Biology Reference
In-Depth Information
Genomics studies and next-generation sequencing to tackle
GVL and MRD
The most notable advances in the identification of new GVL targets and
the separation of GVL from GVHD have occurred thanks to the advent of
next-generation sequencing (NGS). Since 2005, there has been an explo-
sion of published work in hematologic diseases, particularly the discovery
of novel genetic alterations that can encode peptides with restricted tumor
expression; hence, these peptides can serve as potential target antigens of
GVL responses. The NGS technology allows the detection of somatic muta-
tions that are unique to the tumor, necessitating the sequencing of both
the tumor and the normal tissue from the same patient to see the differ-
ences. This approach differs from genome-wide association studies that
detect single-nucleotide polymorphisms that represent variations in the
DNA sequence that are unique to the individual. Researchers distinguish
between the few driver mutations that allow for growth and survival advan-
tages to the tumor from the majority of mutations that occur randomly and
become fixed within the tumor clones (i.e., passenger mutations). With the
cost of this technology falling, we may see the replacement of MRD mea-
surements by RT-PCR with NGS, potentially helping to discover targets of
GVL to distinguish it from GVHD. Tumor neoantigens have previously been
proposed as tumor-specific antigens that are suitable for distinguishing
GVL from GVHD. However, their identification has been difficult because
of technical limitations that can now be overcome with NGS. Similar to
mHAs, tumor neoantigens arise from genetic changes, specifically tumor-
driven mutations such as missense mutations, frameshift insertions or
deletions, gene fusions, and alternative splicing, rather than from polymor-
phisms. The vast majority of these genetic changes appear to be unique to
an individual tumor. These “passenger” mutations that are not interesting
from the standpoint of oncogenesis do have the potential to be recognized
and destroyed by the immune system without inducing associated GVHD.
Thus, it is now possible to capitalize on these tumor-specific neoantigens to
develop focused and potent tumor vaccines post-HSCT
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Possible proteomics approaches to distinguish GVL from
GVHD
There have been no published studies on the use of high-throughput pro-
teomics approaches to identify and validate GVL targets. Below are sugges-
tions for possible approaches aimed at developing a simple, quantifiable,
blood-based test to predict GVL or to monitor MRD post-HSCT. Here, we
need to note that plasma proteome analysis will not reach the depth of DNA
deep sequencing to find neoantigens. Some neoantigens might be found in
the plasma by virtue of immune cells and tumor shedding, but this analy-
sis will not be comprehensive. The major focus of plasma proteome analy-
sis will be to discover proteins associated with the “milieu” (cytokines or
others) that favors GVL responses without concomitant GVHD. One pos-
sible experiment is to use IPAS, which enables the assessment of more than
1000 plasma proteins with a wide range of protein abundance to identify
candidate biomarkers that are differentially expressed at 30, 60, and 100
days post-DLI in patients exhibiting long-term remission without GVHD.
These GVL candidate biomarkers would then be distinguished from those
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