In-depth imaging of AML shows wide heterogeneity
Mapping the spatial architecture of acute myeloid leukemia in the bone marrow microenvironment by multiplexed ion beam imaging
Abstract O79
Inter- and intratumor heterogeneity potentially play a role
in treatment failure and the outgrowth of drug-resistant clones in acute
myeloid leukemia (AML). To better understand the variability in the bone marrow
microenvironment in patients with AML, Xavier Rovira-Clave, PhD (Stanford
University) presented a detailed analysis of tissue microarrays prepared from
FFPE samples from 119 individuals. Using high-resolution multiplexed ion beam
imaging (MIBI), a technology that allows the simultaneous characterization of
numerous parameters with a 5-log dynamic range, the spatial distribution of 40
functional and phenotypic markers were mapped. A range of 500 to 2500 cells were
imaged per patient in the gender-balanced cohort, totaling more than 100,000
cells analyzed in the study. Profound inter-tumor heterogeneity was observed
between samples, as well as intratumor heterogeneity in terms of the levels of proliferation
markers, AML-related markers and other cellular proteins. Such high-resolution
mapping of the bone marrow architecture adds insight into the intra- and
inter-tumor heterogeneity in AML, and this emerging technology could
potentially be used to test if cell specific cell subtype co-occurrence contributes
to driving disease progression.
CD3/CD33 bispecific shows promise in phase I
AMV564, a novel bivalent, bispecific T-cell engager, targets myeloid-derived suppressor cells
Abstract O71
Victoria Smith, PhD (Amphivena Therapeutics, Inc) reported evidence
that treatment with AMV564, a bispecific antibody that engages CD3 and CD33, is
well-tolerated and selectively depletes myeloid-derived suppressor cells
(MDSCs) in patients with acute myeloid leukemia. No dose-limiting toxicities
were reported in ongoing phase 1 clinical trials, and complete responses were
observed in some patients. AMV564 treatment led to rapid depletion of both
monocytic and granulocytic MDSCs as well as CD4+ and CD8+ T cell activation
with no impact on circulating neutrophil or monocyte populations. However,
MDSCs exhibited dynamic responses to T cell activation, and rapid rebounds were
observed when AMV564 was discontinued, leading to a modified dosing strategy. The
ability of AMV564 to deplete MDSCs while activating cytotoxic and helper T
cells may synergize with existing immunotherapies and the results indicate
AMV564 may be beneficial in the treatment of solid tumors, where MDSCs are
associated with reduced responses to immunotherapy and poor outcomes.
Off-the-shelf BCMA CAR therapy shown feasible in preclinical and translational studies
P-BCMA-ALLO1 – a nonviral, allogenic anti-BCMA CAR T therapy with potent anti-tumor function for the treatment of multiple myeloma
Abstract O7
An “off-the-shelf” BCMA-targeting CAR T cell product
candidate described by Maximilian Richter, PhD (Poseida Therapeutics, San
Diego, CA) showed promising anti-myeloma activity in vitro and durable
responses in xenograft mouse models. Using the nonviral PiggyBac DNA
Modification System to deliver the CAR transgene along with a proprietary
“booster molecule” in combination with the high-fidelity Cas-CLOVER
Site-Specific Gene Editing System to knock out expression of the endogenous T
cell receptor and MCH, Richter and colleagues demonstrated efficient
manufacturing of the allogeneic CAR T therapy P-BCMA-ALLO1 from healthy donor
cells, with final product composition greater than 95% CAR+, greater than 99.5%
TCR-KO and a high percentage of T stem cell memory cells (CD45RA+, CD62L+),
which are able to implement effective anti-tumor immunity. The robust,
non-viral gene-modification process was compatible with the majority of healthy
donors, and yielded hundreds of doses per manufacturing run. In NGS xenograft
mice implanted with RPMI-8226, an aggressive human multiple myeloma-derived
tumor model, P-BCMA-ALLO1 treatment led to sustained reduction of tumor burden
below the limit of detection by caliper within roughly 2 weeks, whereas control
animals succumbed to disease within 5-7 weeks. The preclinical evidence sets
the groundwork for advancement of P-BCMA-ALLO1 into clinical studies for the
treatment of multiple myeloma while providing a promising technological
framework for the development of allogeneic CAR T products targeting additional
antigens.
CRS management strategy does not impact CAR efficacy
Myeloid cell-targeted miR-146a mimic alleviates NF-kappaB-driven cytokine storm without interfering with CD19-specific CAR T cell activity against B cell lymphoma
Abstract O61
Cytokine Release Syndrome, a serious adverse event
associated with chimeric antigen receptor (CAR) T cell therapies, is known to
arise due to the NF- kappaB-driven release of IL-1 and IL-6 from
monocytes. Yu-Lin Su, PhD (City of Hope,
Duarte, CA) presented studies of C-miR146a, a myeloid cell targeted NF-kappaB
inhibitor consisting of a chemically-modified miR146a mimic oligonucleotide
tethered to a scavenger receptor/Toll-like receptor 9 (TLR9) ligand. In vitro, the
inhibitor, C-miR146a, was rapidly internalized and delivered to cytoplasm of
target myeloid cells including macrophages and myeloid leukemia cells where it
reduced protein levels of classic miR-146a targets, IRAK1 and TRAF6, thus
blocking NF-kappaB activation. Additionally, C-miR146a treatment reduced CD-19
CAR T cell-induced IL-1 and IL-6 production in human monocytes, in vitro. In a
mouse xenograft model of B cell lymphoma, repeated systemic administration of
C-miR146a oligonucleotide alleviated human monocyte-dependent CRS without
impeding the on-target therapeutic effects of CAR T-cells against lymphoma
cells. In two different mouse models of del(5q) leukemia, repetitive injection
of C-miR146a led to suppression of tumor growth without significant toxicities.
The study provides an outline for the development of miRNA therapeutics to
augment therapeutic efficacy of CAR T cells in acute myeloid leukemia as well
as for the prevention of cytokine release syndrome.
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