CRISPR transforms cancer cells to become anti-cancer weapons, can in situ tumor vaccines attack solid tumors?

January 7, 2023 /eMedClub News/--Researchers at Harvard Medical School have developed a dual-function cancer vaccine that kills brain cancer cells and stimulates the immune system to prevent cancer recurrence.

The study has been published in
Science Translational Medicine.

The researchers used CRISPR-Cas9 gene editing technology to knock out the interferon-β (IFN-β)-specific receptors of tumor cells, make tumor cells tolerate IFN-β, and then engineer them to release immunomodulators IFN-β and granulocyte-macrophage colony-stimulating factor (GM-CSF), improve the ability of dendritic cells to cross-present, co-stimulate molecular expression and pro-inflammatory cytokine production, and enhance the immune system's anti-tumor ability
。 At the same time, for safety reasons, the researchers also equipped tumor cells with a double safety switch composed of herpes simplex virus thymidine kinase (HSV-TK) and Caspase9 activated by rapamycin, which facilitates the eradication of these cells
.
When these therapeutic tumor cells enter the body, they are able to homing into the tumor tissue to kill the tumor cells and stimulate immune cells to prevent the cancer from returning
.

In mouse experiments, this therapeutic tumor vaccine promoted apoptosis of cancer cells, eliminated advanced glioblastoma tumors in mice, and observed significant survival benefits and long-term immune effects in a variety of mouse cancer models, which preliminarily proved the effectiveness and safety of this method and provided a basis
for subsequent clinical translation.

Multiple ideas to construct tumor in situ vaccines

Using the patient's own immune system to attack tumor cells is the most ideal tumor treatment, but the inhibitory immune microenvironment built by tumors often inhibits the role of immune cells, so that DC cells no longer stimulate the proliferation of T cells and stimulate the proliferation of Treg cells, where Treg cells have become "rebels"
at this time.
If the enrichment or exposure of tumor antigens around the tumor is increased by certain means in the tumor, and the function of immune cells is enhanced and antigen presentation is promoted, it is expected to achieve the purpose of
killing the tumor and reducing recurrence.
This method of preparing "vaccines" in situ is called in situ vaccination of tumor vaccines, which is a new form of tumor vaccine, and at present, a variety of methods for preparing in situ tumor vaccines have been reported
.

In January 2022, Wu Jinhui's research group at Nanjing University published a new idea
for an in situ vaccine in Nature Biomedical Engineering.
The researchers modified the surface of attenuated Salmonella with a positively charged cationic polymer that allows the bacteria to capture antigens and carry antigen movements while stimulating the activation of surrounding DC cells
.
At the same time, the researchers found that the modified bacteria can also transfer antigens inside the tumor to the edge
of the tumor.
In mouse tumor models, this method can inhibit and inhibit distant tumor growth and metastasis, and prolong mouse survival
.

▲ Mechanism of action (Image source: Reference 2)

When a patient undergoes radiotherapy, the tumor releases a large number of antigens, and then injects modified Salmonella into the tumor, which can enrich these antigens around the tumor and stimulate the body's immune system to attack the tumor
.
At present, this research has been supported
by the National Natural Science Foundation of China and the National Young Talents Program.

In addition to this method of injecting bacteria into tumors, researchers have proposed in situ tumor vaccine strategies
that inject engineered T cells directly into tumors.
The researchers used electroporation transient transfection technology to make CD8+ T cells express IL-12 or CD137 instantaneously, and then inject them into the tumor
.
Similarly, good tumor-killing effects
were observed in mouse experiments.

However, the researchers pointed out that this method is not as effective as "hot tumors" for "cold tumors", so first make the tumor hot and then treat it can achieve better results, and may continue to engineer T cells to increase their function
of making tumors hot.
The method of engineering T cells can effectively avoid the side effects caused by the use of IL-12 and CD137 agonists in large doses, and the transient transfection of electroporation can effectively reduce the preparation cost
.