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37 Biopsies, Nine Years: Mapping Evolution of Resistance to Melanoma Immunotherapy in a Former Complete Responder

Key findings

  • This study involved molecular analysis of 37 tumor samples over nine years from a patient with metastatic melanoma who had a complete clinical response to immune checkpoint blockade followed by delayed recurrence and death
  • Phylogenetic analysis revealed co-evolution of seven lineages with multiple convergent but independent resistance-associated alterations. The resistant tumors all emerged from a clone with 15q loss
  • Alterations in the resistant lineage included PTEN loss, loss of antigen presentation, genome doubling with increased aneuploidy, and CDKN2A mutation
  • Tumor cells high in nerve growth factor receptor created false vascular channels, likely impacting circulation to melanoma tumors and regulation of immune cell activity, implying they are targets for therapeutic intervention

The most comprehensive study yet of the evolution of resistance to immune checkpoint blockade (ICB) in melanoma has been reported by Genevieve M. Boland, MD, PhD, vice chair of research for the Department of Surgery at Massachusetts General Hospital, section head of the Melanoma and Sarcoma Surgery Programs and surgical director of the Termeer Center for Targeted Therapies at the Mass General Cancer Center, Keith T. Flaherty, MD, director of clinical research at the Mass General Cancer Center, and colleagues.

Over nine years—from diagnosis to rapid autopsy—the team used multiple types of molecular analyses to study 37 biopsies from a patient who had an unusual clinical course. The findings appear in Nature Medicine.

Case Description

The 67-year-old patient had stage IIB nodular melanoma, originally treated surgically, that did not metastasize until 2.5 years later. At that point, he enrolled in a trial of sequential nivolumab, ipilimumab, and maintenance nivolumab. His disease at first progressed rapidly, but during maintenance nivolumab, he demonstrated an abrupt response.

After two total years of ICB, the patient was considered to have a complete clinical response. The next year, he developed autoimmune nephritis requiring steroid therapy, which was followed by indolent disease progression for two years. Later recurrent metastatic disease was resistant to subsequent therapy, including repeated ICB, and the patient died one year later.

Key Observations

  • Seven genomic lineages were identified, but all resistant tumors arose from a clone with 15q loss; this suggests substantial tumor heterogeneity before ICB that persisted through initial therapy but was selected down to a multi-resistant lineage at the time of recurrence
  • Multiple convergent but independent resistance-associated alterations were evident, including PTEN loss and genome doubling with increased aneuploidy
  • Post-treatment tumor cells high in nerve growth factor receptor (NGFR-High) exhibited high expression of PD-L1
  • NGFR-High cells were enriched for hypoxia pathways and the cellular composition was consistent with vascular mimicry
  • At autopsy, NGFR-High cells exhibited two distinct spatial patterns (in subcutaneous metastases, they were in the tumor periphery adjacent to immune cells, and in lung metastases, they were more diffuse), which suggests site-specificity of tumor–immune interactions

Therapeutic Implications

NGFR-High cells seem to help increase circulation to melanoma tumors and regulate immune cell activity, implying they are targets for therapeutic intervention. The researchers are continuing their work to find changes in tumors and their microenvironments during therapy that could identify additional novel targets and inform the design of combination therapies.

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