Direct immune activation via agonistic monoclonal antibodies (mAb) is a potentially complimentary approach to therapeutic blockade of inhibitory immune receptors in cancer. Here, we provide genetic analysis of the immunological consequences associated with use of an agonistic CD40 mAb in a patient with metastatic melanoma who responded, underwent a single metastasectomy, and then achieved a complete remission ongoing for more than 9 years after starting therapy. Tumor microenvironment after immunotherapy was associated with pro-inflammatory modulations and emergence of a de novo T-cell repertoire as detected by next-generation sequencing of T cell receptors (TCR) in tumor and blood. The de-novo T cell repertoire identified in the post-treatment metastasectomy sample was also present - and in some cases expanded - in the circulation years after completion of therapy. Comprehensive study of this "exceptional responder" highlights the emerging potential of direct immune agonists in the next wave of cancer immunotherapies and a potential role for TCR deep sequencing in cancer immune assessment.
- Received August 19, 2014.
- Revision received September 11, 2014.
- Accepted September 15, 2014.
- Copyright © 2014, American Association for Cancer Research.