Anti-programmed PD-1 therapy. Whole-exome sequencing aided to identify

Anti-programmed death-1 (PD-1) therapy is among one
of the many types of immunotherapies available to treat metastatic melanoma,
however patients who have responded to the treatment are known to have delayed
relapses after tumor regression despite continuous therapy, and thus proving a
form of immune-resistant cancer is expressed in these patients. This creates a
requirement for a new method of treatment to be discovered to overcome the
development of acquired immunotherapeutic resistance, but this is only possible
if the mechanisms are comprehended, hence this being the main focus of research
in the paper, ‘Mutations Associated with Acquired Resistance to PD-1 Blockade
in Melanoma. The research involved analysis of biopsy samples from four
selected metastatic melanoma patients. The patients were chosen on the basis
that they had late progression after a preliminary response to anti PD-1
therapy (pembrolizumab), in order to detect potential mechanisms of acquired
resistance to anti PD-1 therapy. Whole-exome sequencing aided to identify the
mechanisms of resistance in three of the four patients. One patient displayed
loss of ?2-microglobulin expression therefore preventing MHC Class I expression
on the surface of melanoma cells and tumor antigens to CD8 T cells. The other
two patients had developed mutations in genes, in particular loss of function,
that encode for interferon-receptor-associated Janus Kinase (JAK) 1 or 2,
resulting in decline in response to interferon gamma with reduced sensitivity
to its proliferative effects on the cancerous cells. Among the results
obtained, the identical mechanism of acquired resistance to anti PD-1 therapy
of two independent cases advocates that conflict to interferon gamma has a
major role in immune resistance, as discussed in the paper (Ribas, A. et al.
(2016)). 

The study was conducted by Dr. Antoni Ribas, a
professor of hematology and oncology, and director of the University of
California Los Angeles Jonsson Comprehensive Cancer Centre Tumor Immunology
program. Dr Ribas has a h-index of 81 and has published 327 documents, where
majority surround research on melanoma, thereby showing that this paper is of
credibility since he has already made a name for himself by producing work in
this area of cancer (Scopus. (2018)). This research paper as a whole has a total of 401
citations, further indicating that the finding discussed in this area of deep
value to the scientific community. To further support this claim, the paper is
found in ‘The New England Journal of Medicine’, one of the most prestigious
scientific journals out there, and has an impact factor of 72.406 as of 2016,
which is one of the highest figures among scientific journals (The New
England Journal of Medicine. (2018)). The h-index
and the impact factor expressed the level of influence the paper has on the
scientific community and as these figures are high, it can be concluded that
this paper has a degree of reliability. The study has effectively established
that molecular targeted therapies, cancerous immunotherapies can distinguish tumor
cells resistant to processes, usually susceptible to T-cell-mediated attack in
humans. This supports the conclusions stated in the paper by Koyama, S. et al
(2016), where they have used mice models to portray that acquired resistance to
anti PD-1 therapy can arise due to non-genetic reaons, however as this research
was not conducted on humans it can be argued that Dr. Ribas’s paper does
require further support for his findings.