{
  "abstract": "Background While initially promising, the activity of anti-CD47 monoclonal antibodies has shown to be non-durable for the treatment of B-cell non-Hodgkin lymphoma (B-NHL). We have previously demonstrated that evorpacept (ALX148), a high-affinity CD47 blocker with an inert Fc region, can induce durable remissions when combined with rituximab and lenalidomide (R 2).1 We present here a detailed biological characterization of patients who progressed on this novel macrophage checkpoint inhibitor.Methods In this single-arm phase 1 trial ( NCT05025800), adult patients with relapsed indolent B-NHL received evorpacept in combination with R2 for 12 cycles. Whole exome sequencing (WES) and single cell RNA sequencing (scRNA-seq) were performed on tumor biopsies collected before treatment, during cycle 1, and at a time of progression. In addition to 102 core B-NHL genes, a curated panel of 53 genes of interest (GOI) was analyzed based on prior transcriptional profiling. Clonality was assessed with variant allele frequency analysis.Results Twenty patients were included in the study; the complete response rate was 80%, and six (30%) patients relapsed or progressed after a median follow-up of 28 months (95% CI, 18-28 months). After quality control, paired tumoral tissue samples for scRNA-seq were available for 12 patients. On differential expression gene analysis and subsequent gene set enrichment analysis/pathway analysis, macrophages showed upregulated genes of differentiation ( CTSB), activation (B2M), polarization (SNX10) and pro-inflammatory responses (CALHM6, VIM, PSME1); and downregulated genes of anti-tumoral activity (EFHD2, ITGAX) and inter-cellular interaction (FOS, CST3, SAT1) in on treatment samples from progressors. Among the GOI, PYHIN1, a key mediator of interferon-induced tumor suppressor activity, known to be associated with CD8+ T cell infiltration, was significantly upregulated in B cells in on-treatment samples from progressors. Conversely, DHX36 and TRIM25 were significantly downregulated. After quality control, tumoral tissue samples for WES were available for 2 patients at time of progression. Among the GOI, WDR70 frameshift and EZH2 missense (Y646 hotspot) mutations were identified. Among core B-NHL genes, other mutations identified included BCL2, CREBBP, KMT2D, and SPEN. No sub-clonal mutations were observed.Conclusions Genetic pathways relevant to lipid metabolism and epigenetics, at the interface between innate and adaptive immunity, may mediate resistance to macrophage checkpoint inhibitors. Functional in vitro and in vivo validation of these findings is ongoing and may help enhance the activity of these agents for the treatment of B-NHL.Reference Strati P, Feng L, Tyshevich A, et al. A phase I trial of evorpacept, lenalidomide, and rituximab for patients with B-cell non-hodgkin lymphoma. Clin Cancer Res. Published online July 29, 2025. doi:10.1158/1078-0432.CCR-25-1826",
  "authors": [
    {
      "affiliations": [
        "University of Texas MD Anderson Cancer Center, Houston, TX, USA"
      ],
      "name": "Zachary Hunzeker"
    },
    {
      "affiliations": [
        "Memorial Sloan Kettering Cancer Center, New York City, NY, USA"
      ],
      "name": "Javier de la Rosa"
    },
    {
      "affiliations": [
        "BostonGene Corporation, Waltham, MA, USA"
      ],
      "name": "Andrey Tyshevich"
    },
    {
      "affiliations": [
        "BostonGene Corporation, Waltham, MA, USA"
      ],
      "name": "Darya Shavronskaya"
    },
    {
      "affiliations": [
        "BostonGene Corporation, Waltham, MA, USA"
      ],
      "name": "Julia E Alesse"
    },
    {
      "affiliations": [
        "BostonGene Corporation, Waltham, MA, USA"
      ],
      "name": "Noel English"
    },
    {
      "affiliations": [
        "BostonGene Corporation, Waltham, MA, USA"
      ],
      "name": "Elizabeth Sheehan"
    },
    {
      "affiliations": [
        "BostonGene Corporation, Waltham, MA, USA"
      ],
      "name": "Nikita Syzrantsev"
    },
    {
      "affiliations": [
        "BostonGene Corporation, Waltham, MA, USA"
      ],
      "name": "Alexander Nesmelov"
    },
    {
      "affiliations": [
        "Memorial Sloan Kettering Cancer Center, New York City, NY, USA"
      ],
      "name": "Hans-Guido Wendel"
    },
    {
      "affiliations": [
        "University of Texas MD Anderson Cancer Center, Houston, TX, USA"
      ],
      "name": "Paolo Strati"
    }
  ],
  "title": "504 Biological mechanisms of resistance to macrophage checkpoint inhibitors in relapsed B-cell non-Hodgkin lymphoma",
  "uid": "7f870f74-73f1-59eb-a4ce-271c70e4e7e7"
}