September 06, 2016 – Genetic mutations associated with acquired resistance to PD-1 blockade in melanoma have been suspected to be involved in the clinical observation that while approximately 75% of objective responses to anti–programmed death 1 (PD-1) therapy in patients with melanoma are durable, lasting for years, delayed relapses have been noted long after initial objective tumor regression despite continuous therapy. The molecular mechanisms of immune escape in this context have largely remained unknown.
To address this question, in a very recent study, biopsy samples from paired baseline and relapsing lesions in four patients with metastatic melanoma were analysed who had had an initial objective tumor regression in response to anti–PD-1 therapy (Pembrolizumab (Keytruda), see the FDA drug label and its exact indication and prescribing information here) followed by disease progression months to years later. Thus, whole-exome sequencing detected clonal selection and outgrowth of the acquired resistant tumors and, in two of the four patients, revealed resistance-associated loss-of-function mutations in the genes encoding interferon-receptor–associated Janus kinase 1 (JAK1) or Janus kinase 2 (JAK2), concurrent with deletion of the wild-type allele. A truncating mutation in the gene encoding the antigen-presenting protein beta-2-microglobulin (B2M) was identified in a third patient. JAK1 and JAK2 truncating mutations resulted in a lack of response to interferon gamma, including insensitivity to its antiproliferative effects on cancer cells. The B2M truncating mutation led to loss of surface expression of major histocompatibility complex (MHC) class I.
In conclusion, in this study, acquired resistance to PD-1 blockade immunotherapy in patients with melanoma was associated with defects in the pathways involved in interferon-receptor signaling and in antigen presentation. If these findings hold tue in extended epidemiological studies involving larger numbers of patients whose tumors eventually become refractive to treatment pembrolizumab or other PD-1 inhibitors, then truncation mutations in JAK1, JAK2, as well as in B2M may become predictive and actionable biomarkers for non-respnsivnes of tumors for PD-1 inhibition as the therapeutic action of mode of choice in carriers of such mutations.