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Based on the characteristics of tumor microenvironment, Luigi Naldini et al.
of the San Rafael Institute of Science in Italy developed a lentiviral engineered hematopoietic stem cell delivery system, which uses Tie2-expressing monocytes to enter tumor tissues and differentiate into Tie2-expressing macrophages to participate in the occurrence and development
of tumors.
Through the modification and modification of TEM, IFN-α is specifically expressed in time and space, and targeted therapy
for GBM is realized.
The results were published online
in the July 2022 issue of Sci Transl Med.
—Excerpted from the article chapter
【Ref: Birocchi F, et al.
Sci Transl Med.
2022 Jul 13; 14(653):eabl4106.
doi: 10.
1126/scitranslmed.
abl4106.
Epub 2022 Jul 13.
】
Research background
The effect of standard therapy for glioblastoma (GBM) is associated with changes in the tumor-associated microenvironment; The tumor microenvironment is in a state of immunosuppression, which is conducive to the immune escape
of tumors.
Based on the characteristics of tumor microenvironment, Luigi Naldini et al.
of the San Rafael Institute of Science in Italy developed a lentiviral engineered hematopoietic stem cell delivery system, which uses Tie2-expressing monocytes (TEMs) to enter tumor tissues and differentiate into Tie2-expressing macrophages to participate in tumor occurrence and development
.
Through the modification and modification of TEM, IFN-α is specifically expressed in time and space, and targeted therapy
for GBM is realized.
The results were published online
in the July 2022 issue of Sci Transl Med.
Research methods
Based on the high expression of TIE2 in tumor-associated monocytes/macrophages, the researchers constructed the lentiviral vector Tie2-Ifna1-mirT for IFN-α delivery and further transfected the vector to hematopoietic stem cell HSCs
.
Engineered HSCs can achieve specific targeted delivery of IFN-α in tumors and verify therapeutic effects
using mouse in situ tumor models.
Subsequently, dihydrofolate reductase (DHFR) derived from Escherichia coli was fused with IFN-α to construct the Tie2-Ifna1-DHFR-mirT vector
.
DHFR can be expressed responsively under the action of trimethoprim (TMP), so as to achieve a controllable "switching effect", and the related effects and mechanisms are studied and verified
.
The above engineered HSCs were transplanted into GBM mouse models
.
The detection found that the expression of IFN-α in peripheral blood of the in situ model of GBM mice increased, the growth of intracranial tumors in mice was significantly inhibited, and the survival time of mice was longer
than that of the control group.
However, this study protocol caused an increase in serum IFN-α expression, further inducing systemic adverse effects
.
Therefore, the authors fused dihydrofolate reductase (DHFR) derived from Escherichia coli with IFN-α to construct a Tie2-Ifna1-DHFR-mirT vector, which can respond under the action of trimethoprim (TMP), so as to realize the use of TMP to regulate the expression of IFN-α-DHFR, and on the basis of reducing the expression of serum IFN-α, it does not affect its therapeutic effect
.
The authors compared
the gene regimen for Tie2-IFN-α-DHFR with the recombinant protein regimen for IFN-α.
The results showed that TMP-induced Tie2-Ifna1-DHFR-mirT vector group had almost no IFN-α detected in peripheral blood, but the IFN-α recombinant protein group detected high concentrations of IFN-α
in plasma.
In addition, the treatment effect of the two groups was comparable, and both could significantly inhibit the growth
of tumors.
However, long-term follow-up found that only the Tie2-IFN-α-DHFR gene therapy regimen was still effective
.
Moreover, transcriptome analysis of mouse brain tissue receiving both treatment regimens showed inflammation, apoptosis, and upregulation
of p53-related signaling pathways in the recombinant protein regimen.
Research results
Through single-cell sequencing of GBM, it was found that by IFN-α-DHFR gene therapy, the IFN-α signaling pathway of macrophages in the GBM cell microenvironment was significantly upregulated, and the activation of T cells and dendritic cells in the microenvironment was obvious, thereby realizing the killing of tumor cells
.
This protocol reprograms tumor-associated macrophages (TAMs) into a pro-inflammatory phenotype and inhibits the expression
of disease-associated adverse genes.
Conclusion of the study
In summary, the authors used lentiviral engineered hematopoietic stem cells for spatiotemporal controlled release to deliver cytokines such as IFN-α, targeted TEM modification, and delivered immune activators into the tumor microenvironment.
By adjusting the relevant immune activity of the tumor microenvironment, it can effectively kill tumor cells without seriously affecting the physiological functions of normal cells, thereby greatly reducing the systemic toxic side effects
of treatment.
This study provides a reliable basis for the subsequent clinical treatment of GBM patients and opens up potential possibilities
for GBM-specific immunotherapy.
