1463P - The presence of liver metastases is associated with systemic immune suppression in gastroesophageal cancer

Background

Immune checkpoint inhibition (ICI) has emerged as a new treatment for gastroesophageal cancer (GEC). Up to 60% of metastasized patients are eligible for ICI. Liver metastases (LM) are the second most common site of synchronous metastatic disease in GEC and are predictive of poor response to ICI. In other tumor types, LM are associated with systemic CD8 T cell depletion. Data on the interaction between LM and circulating peripheral blood mononuclear cells (PBMCs) in GEC are lacking. We investigated the PBMC composition in metastatic GEC patients with and without LM.

Methods

We performed multicolor flow-cytometry analysis of PBMCs from 53 patients with Her2- metastatic GEC before start of first-line systemic treatment in the LyRICX study (NCT03764553). Activation and co-inhibitory markers were determined on T-cell subsets and included Ki67, FoxP3, PD1, LAG-3, CD25, TIM-3, HLA-DR, TIGIT, CD56 and CD39. We performed unpaired Mann-Whitney U tests to compare medians between patients with and without LM.

Results

24 patients had LM, 29 did not. There was no difference in the percentage of CD4 or CD8 T cells between patients with or without LM. Patients with LM had a lower percentage of CD8+ Central Memory (CM) and a higher percentage of CD8+CD45RA+ effector memory cells (EMRA), (Table). The CD8+/regulatory T cell (Treg) ratio was lower in patients with LM. Treg percentages did not differ between patients with and without LM. The aforestated markers on T cell subsets did not differ between both groups. Table: 1463P

CD8+ T cell and Treg subset frequencies in patients with gastroesophageal cancer

Conclusions

Our results demonstrate a remarkable shift within circulating CD8+ T-cells of patients with LM, from long-term memory cells with high proliferative renewal capacity to senescent, terminally differentiated cells. This suggests a systemic defect in clonal expansion capacity of antitumor effector cells associated with LM. In the LyRICX study, we will further investigate ICI efficacy between patients with and without LM, and the effect of ICI on immune subsets in peripheral blood.

Clinical trial identification

NCT03764553.

Editorial acknowledgement

Legal entity responsible for the study

Amsterdam UMC.

Funding

Servier.

Disclosure

S. Derks: Financial Interests, Institutional, Advisory Board: BMS; Financial Interests, Institutional, Invited Speaker: BMS, Servier; Financial Interests, Institutional, Funding, sponsoring investigator initiated study: Incyte. N. Haj Mohammad: Financial Interests, Institutional, Advisory Role: Servier, AstraZeneca, BMS/Pfizer, Merck/Pfizer, Lilly. T.D. de Gruijl: Financial Interests, Institutional, Advisory Board: LAVA Therapeutics, DCPrime, Macrophage Pharma, GE Health; Financial Interests, Personal, Advisory Board: Partner Therapeutics; Financial Interests, Personal, Stocks/Shares: LAVA Therapeutics; Financial Interests, Personal, Advisory Board, Patent: Immunoglobulins binding human Vγ9Vδ2 T cell receptors; P31885NL00: LAVA Therapeutics; Financial Interests, Personal, Advisory Board, Single domain antibodies targeting CD1d; P32016NL00; EP16715360.0-1412: LAVA Therapeutics; Financial Interests, Personal, Advisory Board, Patent: Novel bispecific antibodies for use in the treatment of haematological malignancies. WO/2020/060406, PCT/NL2019/050625: LAVA Therapeutics; Financial Interests, Personal, Advisory Board, Patent: Novel CD40 binding antibodies; WO/2020/159368; PCT/NL2020/050051: LAVA Therapeutics; Financial Interests, Personal, Advisory Board, Patent: Recombinant replication competent viruses comprising a coding region for glycogen synthase kinase- (GSK3) and methods of killing aberrant cells. WO/2020/046130, PCT/NL2019/050562: ORCA Therapeutics; Financial Interests, Institutional, Coordinating PI, Research funding from Idera Pharmaceuticals for an investigator-initiated clinical trial (INTRIM) on the intra-dermal administration of IMO-2125 CpG in early-stage melanoma;: Idera Pharmaceuticals; Financial Interests, Institutional, Research Grant, Contract research with Macrophage Pharma Inc.”Pre-clinical testing of the immune modulating effects of MPL-5821 in the tumor microenvironment”,: Macrophage Pharma; Non-Financial Interests, Leadership Role, Member of the Board of Directors: SITC, Society for the Immunotherapy of Cancer (SITC); Non-Financial Interests, Advisory Role, Member of the grant review committee: MRA; Non-Financial Interests, Advisory Role, Member of their scientific grant reviewing committee: KWF; Non-Financial Interests, Institutional, Product Samples, Provision of Durvalumab for a clinical trial: AstraZeneca; Non-Financial Interests, Institutional, Product Samples, Provision of nivolumab for clinical trials: BMS; Non-Financial Interests, Institutional, Product Samples, Provision of Pembrolizumab for clinical trials: Merck; Non-Financial Interests, Institutional, Product Samples, Anti-CTLA4/PD-1 for clinical trial conduct: Agenus; Non-Financial Interests, Member: AACR. H.W.M. van Laarhoven: Financial Interests, Institutional, Invited Speaker: Astellas, BeiGene, Benecke, BMS, Daiichi Sankyo, JAAP, Medtlaks, Novartis, Springer, Travel Congress Management BV; Financial Interests, Institutional, Advisory Board: Amphera, Anocca, Astellas, AstraZeneca, BeiGene, Boehringer Ingelheim, Daiichi Sankyo, Dragonfly, MSD, Servier; Financial Interests, Institutional, Other, Advices on protocol development: Myeloid; Financial Interests, Institutional, Other, Selection of articles for Framingham: Framingham; Financial Interests, Institutional, Research Grant, LyRICX study: Servier; Financial Interests, Institutional, Research Grant, TAPESTRY study: Merck; Financial Interests, Institutional, Research Grant, AUSPICIOUS study: Incyte; Financial Interests, Institutional, Research Grant, LOAD study: ORCA; Financial Interests, Institutional, Coordinating PI: Auristone; Financial Interests, Institutional, Local PI, DESTINY-GASTRIC03: AstraZeneca; Non-Financial Interests, Leadership Role, Chair upper GI Faculty: ESMO; Non-Financial Interests, Institutional, Product Samples, For all clinical study mentioned, study medication is provided: See 'research funding'. All other authors have declared no conflicts of interest.