Immune Activation and a 9-Year Ongoing Complete Remission Following CD40 Antibody Therapy and Metastasectomy in a Patient with Metastatic Melanoma

Abstract

Direct immune activation via agonistic monoclonal antibodies (mAb) is a potentially complementary approach to therapeutic blockade of inhibitory immune receptors in cancer. Here, we provide genetic analysis of the immunological consequences associated with the 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 the 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.

CD40 Stimulation Obviates Innate Sensors and Drives T Cell Immunity in Cancer

“…To exploit this pathway pharmaceutically, a number of agonistic CD40 antibodies are being evaluated in cancer clinical trials (Melero et al, 2013; Vonderheide and Glennie, 2013). Our group has shown that one such CD40 mAb (CP-870,893) results in modest rates of objective tumor regression as a single agent in patients with melanoma (Bajor et al, 2014; Vonderheide et al, 2007) in the absence of autoimmune-like events associated with αPD-1 or αCTLA-4 therapy. Nevertheless, studies from tumor-bearing mice predict that αCD40 alone in the absence of a “vaccine” to deliver tumor antigen will be an inefficient therapeutic approach.…”

Long-term outcomes of a phase I study of agonist CD40 antibody and CTLA-4 blockade in patients with metastatic melanoma

“…Genomic DNA was isolated from paraffin embedded tumor samples, as previously described 14 and from thawed PBMC samples using the DNeasy kit (Qiagen). TCRβ deep sequencing was then performed by ImmunoSEQ, Adaptive Biotechnologies (Seattle, WA).…”

Therapeutic Activity of Agonistic, Human Anti-CD40 Monoclonal Antibodies Requires Selective FcγR Engagement

“…CP-870,893, a fully human IgG2, is the most potent agonistic CD40 mAb among those tested in clinical trials to date and has demonstrated immune activation in vitro and evidence of objective tumor responses in patients (Bajor et al, 2014; Vonderheide et al, 2007). Based on previous studies using mouse antibodies in wild-type and FcγR deficient mice it was proposed that human, agonistic anti-CD40 antibodies would show a similar dependence on FcγRIIB engagement to optimize CD40 crosslinking (Li and Ravetch, 2011).…”