Nature Chemical Biology: Crazy Idea: Arming CAR-T Cells to Become a 'Micro Pharmacy' for Cancer Drugs

Under the shroud of centralized procurement, "1.
2 million anti-cancer drugs for one injection" and "zero cancer cells in two months" seem more like myths and legends, but they also make CAR-T cells, which have long been the hottest cancer treatment in China's natural world.
pushed to the public
.

Cytotoxic T cells in the human body have the effect of non-specifically killing tumor cells.
The surface of CAR-T cells (chimeric antigen receptor T cells) is artificially chimeric with specific cancer cell antigen recognition receptors, which can target and recognize tumors.
cells, resulting in cytotoxicity
.

CAR-T cells have been designed to treat some B-cell leukemias, but they are helpless for solid tumors, and the artificial chimeric receptors will inevitably damage innocent normal cells when recognizing cancer cells.
Breakthrough barrier
.

On December 30, 2021, a research team from Memorial Sloan Kettering Cancer Center in the United States published an article entitled "Engineering CAR-T cells to activate small- "molecule drugs in situ", a bold vision: transforming CAR-T cells into a "mini pharmacy" of anticancer drugs
.

Research results (Source: Nature Chemical Biology)

David A.
Scheinberg, corresponding author of the study, said: "We call the engineered cells SEAKER cells, SEAKER stands for Synthetic Enzyme-Armed KillER cells, which not only enhance the targeting ability of CAR-T cells, but also combine local Effective small molecule anticancer drugs minimize accidental injury and achieve dual effects
.

SEAKER cells bind a key anti-cancer molecule called AMS, which specifically activates AMS at the tumor site, thereby effectively killing tumor cells without affecting surrounding normal tissue cells
.

"Unique way of administration"

This research has a more advanced advantage, that is, using CAR-T cells with specific tumor cell antigen recognition receptors to carry inactive prodrugs of anticancer drugs to tumor lesions, in the specific microenvironment of tumor lesions Activates prodrugs and exerts anticancer effects
.

In fact, this is not the first time that CAR-T cells are used as carriers to present drugs.
Previous studies have shown that CAR-T cells can produce proteins such as antibodies and cytokines, but how to make CAR-T cells carry small-molecule anticancer drugs is still an issue.
A tough question
.

Dr.
Derek S.
Tan, the co-corresponding author of this study, said: "Human cells cannot make small molecule compound drugs under normal circumstances, but can generate various enzymes.
CAR-T cells carry small molecule compound drugs to sense the corresponding cancer cell antigens.
The cleavage enzyme is then produced, releasing the active part of the prodrug
.

The cleavage enzyme produced by CAR-T cells releases the active portion of the prodrug at the tumor site (Credit: Nature Chemical Biology)

The highlight of this study is this, linking an anticancer drug with another chemical that "masks" its function.
The combined drug has no anticancer ability.
After reaching the tumor lesion, the T cells are genetically modified.
After a series of Expression produces a cleavage enzyme that removes masking molecules from the drug, allowing it to function as an anticancer agent
.

Tests on in vitro cultured cancer cells and mouse model cancers show that SEAKER cells combined with small molecule anticancer drugs have stronger killing effect on cancer cells than ordinary CAR-T cells
.

Modular prodrug design for SEAKER cells (Credit: Nature Chemical Biology)

In addition, Dr Tan said it was a "high risk, high reward" study, one of the craziest he's ever been through, and it's very exciting now that the system is working successfully
.

"Wide application prospects"

The SEAKER cell technology platform has been licensed to CoImmune to develop innovative CAR-T cell technology for human trials
.

"We have the opportunity to better understand the limitations of CAR-T cells and specifically design new therapeutic regimens that target solid tumor cells to further optimize tumor shrinkage, downstaging, and reduced toxicity," said Dr.
Charles Nicolette, CEO of CoImmune.
, this new approach may provide a new treatment option for patients with solid tumors
.

CoImmune's current research focus is still in cancer, and Dr.
Scheinberg speculates that it will take about two to three years to move to the clinic
.

In conclusion, this study establishes a new targeted "micro-drug" cell therapy platform that combines CAR-T cell immunotherapy with local activation of small-molecule prodrugs, showing robust antitumor activity in vitro and in vivo, we It is expected that SEAKER cells will enter the clinical trial stage as soon as possible and play their due role in the field of cancer treatment

Original source:

Gardner TJ, Lee JP, Bourne CM, et al.