological cancers were also targeted. Evaluated ATMPs were mainly ex-vivo manipulated T lymphs, cultured and, in more than 50% of the cases, gene-modified either with CAR sequence or TCR transgene. TILs were the most frequently used non-gene modified products. In as many as 67% of the cases, ATMPs were combined with other treatment modalities, largely represented by ICIs. Small scale cell and gene engineering was mostly performed onsite by point-of-care manufacturing facilities. A minority of the studies were supported by EU funding.

Conclusions

Our survey shows that, although increasingly used, gene-modified T-cells represent little more than 50% of ATMPs employed in ST. Many clinical trials are based on point-of-care ATMPs production at academic centers, although industry-sponsored trials are running in at least half of the centers. In perspective, while waiting for breakthrough cellular products to treat ST, the field may benefit from network models for ATMPs production in academic centers.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

S. Peters: Consultation/Advisory role: AbbVie, Amgen, AstraZeneca, Bayer, Beigene, Biocartis, Bio Invent, Blueprint Medicines, Boehringer Ingelheim, Bristol-Myers Squibb, Clovis, Daiichi Sankyo, Debiopharm, Eli Lilly, Elsevier, F. Hoffmann-La Roche/Genentech, Foundation Medicine, Illumina, Incyte, IQVIA, Janssen, Medscape, Merck Sharp and Dohme, Merck Serono, Merrimack, Mirati, Novartis, PharmaMar, Phosplatin Therapeutics, Pfizer, Regeneron, Sanofi, Seattle Genetics, Takeda, Vaccibody; Talk in a company’s organized public event: AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, e-cancer, Eli Lilly, F. Hoffmann-La Roche/Genentech, Illumina, Medscape, Merck Sharp and Dohme, Novartis, PER, Pfizer, Prime, RTP, Sanofi, Takeda; Receipt of grants/research supports: (Sub)investigator in trials (institutional financial support for clinical trials) sponsored by Amgen, AstraZeneca, Biodesix, Boehringer Ingelheim, Bristol-Myers Squibb, Clovis, F. Hoffmann-La Roche/Genentech, GSK, Illumina, Lilly, Merck Sharp and Dohme, Merck Serono, Mirati, Novartis, and Pfizer, Phosplatin Therapeutics.

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Investigational immunotherapy

1016P - ImmTAC redirect exhausted tumor-infiltrating T-cells: An effect enhanced by pembrolizumab against PD-L1+ tumors

Presentation Number
1016P
Speakers
  • Kristina Petrovic (Abingdon, United Kingdom)

Abstract

Background

ImmTAC molecules are TCR-anti-CD3 bispecific fusion proteins that can redirect polyclonal T-cell activation. Tebentafusp, a gp100-directed ImmTAC, has demonstrated survival benefit in metastatic uveal melanoma (1). ImmTAC activate TILs or recruit circulating T-cells into tumors before redirecting them to kill cancer cells. Here, we examined in vitro whether ImmTAC can redirect exhausted (defined as PD1+) TILs or circulating T-cells to kill tumor cells and assessed the effect of anti-PD1 combination.

Methods

TILs and circulating T-cells were isolated from melanoma patients’ biopsies and blood respectively. Chronic T-cell activation was modelled in vitro by repeated stimulations. The capacity of purified PD1+ TILs and T-cells to be redirected by ImmTAC was tested in vitro with or without pembrolizumab. The target melanoma cell line Mel624 was untransduced or transduced to overexpress PD-L1.

Results

T-cells chronically stimulated in vitro express high levels of PD1. While ImmTAC can redirect both PD1+ and PD1- T-cells to kill PD-L1- tumor cells, chronically stimulated PD1+ T-cells have up to two-fold reduced capacity to kill PD-L1+ tumors compared to non-chronically stimulated T-cells. PD1+ T-cell killing activity against PD-L1+, but not PD-L1-, tumors was improved by pembrolizumab (from 40±8 % to 69±4 % maximum killing) at clinically relevant ImmTAC concentrations. Ex vivo purified PD1+ TILs and PD1+ circulating T-cells were as efficiently redirected by ImmTAC as their PD1- counterparts to kill tumor cells lacking PD-L1 expression; addition of pembrolizumab had no effect. However, ImmTAC-mediated killing by PD1+ TILs was reduced from 78±17 % killing without PD-L1 to 30±3 % with PD-L1 expressed on tumor cells, which was reversed to 68±4 % in the presence of pembrolizumab.

