{
  "abstract": "Background ICI are widely prescribed to cancer (CA) patients (pts), however, on average 85% of pts are resistant. Annually 2 million new pts are diagnosed with CA, of which ~750,000 are candidate for ICI. 1 Annual spending on ICI is >$40 billion worldwide of which billions of dollars will be ‘lost’ on resistant pts (~85%) due to receiving at least 2 ICI cycles to enable response evaluation. Furthermore, the ‘non-responders’ could have received a more effective (and less expensive) treatment, such as chemotherapy, if their ‘non-response’ status could have been predicted at baseline. ICI requires activated CD8+ T-cells (TCs) to be effective, which is achieved by Dendritic Cells (DCs) processing and presenting CA antigen to TCs. CA tissue (including stromal cells) can produce TDCMs that can tolerize DCs, which no longer are capable of activating TCs.2 We aimed to validate a panel of TDMCs for the prediction of resistance to ICI.Methods We conducted a meta-analysis and summarized 1. Reported TDCM prevalence by human CA type (n=521 papers), and 2. Outcomes of ICI in the same CA types (Objective Response Rate [ORR (%); n= 116 papers] and Overall Survival Hazard Ratio [OS HR; n=32 papers] from published ICI clinical trials. Next, we correlated TDCM prevalence with ICI outcomes by CA type, to obtain correlation coefficient (r-value) after linear regression. ORR represents ‘tumor shrinkage’ and OS HR represents ‘mortality risk’ after ICI. ORR was typically obtained from Phase 1/2 trials with ICI monotherapy, whereas OS HR from Phase 2/3 trials with an ‘ICI+ treatment x’ arm and an ‘treatment x’ alone control arm. The TDCMs evaluated were DC-Sign, IDO, TGF-β, HGF, Galectin-1, RA, AhR, IL-27, NO, VIP, VDR, TRAIL, and the Ca types were NSCLC, SCLC, HNSCC, Melanoma, GBM, Pancreatic, Bladder, Gastric, Prostate, Breast, TNBC, Esophageal, CRC, HCC, RCC.Results TDCM prevalence correlated with ICI outcomes. A subset of 4 TDCMs were the best predictors of ICI outcomes, analyzed separately with both the ORR and OS HR dataset. After correlating this 4-panel TDCM subset with ICI outcomes, the r-value was +0.59 for OS HR (n=9809 pts; p<0.0001) and -0.45 for ORR (n=18921pts; p<0.0001) ( figure 1).Conclusions We provide meta-analytical evidence that TDCMs in CA tissue are associated with ICI resistance. We aim to develop a predictive test wherein TDCMs are characterized in baseline (pre-treatment) CA tissue samples to guide patient selection for ICI.References Haslam A, Gill J, Prasad V. Estimation of the percentage of US patients with cancer who are eligible for immune checkpoint inhibitor drugs. JAMA Netw Open. 2020;3(3):e200423. doi:10.1001/jamanetworkopen.2020.0423DeVito NC, Plebanek MP, Theivanthiran B, Hanks BA. Role of tumor-mediated dendritic cell tolerization in immune evasion. Front Immunol. 2019 Dec 10;10:2876. doi: 10.3389/fimmu.2019.02876. PMID: 31921140; PMCID: PMC6914818.Abstract 52 Figure 1A novel approach for the prediction of resistance to immune checkpoint inhibitors (ICI), based on tolerogenic dendritic cell mediators (TDCMs)",
  "authors": [
    {
      "affiliations": [
        "RND Pharmaceuticals Inc, New York, NY, USA"
      ],
      "name": "Ramon Mohanlal"
    },
    {
      "affiliations": [
        "RND Pharmaceuticals Inc, New York, NY, USA"
      ],
      "name": "Maya Mohanlal"
    }
  ],
  "title": "52 A novel approach for the prediction of resistance to immune checkpoint inhibitors (ICI), based on tolerogenic dendritic cell mediators (TDCMs)",
  "uid": "79693634-d86b-511a-8e22-e2ec3fa65c77"
}