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With the deepening of tumor research, tumor therapy has become more and more diverse, and immunotherapy has gradually become a research hotspot
in recent years.
Chimeric Antigen Receptor T Cell (CAR-T) is a kind of adoptive cell therapy
that genetically engineered T cells isolated from patients or allogeneic donors to express chimeric antigen receptors to specifically recognize and kill tumor cells.
in the treatment of solid tumors.
To this end, researchers in various countries are constantly working hard to develop CAR-T therapy
that can effectively treat solid tumors.
Recently, Science published two research articles in a row, proposing a new method
to improve the efficacy of CAR-T in the treatment of solid tumors.
These two studies are based on the strategy of synthetic biology, respectively, to upgrade CAR-T cells and enhance the immune response caused by CAR T cells against diseased tissues, showing how synthetic biology can be used to solve a difficult problem
in cancer immunotherapy.
On December 15, Science published a paper titled "Multidimensional control.
" of therapeutic human cell function with synthetic gene circuits"
.
In this study, a team led by Professor Ahmad Khalil of Boston University developed a toolkit containing 11 programmable synthetic transcription factors that can be activated
on demand by timed administration of FDA-approved small molecule inducers.
Using these tools, the researchers engineered human immune cells that activate specific cellular programs, such as proliferation and antitumor activity
, on demand.
Figure 1 Research results (Source: [1])
The researchers tested the in vivo efficacy of synZiFTR-regulated CAR-T cells using a simple xenograft blood tumor model.
The results show that synZiFTR circuits can be used to program
drug-dependent, post-delivery control of antitumor activity of T cells in vivo.
In addition to controlling CAR-mediated tumor targeting, synZiFTR is also suitable for controlling the expression of other proteins, such as IL-2 or Il-12, and the regulation of these cytokines represents a safer way to use them to enhance the efficacy
of immune cells.
To establish the proliferative gene switch, the researchers used TMX-induced synZiFTR to regulate the expression of super IL-2, effectively providing dose- and time-dependent control
of treatment-related genes in vivo and in vitro.
In conclusion, with this study, the researchers designed and tested a set of clinically inspired synthetic gene regulators and circuits in human cells with certain therapeutic potential
.
In another study published Dec.
16 in Science, a team of researchers from the University of California, San Francisco used the recently developed synthetic Notch receptor to design enhanced CAR-T cells with a second receptor that recognizes tumor antigens and subsequently causes T cells to release the cytokine interleukin-2 (IL-2).
。 In mouse models, this method allows CAR-T cells to infiltrate into solid pancreas and melanoma, resulting in the eradication
of a large number of tumors.
The research paper is "Synthetic cytokine circuits that drive T cells into immune-excluded.
" tumors”
。
Fig.
2 Research results (Source: [2])
A variety of solid tumors do not respond to T cell therapy because their immunosuppressive microenvironment prevents T cell infiltration, activation and proliferation.
Major tumor suppressor mechanisms include inhibition of T cell receptor signaling and depletion of inflammatory cytokines
.
Based on this, overcoming the suppressor tumor microenvironment is a major obstacle
to immunotherapy for solid tumors.
Supplementation of T cell activity with inflammatory cytokines (e.
g.
, high doses of IL-2) can drive effective antitumor function, but systemic IL-2 therapy can cause serious adverse effects
.
With the potential for autonomous cytokine production to overcome toxicity by delivering cytokines locally and directly to tumors, the researchers designed therapeutic T cells with synthetic cytokine circuits in which tumor-specific synthesis of Notch (synNotch) receptors drive IL-2 production
.
These tumor-targeting IL-2 delivery circuits offer a potential approach to overcome local tumor suppression while minimizing systemic IL-2 toxicity
.
The researchers observed that engineered synNotch→IL-2 induction circuitry drives chimeric antigen receptors, or TCR-T cells, to efficiently infiltrate immunoexclusionary tumor models
of pancreatic cancer and melanoma.
In these challenging immunocompetent tumor models, significantly improved invasion was associated with
tumor clearance and survival.
Unlike systemic delivery of IL-2, local cell-based IL-2 circuits did not show toxicity because synNotch→IL-2 circuits are not dependent on TCR/CAR activation but remain tumor-targeted
.
Immunoassays showed that CAR-T cells expanded only within the tumor, with increased activation markers and reduced
failure markers.
Synthetic IL-2 production keeps infiltrating T cells alive and initiates sustained CAR-mediated activation, expansion, and tumor killing
.
These engineered T cells appear to act as precursors, triggering tumor expansion through their synNotch-induced IL-2 production, followed by synergistic initiation of sustained CAR/TCR-mediated T cell activation and
killing.
This type of synthetic cytokine delivery circuit could provide a powerful universal method
for remodeling and overcoming immunosuppressive solid tumors.
Figure 3 The synthetic IL-2 circuit drives the autocrine proliferation of primary human T cells in vitro only when the circuit is triggered (Source: [2])
It is possible to reconfigure the T cell circuit to re-establish the critical outputs needed for a robust anti-tumor response, but in a way that bypasses the tumor immunosuppressive critical points
.
Therefore, these types of engineered local cytokine delivery circuits may provide a potentially generic strategy for driving efficient T cell activity against immunosuppressed solid tumors
.
Fig.
4 CAR-T cells (red) with IL-2 induction circuit can clear pancreatic cancer tumors, while standard CAR-T cell therapy (black) is ineffective (Source: [2])
In the above two studies, The two research teams proposed a strategy that uses synthetic gene circuits to better control the timing of immunotherapy, allowing anti-tumor cell function
to be activated on demand.
These studies are not limited by natural immunology, but expand the range of immune responses triggered by CAR-T cells against diseased tissue, offering some hope
for difficult-to-treat solid tumors.
Written by| Mu Zijiu
Typesetting| Competition for Text
End
Resources:
[1]Li HS, Israni DV, Gagnon KA, et al.Multidimensional control of therapeutic human cell function with synthetic gene circuits.
Science.
2022 Dec 16; 378(6625):1227-1234.
doi: 10.
1126/science.
ade0156.
Epub 2022 Dec 15.
PMID: 36520914.
[2]Allen GM, Frankel NW, Reddy NR, et al.
Synthetic cytokine circuits that drive T cells into immune-excluded tumors.
Science.
2022 Dec 16; 378(6625):eaba1624.
doi: 10.
1126/science.
aba1624.
Epub 2022 Dec 16.
PMID: 36520915.
