Therapeutic tumor cells (ThTCs) are expected to become a new class of anticancer drugs because they naturally carry new tumor antigens. This strategy has been proven to induce an anti-tumor immune response in a variety of cancers by triggering the translocation of strong immune cells to the tumor site. Inactivated tumor cell therapy is now being tested in the clinical for the treatment of a variety of diseases, including non-small cell lung cancer, colorectal cancer, melanoma, and others.
However, the therapeutic value of these tumor cells is low, if not nonexistent, possibly because they cannot directly cause cytotoxicity in tumor cells and cannot stimulate an effective anti-tumor immune response.
Different from inactivating tumor cells, living tumor cells have the unique potential to locate and target tumors. Therefore, it is a reasonable method to express therapeutic drugs through engineered tumor cells, and its natural new antigen source can also be used. Among all kinds of drugs used in the treatment of cancer, interferon-β (IFN-β) has attracted much attention because of its direct effect (inhibiting tumor cell proliferation and angiogenesis) and indirect effect (activating anti-tumor immune response). However, the stable secretion of IFN-β by engineered tumor cells will not only kill tumor cells but also themselves.
On January 4, 2022, researchers at 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 new method of transforming cancer cells into effective anticancer vaccines has been developed that can eliminate existing tumors, induce long-term immunity, and train the immune system to prevent cancer recurrence. The team demonstrated the promising effect of this bifunctional anticancer vaccine in a mouse model of glioblastoma, an advanced, fatal brain tumor.
Professor Khalid Shah, the paper’s correspondent, said they had been pursuing a simple idea—to turn cancer cells into cancer killers and vaccines. Through genetic engineering, the team developed a treatment utilizing cancer cells—killing cancer cells and stimulating the immune system to destroy primary tumors and prevent cancer.
Cancer vaccine is a hot research direction at present. Inactivating tumor cells can induce an effective anti-tumor immune response. However, the effectiveness of this method is limited because it can not kill tumor cells before inducing an immune response. Unlike inactivating tumor cells, living tumor cells have the ability to track and target tumors.
The research used an unconventional methodology. Instead of eliminating tumor cells, they used live tumor cells to create a therapy that kills tumors directly while also stimulating the immune system. These cancerous cells “trek” across the brain to find their mates.
Using this property, the team used CRISPR-Cas9 gene editing technology to modify living tumor cells, by knockout IFN-β-specific receptors, to transform these tumor cells to tolerant type, and then modified them to release the immunomodulator IFN-β and granulocyte-macrophage colony-stimulating factor (GM-CSF). The expression of GM-CSF promotes the ability of antigen cross-presentation, costimulatory molecule expression, and pro-inflammatory cytokine production of dendritic cells, thus preparing for the long-term anti-tumor response of the immune system. Thus, the dual functions of anticancer and prevention of recurrence are realized by these genetically engineered tumor cells, which can kill tumor cells and also be easily detected, labeled, and remembered by the immune system.
These ThTCs can induce caspase-mediated apoptosis, down-regulate the expression of platelet-derived growth factor receptor β in cancer-related fibroblasts, activate anti-tumor immune cell transport and antigen-specific T cell activation signals, and eliminate advanced glioblastoma tumors in mice.
The team also tested the efficacy of the ThTC in a variety of primary, recurrent, and metastatic mouse models, as well as humanized mouse models, including bone marrow, liver, and thymocytes from humans to mimic the human immune microenvironment. The results show that ThTC can bring survival benefits and build long-term immunity.
Because the cancer vaccine uses live tumor cells, to ensure safety, the team added a double safety switch consisting of herpes simplex virus thymidine kinase type 1 (HSV-TK) and rapamycin-activated caspase-9 to eradicate these therapeutic tumor cells by activating this safety switch.
In general, this study developed a bifunctional anticancer vaccine based on obtaining tumor cells and verified its safety and effectiveness in a variety of tumor mouse models. It also shows that this bifunctional therapy arming natural tumor cells rich in new antigens represents a promising solid tumor cell immunotherapy and lays the foundation and direction for clinical transformation.
Professor Khalid Shah said their goal is to develop an innovative and transformable approach to developing therapeutic cancer vaccines that will eventually have a lasting impact on medicine, a treatment strategy that applies to a wider range of solid tumors and is worthy of further exploration.