Conclusions

ImmTAC mediated killing by exhausted PD1+ TILs was efficient against PD-L1- but reduced against PD-L1+ tumor cells. This reduced killing activity was reversed by pembrolizumab. These data provide the rationale for clinical investigation of ImmTAC combinations with anti-PD1/L1 in tumors where both PD1 and PD-L1 are expressed on TILs and tumor cells respectively. (Piperno-Neumann et al. AACR 2021 Abstract # 5342).

Legal entity responsible for the study

The authors.

Funding

Immunocore Ltd.

Disclosure

K. Petrovic: Financial Interests, Full or part-time Employment: Immunocore Ltd. D. Depoil: Financial Interests, Personal, Full or part-time Employment: Immunocore Ltd; Financial Interests, Personal, Stocks/Shares: Immunocore Ltd; Non-Financial Interests, Personal, Proprietary Information: Immunocore Ltd. D.M. Gascoyne: Financial Interests, Full or part-time Employment: Immunocore Ltd. K. Page: Financial Interests, Full or part-time Employment: Immunocore Ltd. A. Curnock: Financial Interests, Full or part-time Employment: Immunocore Ltd. A. Benlahrech: Financial Interests, Full or part-time Employment: Immunocore Ltd.

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NSCLC, locally advanced

1185P - Induction immunotherapy in resectable non-small cell lung cancer harboring driver mutations: A multi-center retrospective study

Presentation Number
1185P
Speakers
  • Chao Zhang (Guangzhou, China)

Abstract

Background

Neoadjuvant targeted therapy remained controversial for mutant early-stage NSCLC. Despite limited efficacy of immunotherapy for advanced NSCLC with driver mutations, whether induction immunotherapy could be feasible for these patients warrants further exploration.

Methods

We retrospectively collected 24 NSCLC patients who harbored driver mutations including EGFR, KRAS, ALK, HER2, BRAF, RET, and received induction immunotherapy from 7 renowned centers. Radiological and pathological evaluation were measured for all patients as well as dynamic multi-omics sequencing including WES, TCR, RNA and mIHC in some patients (results pending).

Results

Of the 24 patients, 15 (62.5%) patients had a partial response, 7 (29.2%) had a stable disease and 2 (8.3%) had a progression disease after induction immunotherapy. Detailed clinical demographic data was summarized in the table. Most of the patients (21/24) received induction immunotherapy plus chemotherapy. Only one patient did not receive surgery due to newly metastatic lesions. Surgical complication was mild for most patients except for one needed blood transfusion. 12 patients had been pathologically or radiologically diagnosed with N2 metastatic lymph nodes. The pathological N2 downstaging rate was 66.7% (8/12). For patients with available pathological assessment, overall major pathological response (MPR) rate was 34.8% (8/23) and pathological complete response (pCR) rate was 17.4% (4/23). For EGFR mutations, MPR rate was 33.3% (3/9) and pCR rate was 22.2% (2/9). For KRAS mutations, MPR rate was 50.0% (3/6) and pCR rate was 16.7% (1/6).

Characteristics All patients (N=24) Patients with major pathological response (N=8) Patients without major pathological response (N=15)
Age —— yrs
Mean ±SD 58.1±9.2 57.5±8.2 58.5±10.2
Median (range) 60 (36-72) 60 (47-70) 62 (36-72)
Gender —— no. (%)
Female 10 (41.7) 2 (25.0) 8 (53.3)
Male 14 (58.3) 7 (75.0) 7 (46.7)
Smoking status —— no. (%)
Never 11 (45.8) 3 (37.5) 8 (53.3)
Former/current 13 (54.2) 5 (62.5) 7 (46.7)
Clinical stage —— no. (%)
IB-II 7 (29.2) 3 (37.5) 3 (20.0)
IIIA 12 (50.0) 3 (37.5) 9 (60.0)
IIIB-IVA 5 (20.8) 2 (25.0) 3 (20.0)
Mutation features —— no. (%)
EGFR alteration 9 (37.5) 3 (37.5) 6 (40.0)
KRAS alteration 7 (29.2) 3 (37.5) 3 (20.0)
Other mutations 8 (33.3) 2 (25.0) 6 (40.0)

Conclusions

Induction immunotherapy plus chemotherapy may be potentially optional for oncogene mutant NSCLC. Further studies are warranted to clarify the response mechanism of immunotherapy and determine the most optimal treatment modalities for resectable NSCLC harboring driver mutations.

