CCL21 And Checkpoint Inhibitors For The Treatment Of Cancer
Tech ID: 29788 / UC Case 2018-912-0
Researchers at the UCLA David Geffen School of Medicine have demonstrated a combination therapy of intratumoral administration of
CCL21-gene modified human monocyte-derived dendritic cells and intravenous
administration of anti-PD-1 inhibitor enhances tumor CD8+ T cell infiltration
and reduces tumor growth.
inhibitors, such as anti-programmed death-1 receptor/programmed death-ligand 1
(anti-PD-1/PD-L1) elicit promising antitumor responses in the treatment of a
broad spectrum of cancers, through modulation of immune cell-tumor cell
interaction. However, the majority of the patients exhibit poor clinical
responses to PD-1/PD-L1 inhibitor treatment due to primary, adaptive, or
acquired resistance to the treatment. Thus, an effective cancer immunotherapy requires
methods to restore deficits in tumor antigen presentation and functional
antitumor effector activities.
CCL21 is a secondary lymphoid
chemokine that, upon binding to the CCR7 gene receptor, functions as a
chemo-attractant for mature dendritic, naïve, and memory T cells, enhancing
cell-mediated immunity against tumor cells. Intratumoral administration of
CCL21 gene-modified dendritic cells (AdCCL21-DC) leads to increases of CD4+,
CD8+, and CD11c+DEC205+ DCs infiltration of the tumor, decrease of immune-suppressive
molecules in the tumor microenvironment, as well as reduction of tumor burden
in murine lung cancer model. More importantly, intratumoral administration of
AdCCL21-DC also enhances CD8+ T cell infiltration and increased tumor PD-L1
expression in advanced non-small cell lung cancer (NSCLC) patients.
Researchers at UCLA have shown
that advanced NSCLC patients with baseline PD-L1 expression benefit the most
from anti-PD-1 treatment, suggesting responses to PD-1/PD-L1 blockade are more
likely in the setting of tumor PD-L1 expression and a pre-existing T lymphocyte
infiltration of the tumor. Indeed, these researchers have shown that AdCCL21-DC
and anti-PD-1 combination therapy outperforms both mono-therapies in syngeneic murine
lung cancer models. Specifically, the combination therapy significantly
enhances the cytolytic activity of tumor-infiltrating lymphocytes (TILs)
against tumor, accompanied by significant reduction in tumor volume and tumor
NSCLC, melanoma and other types of solid tumors.
- Improve clinical
response to anti-PD-1/PD-L1 therapy
- Boosts local and
systemic immune responses
- Reduce tumor
burden and tumor growth
State Of Development
Completed pre-clinical studies in murine lung cancer models and phase I trials. The combination trial
with anti-PD1 is starting now.
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