Cooperative Targeting of Immunotherapy-Resistant Melanoma and Lung Cancer by an AXL-Targeting Antibody-Drug Conjugate and Immune Checkpoint Blockade

Cancer Res. 2021 Apr 1;81(7):1775-1787. doi: 10.1158/0008-5472.CAN-20-0434. Epub 2021 Feb 2.


Although immune checkpoint blockade (ICB) has shown remarkable clinical benefit in a subset of patients with melanoma and lung cancer, most patients experience no durable benefit. The receptor tyrosine kinase AXL is commonly implicated in therapy resistance and may serve as a marker for therapy-refractory tumors, for example in melanoma, as we previously demonstrated. Here, we show that enapotamab vedotin (EnaV), an antibody-drug conjugate targeting AXL, effectively targets tumors that display insensitivity to immunotherapy or tumor-specific T cells in several melanoma and lung cancer models. In addition to its direct tumor cell killing activity, EnaV treatment induced an inflammatory response and immunogenic cell death in tumor cells and promoted the induction of a memory-like phenotype in cytotoxic T cells. Combining EnaV with tumor-specific T cells proved superior to either treatment alone in models of melanoma and lung cancer and induced ICB benefit in models otherwise insensitive to anti-PD-1 treatment. Our findings indicate that targeting AXL-expressing, immunotherapy-resistant tumors with EnaV causes an immune-stimulating tumor microenvironment and enhances sensitivity to ICB, warranting further investigation of this treatment combination. SIGNIFICANCE: These findings show that targeting AXL-positive tumor fractions with an antibody-drug conjugate enhances antitumor immunity in several humanized tumor models of melanoma and lung cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Axl Receptor Tyrosine Kinase
  • Cell Line, Tumor
  • Combined Modality Therapy
  • Drug Resistance, Neoplasm / immunology
  • Drug Synergism
  • HEK293 Cells
  • Humans
  • Immune Checkpoint Inhibitors / administration & dosage
  • Immune Checkpoint Inhibitors / therapeutic use*
  • Immunoconjugates / administration & dosage
  • Immunoconjugates / therapeutic use*
  • Immunotherapy
  • Lung Neoplasms / pathology
  • Lung Neoplasms / therapy*
  • Male
  • Melanoma / pathology
  • Melanoma / therapy*
  • Mice
  • Mice, Nude
  • Mice, Transgenic
  • Molecular Targeted Therapy / methods
  • Proto-Oncogene Proteins / antagonists & inhibitors
  • Proto-Oncogene Proteins / immunology*
  • Receptor Protein-Tyrosine Kinases / antagonists & inhibitors
  • Receptor Protein-Tyrosine Kinases / immunology*
  • Xenograft Model Antitumor Assays


  • Immune Checkpoint Inhibitors
  • Immunoconjugates
  • Proto-Oncogene Proteins
  • Receptor Protein-Tyrosine Kinases
  • Axl Receptor Tyrosine Kinase