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Preclinical efficacy of a HER2 synNotch/CEA-CAR combinatorial immunotherapy against colorectal cancer with HER2
Marco Cortese1, Erica Torchiaro1, Alice D'Andrea1
1Candiolo Cancer Institute, FPO-IRCCS, 10060 Candiolo (TO), Italy; University of Turin, Department of Oncology, 10060 Candiolo (TO), Italy.
Abstract:
HER2 amplification occurs in approximately 5% of colorectal cancer (CRC) cases and is associated only partially with clinical response to combined human epidermal growth factor receptor 2 (HER2)/epidermal growth factor receptor (EGFR)-targeted treatment. An alternative approach based on adoptive cell therapy using T cells engineered with anti-HER2 chimeric antigen receptor (CAR) proved to be toxic due to on-target/off-tumor activity. Here we describe a combinatorial strategy to safely target HER2 amplification and carcinoembryonic antigen (CEA) expression in CRC using a synNotch-CAR-based artificial regulatory network. The natural killer (NK) cell line NK-92 was engineered with an anti-HER2 synNotch receptor driving the expression of a CAR against CEA only when engaged. After being transduced and sorted for HER2-driven CAR expression, cells were cloned. The clone with optimal performances in terms of specificity and amplitude of CAR induction demonstrated significant activity in vitro and in vivo specifically against HER2-amplified (HER2amp)/CEA+ CRC models, with no effects on cells with physiological HER2 levels. The HER2-synNotch/CEA-CAR-NK system provides an innovative, scalable, and safe off-the-shelf cell therapy approach with potential against HER2amp CRC resistant or partially responsive to HER2/EGFR blockade.
Insights
A novel cell therapy safely targets HER2-amplified colorectal cancer (CRC) by using engineered NK cells. This approach precisely targets tumors expressing both HER2 and CEA, offering a new treatment option for resistant CRC cases.
Area of Science:
- Oncology
- Immunotherapy
- Molecular Biology
Background:
- HER2 amplification is present in ~5% of colorectal cancers (CRC), but response to HER2/EGFR-targeted therapies is variable.
- Previous adoptive cell therapies targeting HER2 were limited by toxicity due to on-target/off-tumor effects.
- Carcinoembryonic antigen (CEA) is another potential target in CRC.
Purpose of the Study:
- To develop a safe and effective cell therapy for HER2-amplified CRC.
- To engineer a regulatory network that precisely targets cancer cells expressing both HER2 and CEA.
- To evaluate the efficacy and safety of this novel approach in preclinical models.
Main Methods:
- Engineered NK-92 cells with a synNotch receptor targeting HER2, which drives CAR expression against CEA.
- Developed a HER2-synNotch/CEA-CAR-NK system for specific targeting of HER2amp/CEA+ CRC.
- Cloned and optimized NK cell lines for enhanced specificity and CAR induction.
Main Results:
- The engineered NK cells demonstrated significant in vitro and in vivo activity against HER2amp/CEA+ CRC models.
- The system showed high specificity, with no observed effects on cells with physiological HER2 levels.
- The approach proved to be safe, avoiding on-target/off-tumor toxicities.
Conclusions:
- The HER2-synNotch/CEA-CAR-NK system represents an innovative and scalable off-the-shelf cell therapy.
- This approach holds potential for treating HER2amp CRC, particularly in cases resistant or partially responsive to current therapies.
- This combinatorial strategy offers a promising new avenue for targeted cancer treatment.
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