Legal entity responsible for the study

The authors.

Funding

National Natural Science Foundation of China.

Disclosure

All authors have declared no conflicts of interest.

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Oesophagogastric cancer

1393P - Phase I/II clinical trial of combination of anti-PD-1 mAb, nivolumab with radiotherapy for unresectable and recurrent gastric cancer who failed to standard chemotherapy

Presentation Number
1393P
Speakers
  • Koji Kono (Fukushima, Japan)

Abstract

Background

Although basic, translational and clinical research suggest a possibility of synergistic effect of radiation-induced immunogenic cell death with immune checkpoint inhibitors, the effectiveness of concurrent therapy with radiotherapy and immunotherapy is not fully established.

Methods

Phase I/II, open single arm, prospective clinical trial was conducted and eligible patients were unresectable advanced or recurrent gastric cancer patients (n = 40) who developed progression after primary and secondary chemotherapy with multiple metastasis assessable in imaging (one lesion must be ≥2cm). Radiotherapy of total 22.5 Gy/5 fractions/5 days was given to the largest or symptomatic lesion and nivolumab was administered day 15-22 at 3 mg/kg or 240mg/body every 2 weeks to a total of 6 administrations. The primary endpoint is disease control rate of non-irradiated lesions as an abscopal effect. The secondary endpoints are MST, safety and proportion of local control rate for irradiated lesion. As an ancillary analysis, immunologic parameters including high-dimensional MHC multimer analysis and TCR repertoire analysis, and ctDNA analysis are designed.

Results

Total 41 patients were enrolled and 40 patients were evaluated as full analysis set, since 1 patient was judged as an unmatched case to inclusion criteria. The clinical evaluation as an abscopal effect were CR=1 (2.5%), PR=5 (12.5%), SD=3 (7.5%), PD=15 (37.5%) and NE=16 (40%). The disease control rate and the response rate for non-irradiated target lesions was 22.5% and 15%, respectively. The MST was 230 days (157-330, 95%CI) and 1-year survival rate was 28.6%. Any adverse event more than Grade 3 was observed in 16 cases in 41 patients (39%). The most frequent AE more than grade 3 were anemia (19%) and appetite loss (12%). The local control for irradiated lesions were seen in CR=5 (12.5%), PR=6 (15%), SD=5 (12.5%), PD=4 (10%) and NE=20 (50%). The ancillary analysis for immunological monitoring is under investigation.

Conclusions

The combination of nivolumab with radiotherapy demonstrated promising anti-tumor activity with marked prolonged survival time in gastric cancer. No new safety issues were detected in the combination.

Clinical trial identification

NCT03453164.

Legal entity responsible for the study

Clinical Research Center, Fukushima Medical University Hospital; Clinical Research Center, Kanagawa Cancer Center Hospital.

Funding

Ono Pharmaceutical company.

Disclosure

K. Kono: Financial Interests, Institutional, Sponsor/Funding: Ono Pharmaceutical company; Financial Interests, Personal, Speaker’s Bureau: Ono Pharmaceutical company. K. Mimura: Financial Interests, Personal, Speaker’s Bureau: Ono Pharmaceutical company. T. Ogata: Financial Interests, Personal, Speaker’s Bureau: Ono Pharmaceutical company. T. Yamada: Financial Interests, Personal, Speaker’s Bureau: Ono Pharmaceutical company. H. Katoh: Financial Interests, Institutional, Research Grant: KOWA electric industry. Y. Suzuki: Financial Interests, Personal, Speaker’s Bureau: Ono Pharmaceutical company; Financial Interests, Personal, Advisory Board: Chugai Pharmacetical; Financial Interests, Personal, Advisory Board: Kyowa Kirin. All other authors have declared no conflicts of interest.

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Translational research (agnostic)

1770P - Genomic correlates of clinical outcomes in patients with metastatic uveal melanoma (mUM) treated with tebentafusp (tebe)

Presentation Number
1770P
Speakers
  • Luis De la Cruz Merino (Seville, Spain)

Abstract

Background

Tebe, an investigational TCR–anti-CD3 bispecific fusion protein that targets gp100 and activates T cells, has shown survival benefit in mUM. In a phase 2 trial enrolling patients (pts) with mUM, we explored genomic correlates of clinical outcomes.

