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The Lab: Department of Immune Medicine
(NCCRI)
Led
by Dr. Chie Kudo-Saito, the Department of Immune Medicine
at the National Cancer Center Research Institute in Tokyo
is tackling one of the most frustrating hurdles in
oncology: why only approximately 15% of patients with
advanced gastric cancer (AGC) respond to anti-PD1/-PDL1
therapies. Their work focuses on identifying molecules in
the peripheral circulation that act as "brakes"
on the immune system.
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The Breakthrough:
Targeting ANGPTL3
In
their most recent study, the team analyzed the plasma of 91
patients receiving nivolumab. They discovered that
Angiopoietin-like 3 (ANGPTL3) is a major player in
therapeutic resistance.
Key
Findings:
- A Reliable
Biomarker: Patients with high levels of ANGPTL3,
either before or after starting treatment, showed
significantly worse progression-free and overall
survival.
- Host-Derived
Resistance: While many biomarkers are tumor-specific,
ANGPTL3 appears to be host-derived (likely from the
liver), with production further elevated by the
presence of a tumor.
- Synergistic
Efficacy: In mouse models, combining anti-ANGPTL3
therapy with anti-PD1 treatment led to a 70% complete
cure rate.
- Memory
Induction: Successfully treated mice rejected
subsequent tumor rechallenges, suggesting the
induction of long-term immunologic memory.
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Future
Directions & Collaboration
The
NCCRI team is now exploring how to translate these findings
into clinical practice. Potential next steps include:
- Repurposing
Existing Drugs: Investigating the use of ANGPTL3
inhibitors already developed for lipid disorders, such
as evinacumab or zodasiran, in a cancer context.
- Mechanistic
Deep-Dives: Clarifying how ANGPTL3 forms complexes
with ANGPTL8 to inhibit immune activation.
Read
Our Full Analysis:
We’ve
published a technical review of this citation including a
deeper look at the in vivo data and the specific antibodies
used in the study.
Read
the Full Post Here
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