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CAR-engineering of innate and innate-like immune cells: a new horizon in adoptive cell therapy for solid tumors
Giuseppe Nardo1, Francesca Putti2, Alice Indini3,4
1Department of Medical Oncology and Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy giuseppe.nardo@istitutotumori.mi.it.
Background:
Chimeric antigen receptor (CAR) therapies have revolutionized cancer immunotherapy, particularly in hematologic malignancies, but their efficacy in solid tumors remains limited. Key barriers include tumor antigen heterogeneity, on-target/off-tumor toxicity, impaired trafficking, and an immunosuppressive tumor microenvironment.
Methods:
We conducted a narrative review of preclinical and clinical studies investigating CAR-engineered innate and innate-like immune cells, including CAR-natural killer, CAR-γδ T, CAR-natural killer T (NKT), and CAR-macrophages, focusing on their biological features, therapeutic potential, and current clinical development in solid tumors.
Results:
These alternative platforms exhibit distinct advantages over conventional CAR-T cells, including reduced risk of severe toxicities, improved trafficking, overcoming antigen loss, and higher allogeneic potential. Emerging clinical data suggest favorable safety profiles, although limited persistence and variable efficacy remain key challenges. Advances in cell engineering, such as cytokine armoring and non-viral gene transfer, are further enhancing their therapeutic potential.
Conclusions:
CAR-engineered innate and innate-like immune cells represent a promising next-generation strategy to overcome the limitations of conventional CAR-T therapies in solid tumors. Among these, CAR-NKT and CAR-γδ T cells may offer particular advantages for clinical translation, warranting further investigation in future trials.
Insights
Chimeric antigen receptor (CAR) therapies show promise for solid tumors using innate immune cells. CAR-engineered natural killer (NK) and gamma-delta T cells offer advantages for future cancer immunotherapy trials.
Area of Science:
- Immunotherapy
- Oncology
- Cellular Therapy
Background:
- Chimeric antigen receptor (CAR) T-cell therapy excels in blood cancers but faces challenges in solid tumors.
- Barriers include tumor antigen heterogeneity, toxicity, poor trafficking, and immunosuppression.
Purpose of the Study:
- To review CAR-engineered innate and innate-like immune cells for solid tumor treatment.
- To assess their biological features, therapeutic potential, and clinical development.
Main Methods:
- Narrative review of preclinical and clinical studies.
- Focus on CAR-natural killer (NK), CAR-γδ T, CAR-natural killer T (NKT), and CAR-macrophages.
Main Results:
- Alternative CAR platforms offer reduced toxicity, better trafficking, and overcome antigen loss.
- Early clinical data show good safety, but persistence and efficacy need improvement.
- Advancements like cytokine armoring enhance therapeutic potential.
Conclusions:
- CAR-engineered innate cells are a next-generation strategy for solid tumors.
- CAR-NKT and CAR-γδ T cells show particular promise for clinical translation.
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