Methods

127 HLA-A*02:01+ pts with advanced UM were treated weekly with 68mcg tebentafusp after intra-patient dose escalation (NCT02570308). RECISTv1.1 was evaluated by IRC. Whole exome sequencing and RNAseq was performed on frozen tumor biopsies collected at baseline (N=63 and N=70, respectively) and after the third dose of tebe (RNAseq, N=up to 35). 100 mRNA signatures cut at the median were tested for association with tumor shrinkage (TS) and overall survival (OS).

Results

Tumor mutations in GNAQ, GNA11, SF3B1 were not associated with TS or OS. Consistent with TCGA, tumor mutation burden was low (0.3-2.4 muts/Mb) and was not associated with TS or OS; however, novel somatic missense mutations in 7 genes (N=32/63) including UCP1 and NOTCH4 were identified and as a group associated with better OS (hazard ratio [HR] 0.2, 95% CI 0.1-0.47). In the tumor and/or microenvironment, high baseline mRNA levels of the type 1 IFN inducible and ISGylation gene UBA7 were associated with greater TS (odds ratio OR 0.2, 0.04-0.53) and OS (HR 0.3, 0.14-0.57). High expression of the type 2 IFN inducible GTPase binding gene, GBP1, was associated with better TS (OR 0.3, 0.08-0.93) and OS (HR 0.4, 0.19-0.73). In contrast, high GBP1 expression was associated with worse OS in TCGA UM (HR 4.3, 1.67,11.14). Expression of these and other type 1&2 IFN genes was significantly induced by tebentafusp (2-4-fold). High baseline levels of JAK2/STAT4, but not other JAK/STATs, were associated with increased TS (OR 0.3, 0.07-0.85) and OS (HR 0.4, 0.18-0.72), implicating IL12-induced type 2 IFN expression. Among the checkpoints, only high baseline levels of CTLA4 mRNA, which were further induced 1.7-fold by tebe, were associated with TS (OR 0.3, 0.08-0.94) and OS (HR 0.3, 0.16-0.62). PD-1-PDL1 axis was not associated with TS or OS.

Conclusions

Genomic analysis provides new insight into the potential role of ISGylation in UM and highlights the importance of type 1&2 IFN pathway genes in the anti-tumor immune response on tebe.

Clinical trial identification

NCT02570308.

Legal entity responsible for the study

Immunocore Ltd.

Funding

Immunocore Ltd.

Disclosure

L. de la Cruz Merino: Other, Personal, Advisory Board: MSD-Merck; Other, Personal, Advisory Board: Roche Farma; Other, Personal, Advisory Board: Bristol-Myers-Squibb; Other, Personal, Advisory Board: Pierre-Fabré; Other, Personal, Advisory Board: Amgen; Other, Personal, Advisory Board: Novartis; Financial Interests, Personal, Funding: MSD-Merck; Financial Interests, Personal, Funding: Roche Farma; Financial Interests, Personal, Funding: Celgene. Z. Eroglu: Other, Personal, Advisory Board: Array Biopharma; Other, Personal, Advisory Board: OncoSec; Other, Personal, Advisory Board: Regeneron; Other, Personal, Advisory Board: Genentech; Other, Personal, Advisory Board: Novartis; Other, Personal, Advisory Board: SunPharma; Other, Personal, Advisory Board: Natera; Other, Personal, Funding: Novartis; Other, Personal, Funding: Pfizer. L. Collins: Financial Interests, Personal, Full or part-time Employment: Immunocore Ltd. A. Greenshields-Watson: Financial Interests, Personal, Full or part-time Employment: Immunocore Ltd. S. Stanhope: Financial Interests, Personal, Full or part-time Employment: Immunocore Ltd. S. Abdullah: Financial Interests, Personal, Full or part-time Employment: Immunocore Ltd. K. Ranade: Financial Interests, Personal, Full or part-time Employment: Immunocore Ltd. J. Sacco: Other, Personal, Advisory Board: Immunocore,; Other, Personal, Advisory Board: Delcath; Other, Personal, Advisory Board: BMS; Other, Personal, Advisory Board: MSD; Financial Interests, Institutional, Funding: Immunocore; Financial Interests, Institutional, Funding: BMS; Financial Interests, Institutional, Funding: AZ; Financial Interests, Institutional, Funding: Replimmune; Financial Interests, Institutional, Funding: MSD; Financial Interests, Institutional, Funding: Amgen.

