Harvard: How to transform cancer cells into the cancer vaccine?

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Harvard: How to transform cancer cells into the cancer vaccine?

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Harvard: How to transform cancer cells into the cancer vaccine?Harvard: How to transform cancer cells into the cancer vaccine?

Science Translational Medicine: Transform cancer cells into cancer vaccines, eliminate cancer cells and prevent recurrence

Therapeutic tumor cells (ThTC) hold promise as a new class of anticancer drugs because they naturally carry tumor neoantigens.

This approach has been shown to trigger a potent transport of immune cells to tumor sites, thereby inducing anti-tumor immune responses in different types of cancer.

Currently, there are several clinical trials of inactivating tumor cells for the treatment of non-small cell lung cancer, colorectal cancer, melanoma and other cancers.

However, this therapeutic approach has limited or even ineffective clinical benefit, which may be due to the lack of direct cytotoxicity of these therapeutic tumor cells to trigger a strong anti-tumor immune response.

Unlike inactivated tumor cells, live tumor cells have unique localization and tumor-targeting potential.

Therefore, expressing therapeutics by engineering tumor cells is a logical approach that also exploits their natural source of neoantigens.

Among various drugs used in cancer therapy, interferon beta (IFN-β) has attracted much attention due to its simultaneous direct ( inhibition of tumor cell proliferation and angiogenesis) and indirect (activation of antitumor immune responses) effects.

However, the stable secretion of IFN-β by engineered tumor cells will not only kill tumor cells, but also self-kill.

In January 2022, researchers from Harvard Medical School published a research paper entitled: Bifunctional cancer cell–based vaccine concomitantly drives direct tumor killing and antitumor immunity in Science Translational Medicine, a sub-journal of Science .

The research has developed a new method to convert cancer cells into an effective anti-cancer vaccine , which can eliminate the tumors that have developed, and induce long-term immunity, training the immune system to prevent cancer recurrence.

The research team tested the promising efficacy of the bifunctional anticancer vaccine in a mouse model of the late-stage, deadly brain tumor glioblastoma.

Professor Khalid Shah , the corresponding author of the paper , said that the team has been pursuing a simple idea: to transform cancer cells into cancer killers and vaccines, and now, through genetic engineering techniques, the team is repurposing cancer cells to develop a treatment method – Kills cancer cells and stimulates the immune system to destroy primary tumors and prevent cancer.

Cancer vaccines are currently a hot research direction , and inactivating tumor cells can induce effective anti-tumor immune responses, however, the effectiveness of this approach is limited because it cannot kill tumor cells before inducing an immune response.

Unlike inactivated tumor cells, live tumor cells have the ability to track and target tumors.

In this study, Khalid Shah’s team took a unique approach. Instead of using inactivated tumor cells, they developed a dual-function therapy based on live tumor cells, which has direct tumor-killing and immune-stimulating effects .

These living tumor cells “travel long distances” in the brain, returning to their fellow tumor cells.

Taking advantage of this characteristic, the research team used CRISPR-Cas9 gene editing technology to modify live tumor cells, and transformed these tumor cells from IFN-β-sensitive to Tolerant forms, which were subsequently engineered to release the immunomodulators IFN-β and granulocyte-macrophage colony-stimulating factor (GM-CSF) .

Expression of GM-CSF promotes the capacity of dendritic cells for antigen cross-presentation, expression of co-stimulatory molecules, and production of pro-inflammatory cytokines, thereby preparing the immune system for a long-term antitumor response.

Therefore, these genetically engineered tumor cells can not only kill tumor cells, but also be easily found, marked and remembered by the immune system, so as to achieve the dual function of anti-cancer and preventing recurrence.

These therapeutic tumor cells (ThTC) activate antitumor immune cell trafficking and antigen-specific T cell activation signaling by inducing caspase-mediated apoptosis of cancer cells, downregulating platelet-derived growth factor receptor β expressed by cancer-associated fibroblasts, Elimination of established advanced glioblastoma tumors in mice .

The research team also tested the drug in multiple primary, recurrent and metastatic mouse cancer models, as well as in humanized mouse models , including bone marrow, liver and thymocytes from humans, mimicking the human immune microenvironment Efficacy of therapeutic tumor cells (ThTC) , results show that ThTC can confer survival benefit and establish long-term immunity.

Since this cancer vaccine uses live tumor cells, in order to ensure safety, the research team added a herpes simplex virus type 1 thymidine kinase (HSV-TK) and rapamycin-activated Caspase9 to the tumor cells . A double safety switch , activated to eradicate these therapeutic tumor cells.

Overall, this study developed a bifunctional anti-cancer vaccine based on obtained tumor cells, and verified its safety and efficacy in various tumor mouse models.

This also indicates that arming naturally neoantigen-rich tumor cells with this bifunctional therapy represents a promising cellular immunotherapy for solid tumors, laying the foundation and direction for clinical translation.

Professor Khalid Shah said that the team’s goal is to adopt an innovative and transformable approach to develop a therapeutic anti-cancer vaccine, which will eventually have a lasting impact on medicine.

This treatment strategy is applicable to a wider range of solid tumors and deserves further exploration.

Paper link :
https://www.science.org/doi/10.1126/scitranslmed.abo4778

Harvard: How to transform cancer cells into the cancer vaccine?

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