IsoPlexis Roundtable/Literature Review - 8

LITERATURE REVIEW

Literature Review
Parisi G, Saco JD, Salazar FB, et al.
Persistence of adoptively transferred
T cells with a kinetically engineered
IL-2 receptor agonist. Nat Commun.
2020;11:660.
DOI:10.1038/s41467-019-12901-3
Background: Interleukin-2 (IL-2) is a component of
most protocols of adoptive cell transfer (ACT) therapy
for cancer, but is hampered by high peaks of exposure
that prove toxic to patients, sub-optimally activating
the IL-2 receptor (IL-2R). Various strategies have been
pursued to develop modified IL-2R-activating cytokines with improved pharmacokinetics and a better
safety profile relative to the native IL-2. NKTR-214
(also known as bempegaldesleukin) is a prodrug with
the same amino acid sequence as IL-2 but conjugated
to releasable chains of polyethylene glycol (PEG).
Methods: The investigators conducted various studies
including immunohistochemistry, bioluminescence imaging, immune-PET imaging, mass cytometry, and RNA
analysis. Single-cell proteomics analysis of mouse T cells
and human peripheral blood mononuclear cells was performed using the IsoCode chip from IsoPlexis.
Results: The data in this article show that antitumor
efficacy of NKTR-214 is superior to IL-2 to support
the antitumor activity of adoptively transferred T cells
in a preclinical mouse model. The combined therapy
including NKTR-214 controlled the growth of large,
poorly immunogenic tumors and was associated with
substantially higher expansion, tumor targeting and
persistence of polyfunctional antitumor CD8 effector
T cells. IsoPlexis' single-cell proteomics was used to
identify and characterize unique polyfunctional subsets of CAR T cells that correlated to increased proliferation, homing, and persistence of antitumor T cells
in vivo. The investigators also observed an increased
number of polyfunctional CD8 T cells in the peripheral
blood of patients treated with NKTR-214 as a single
agent within a phase 1 clinical trial.
Discussion: These results from the Ribas lab at UCLA
suggest that NKTR-214 supports the expansion and
functionality of adoptively transferred T cells. These
characteristics, together with low levels of immune
suppressive Tregs at the tumor site, are extremely im8

portant for the proper efficacy of immunotherapies. The
robust and long-lasting effect of NKTR214 in our
preclinical ACT model supports its additional potential
use in combination with T cell-based adoptively
transferred therapeutics.

Li D, Li N, Zhang YF, et al. Persistent
polyfunctional chimeric antigen receptor
T cells that target glypican 3 eliminate
orthotopic hepatocellular carcinomas
in mice. Gastroenterology.
2020;158(8):2250-2265.e20.
DOI:10.1053/j.gastro.2020.02.011
Background: Glypican 3 (GPC3) is an oncofetal antigen involved in Wnt-dependent cell proliferation that is
highly expressed in hepatocellular carcinoma (HCC).
This study set out to understand whether the functions of
chimeric antigen receptors (CARs) that target GPC3 are
affected by their antibody-binding properties.
Methods: The investigators collected peripheral blood
mononuclear cells from healthy donors and patients
with HCC and used them to create CAR T cells. This
was based on the humanized YP7 (hYP7) and HN3
antibodies, which have high affinities for the C-lobe
and N-lobe of GPC3, respectively. The researchers
developed droplet digital polymerase chain reaction
and genome sequencing methods to analyze persistent
CAR T cells in mice. IsoPlexis' single-cell proteomics
platform was used to identify and characterize unique
polyfunctional subsets of CAR T cells.
Results: Injections of CAR (hYP7) T cells eliminated
tumors in 66% of mice by week 3, whereas CAR
(HN3) T cells did not reduce tumor burden. Mice given CAR (hYP7) T cells remained tumor free after
rechallenge with additional Hep3B cells. The CAR
(hYP7) T cells demonstrated remarkably higher
polyfunctionality than the CAR (HN3) T cells, and a
subset of CAR (hYP7) T cells were 8-11 times more
polyfunctional than the rest. This unique subset of
CD8 + CAR (hYP7) T cells contained effector cytokines and other cytokines not secreted by the CAR
(hYP7) T cells derived from healthy donors. IsoPlexis'
single-cell proteomics revealed critical functional
drivers that correlated to CAR T cell persistence in
solid tumor. The CAR T cells induced apoptosis and
ª 2020 by Mary Ann Liebert, Inc.

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