{
  "abstract": "Background The PI3K/AKT/mTOR axis is often constitutively activated in relapse/refractory solid cancers. By targeting this axis with a immune checkpoint blockade (ICB) based-triplet drug combination of capivasertib (Cap), olaparib (Ola) and durvalumab (Durva), the MEDIPAC trial has demonstrated meaningful anti-tumor activity, and patients who experienced partial response (PR) exhibited downregulation of Tregs. 1 2 We hypothesize that AKT inhibition synergizes with Ola and Durva to elicit anti-tumor responses via remodelling of the tumour microenvironment (TME).Methods Patient tissues evaluated were collected from the MEDIPAC trial with trial design and patient characteristics described in figure 1. Longitudinal biopsies of treatment timepoints: baseline (TP1), post-Cap monotherapy (TP2) and triplet therapy (TP3) were subjected to spatial transcriptomic profiling utilising the Nanostring GeoMX platform. Profiles of tumor (PanCK+), T cell (CD3+) and stromal (PanCK-CD3-) compartments were collected. In this study, responders were patients who did no experience disease progression. Pathway analysis of differentially expressed genes were conducted to delineate changes in response to therapy and between responder groups. Immune deconvolution using a published scRNA-seq atlas of pan-cancer T cells was performed to identify the composition of T cells subpopulations.Results Upon treatment of triplet therapy, tumors of responders exhibited upregulation of inflammatory genes associated with better ICB response like MHC molecules and CXCL9, not seen in non-responders. Indeed, non-responders demonstrated higher suppressive Treg enrichment in their TME compared to responders. Therefore, we postulate that responders may be primed for optimal response to ICB-triplet based therapy, possibly on several fronts including the TME. As Cap was administered as a pre-treatment regimen before triplet therapy, AKT inhibition may influence the divergence of ICB-based triplet therapy responses. After Cap monotherapy, responders showed decreased proportion of exhausted T cells in the CD3 + compartment, in contrast to non-responders. Notably, tumors of responders downregulated immune-inhibitory genes like CD46 and CD24 which may predispose the TME for enhanced T cell response. Contrarily, non-responders demonstrated elevated IL4 signalling pathways and CCL5 expression, which were associated with anti-inflammatory M2 macrophage polarization to augment pro-tumor activity. At baseline, differentially expressed pathway analysis determined that responders were largely enriched in PI3K/AKT signalling. Whereas, in non-responders, TGFβ and RAS signalling pathways were enriched, potentially informing on alternative combination therapies.Conclusions Overall, we identify that in PI3K/AKT-dependent advanced/metastatic tumors, AKT inhibition exerts control over the TME for optimal response to ICB-based triplet therapy. Characterization of other TME components, including macrophages and stromal cells are underway.Acknowledgements AstraZeneca’s support is gratefully acknowledgedTrial Registration NCT03772561References Lim JS, Sundar R, Wong A, Yong WP, Soo R, Chee CE, Tan DS. 515MO A phase I trial of durvalumab (Durv) in combination with olaparib (Ola) and capivasertib (Cap) in patients (pts) with advanced or metastatic cancers (Ca)(MEDIPAC). Annals of Oncology 2021;32:S585-S586.Lim J, Raghav S, Wong A, Yong WP, Soo RA, Chee CE, Tan DS. 458MO Efficacy of durvalumab (Durva) in combination with olaparib (Ola) and capivasertib (Cap) in patients (pts) with advanced or metastatic (met) cancers (Ca)(MEDIPAC). Annals of Oncology 2022;33:S748.Abstract 518 Figure 1(A) Schematic of MEDIPAC trial treatment regimen, with reported median interval days of each treatment. (B) Table of patient characteristics in current study",
  "authors": [
    {
      "affiliations": [
        "National University of Singapore, Singapore, Singapore"
      ],
      "name": "Clemence Lai"
    },
    {
      "affiliations": [
        "National University Cancer Institute, Singapore, Singapore"
      ],
      "name": "Joline Lim"
    },
    {
      "affiliations": [
        "National University Cancer Institute, Singapore, Singapore"
      ],
      "name": "Raghav Sundar"
    },
    {
      "affiliations": [
        "National University Cancer Institute, Singapore, Singapore"
      ],
      "name": "David Tan"
    }
  ],
  "title": "518 Capivasertib, an AKT inhibitor, remodels the tumor microenvironment to synergize with combination therapy of olaparib and durvalumab in susceptible advanced/metastatic solid cancers",
  "uid": "e0b316ea-9d9b-5416-b45f-ce8cfe7ddd07"
}