Study working to determine key mechanisms at play in acquired resistance to immunotherapy in advanced melanoma...and related trial!!!

Thanks to dear Eric who shared this report with me:  UCLA study unlocks key mechanisms that determine acquired resistance to immunotherapy in advanced melanoma

Here the author talks about work Ribas and others are doing to figure out how melanoma, once responsive to immune check point inhibitors (like anti-PD1), becomes resistance and tumors begin to reappear and progress.  Through biopsies, researchers looked at tumors of patients given pembro BEFORE treatment and compared them to biopsies after relapse.  They found one tumor no longer showed the gene B2M thus changing how the immune system recognized the tumor.  Two other tumors changed the function of genes JAK1 and JAK2, again limiting the ability of T cells to recognize and attack the tumor.

Here's a link to the actual study:  Mutations associated with acquired resistance to PD-1 blockade in melanoma

Here is the abstract:

Mutations Associated with Acquired Resistance to PD-1 Blockade in Melanoma.  Zaretsky,  Garcia-Diaz, Shin,...Ribas, et al. New England Journal of Medicine.  7/13/16. 

Approximately 75% of objective responses to anti–programmed death 1 (PD-1) therapy in patients with melanoma are durable, lasting for years, but delayed relapses have been noted long after initial objective tumor regression despite continuous therapy. Mechanisms of immune escape in this context are unknown.  We analyzed biopsy samples from paired baseline and relapsing lesions in four patients with metastatic melanoma who had had an initial objective tumor regression in response to anti–PD-1 therapy (pembrolizumab) followed by disease progression months to years later.  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 class I.  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.

 And here is a link to a phase 1, 2 part study, looking at pembrolizumab + INCB039110 (to evaluate a JAK inhibitor with JAK1 selectivity) or pembrolizumab + INCB050465 (to evaluate a PI3K-delta inhibitor):  Pembrolizumab Combined With INCB039110 and/or Pembrolizumab Combined With INCB050465 in Advanced Solid Tumors

For participation...ratties must have a solid tumor from a variety of cancers, melanoma included, and for part 1b, must have  "documented confirmed disease progression on a prior PD-1 pathway targeted agent or must be PD-1 pathway-targeted treatment naïve."  Exclusions include active or inactive autoimmune process or immune suppressive treatment 14 days prior.  Appears to be recruiting actively in:  Santa Monica, Washington D.C., Port St Lucie, FL, Durham, NC, and Pittsburgh.  Not yet recruiting in:  NY, Boston, San Fran.

For what it's worth.  It is very hopeful that researchers continue to seek to find answers as to why some folks fail to respond to immunotherapy and others fail to maintain that response!!!  Keep on hanging on, ratties!!! love, c