The Sentinel


Saturday, November 9, 2019

SITC 2019 Scientific Highlights - Nov. 7

The Society for Immunotherapy of Cancer (SITC) is pleased to present scientific highlights from the Nov. 7, 2019, sessions of the 34th Annual Meeting.

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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