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Translational research (agnostic)

1772P - Demonstration of T cell redirection and immune activation in skin rash following tebentafusp treatment

Presentation Number
1772P
Speakers
  • Ramon Stäger (Zurich, Switzerland)

Abstract

Background

Tebentafusp (tebe) is an investigational TCR–anti-CD3 bispecific fusion protein that targets gp100 and activates T cells. In a recent phase 3 study, tebe improved overall survival (OS) in metastatic uveal melanoma patients (pts)1. Most pts developed skin rash after dose 1, an expected adverse event since melanocytes also express gp100; however, rash was not an independent predictor of OS benefit2.

Methods

12/14 pts developed >1 grade rash within 7 days post 1st dose. Paired skin biopsies from pts with metastatic melanoma (NCT01211262) were collected pre and post the 1st (N=12) or 4th (N=2) dose of tebe. Fixed samples were assessed by hematoxylin and eosin and CD3 immunohistochemistry (IHC). On 5 additional skin biopsies, dual IHC for Melan-A and CD4/8 was performed. RNAlater® samples were analyzed by RNAseq. Differential gene expression, pathway and cell type composition analysis were performed using R software.

Results

Biopsies from these pts showed increase in lymphocytic infiltrate, exocytosis of lymphocytes and basal cell vacuolization (p=0.002) along the dermo-epidermal junction (DEJ) and upper dermal perivascular inflammatory infiltrate (p=0.01) post treatment compared to baseline. The DEJ inflammatory infiltrate consisted of CD3+ T cells, which were predominantly CD8+ and localized close to melanocytes. RNAseq identified 1786 differentially expressed genes (threshold: p-adj≤0.05, log2-ratio≥0.75), with enrichment of innate and adaptive pathways, including IFNγ signaling, post treatment compared to baseline (p-adj<10-17). An increase in macrophage and CD8+ T cell genes was accompanied by upregulation of the cytotoxic genes GZMB and PRF1 (p-adj<10-6). Chemokines CXCL9/10/11 and cytokines IL-10/15/32 were overexpressed (p-adj<10-7). Expression of melanocyte markers, PMEL, MLANA and DCT were decreased.

Conclusions

Tebe induced rapid recruitment of T cells in the proximity of intraepidermal melanocytes in addition to macrophage activation. Thus tebe-induced skin rash is an on-target effect and may be an important pharmacodynamic tool to better understand the precise molecular and cellular cascades of T cell redirection in the tumor. 1Piperno-Neumann S. AACR 2021 CT002. 2Hassel J. ASCO 2021 #9527.

Clinical trial identification

NCT01211262.

Legal entity responsible for the study

Immunocore Ltd.

Funding

Immunocore Ltd.

Disclosure

S. Stanhope: Financial Interests, Institutional, Full or part-time Employment: Immunocore Ltd. A. Greenshields-Watson: Financial Interests, Institutional, Full or part-time Employment: Immunocore Ltd. L. Collins: Financial Interests, Institutional, Full or part-time Employment: Immunocore Ltd. E. Ramelyte: Financial Interests, Institutional, Full or part-time Employment: University Hospital Zurich; Financial Interests, Personal, Advisory Role: Amgen; Financial Interests, Personal, Advisory Role: BMS; Financial Interests, Personal, Advisory Role: Novartis; Financial Interests, Personal, Advisory Role: Sanofi; Financial Interests, Personal, Advisory Board: Sunpharma. R. Dummer: Financial Interests, Personal, Advisory Role: Novartis; Financial Interests, Personal, Advisory Role: Merck Sharp & Dhome (MSD); Financial Interests, Personal, Advisory Role: Bristol-Myers Squibb (BMS); Financial Interests, Personal, Advisory Role: Roche; Financial Interests, Personal, Advisory Role: Amgen; Financial Interests, Personal, Advisory Role: Takeda; Financial Interests, Personal, Advisory Role: Pierre Fabre; Financial Interests, Personal, Advisory Role: Sun Pharma; Financial Interests, Personal, Advisory Role: Sanofi; Financial Interests, Personal, Advisory Role: Catalym; Financial Interests, Personal, Advisory Role: Second Genome; Financial Interests, Personal, Advisory Role: Regeneron; Financial Interests, Personal, Advisory Role: Alligator; Financial Interests, Personal, Advisory Role: T3 Pharma; Financial Interests, Personal, Advisory Role: MaxiVAX SA; Financial Interests, Personal, Advisory Role: touchIME. All other authors have declared no conflicts of interest.

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