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Page 6 of 15 D'Souza et al. J Cancer Metastasis Treat 2022;8:28 https://dx.doi.org/10.20517/2394-4722.2022.51

also observed in MM. In a study using whole-exome sequencing in MPM samples of several patients and
from three different locations (anterior, posterior and diaphragm positions), distinct mutational patterns at
the three different locations with a high degree of intratumoral spatial heterogeneity by varying amounts of
[52]
subclonal fractions were found . In addition to this, the TCRβ sequencing and immune gene expression
revealed that this heterogeneity also extended to the TME . These intratumoral differences in the TME
[52]
[53]
may result in treatment resistance . Finally, the temporal MPM heterogeneity is another issue - tumors can
evolve during multiple rounds of cell division, and the presence of selective treatment with an anti-cancer
drug further drives the tumor clonal evolution . This temporal heterogeneity has important implications
[54]
for treatment decisions and treatment outcomes.

Immunoproteogenomic analysis of MPM suggested the requirement for high measured abundance of
neopeptides in the presence of high expression of MHC proteins specific for these neopeptides that
predicted response to ICI treatment in MPM patients . There is also evidence that MPM patients post-
[55]
dasatinib treatment presented with higher T-cell clonality and a higher portion of T cells/T cell response
across all tumor regions, which possibly led to their significantly longer survival and a clear sign of the
extremely heterogeneous TCR repertoire in MPM . A study by Sneddon et al. supported the existence of
[56]
candidate neoantigens in MM that induced specific T-cell response to a set of predicted neoantigens from
[57]
MPM effusions despite the low mutation burden of tumor ; these neoantigens may provide an actionable
target/vaccine candidates for personalized therapeutics in difficult to treat cancers like MM, and the
selection of patients to receive immunotherapies. Whereas the findings of another study by Mansfield et al.
represented the discovery of potential neoantigen expression driven by structural chromosomal
rearrangements , these results may have implications for developing novel immunotherapeutic strategies
[58]
and selecting patients to receive immunotherapies.

TAA HETEROGENEITY AND CARS
Contrasting with acute lymphoblastic leukaemia (ALL) and other hematologic malignancies, TAA
heterogeneity in solid tumors hampers effective CAR-T cell therapy. The inherent heterogeneous expression
of the TAAs, combined with immune escape caused by low antigen levels on tumor cells, is the leading
cause of resistance to CAR-T-cells and determines the efficacy of CAR-T cell therapy [59,60] . Antigen
heterogeneity is defined as the differential expression of a number of TAAs, resulting in variation in the
tumor cell phenotype and distribution of tumor antigen-positive cells. MM has both tumor cell and TME
[61]
heterogeneity , and clinical studies of TAAs have observed the outgrowth of variants that lose the target
antigen due to significant heterogeneity within the tumors. Hence, screening and stratifying patients based
on the percentage of target antigen-expressing cells is essential, and selecting the patients over certain
threshold levels of antigen-expressing cells for therapy . For CAR-T cell therapy, choosing a target with
[62]
high specificity and stability in addition to the high density of antigen-expressing cells within the tumor
would play a vital role in the tumor cell lysis .
[63]

Role of intrinsic activity of CARTs
The critical determinants of CAR-T cell therapy-induced antitumor responses are CAR-T expression
density on T cells and the affinity of CAR-T cells to recognize TAAs at even low expression levels. The
affinity of CAR-T cells is determined by their binding kinetics and the rates at which they associate with and
dissociate from their targets. The T cell receptors (TCRs) usually have a higher affinity to foreign antigens
than the TAAs, yet the TCRs can recognize very low levels of antigens via the serial triggering
[64]
mechanism . On the other hand, higher levels of TAA density are required by the CAR-T cells for their
activation, commonly known as the activating threshold , which induces cytokine production and cell
[65]
proliferation as opposed to triggering cytolytic activity (lytic threshold) [66,67] . The expression of CARs on the