Therapeutic tumor cells (ThTC) are expected to become a new class of anticancer drugs because they naturally carry new tumor antigens. This method has been shown to trigger the transfer of powerful immune cells to the tumor site, thus inducing an anti-tumor immune response in different cancers. At present, there are several clinical trials of inactivated tumor cell therapy, including non-small cell lung cancer, colorectal cancer, melanoma, and other cancers.
However, the clinical benefit of this treatment is limited or even ineffective due to the lack of direct cytotoxicity of these therapeutic tumor cells and their inability to trigger a strong anti-tumor immune response.
Different from inactivated 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 their 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 kill themselves.
Recently, 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 sub-journal of Science.
A new method of transforming cancer cells into effective anticancer vaccines has been developed, which 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 with glioblastoma, an advanced fatal brain tumor.
Professor Khalid Shah said the team has been pursuing a simple idea of turning cancer cells into cancer killers and vaccines. Now, through genetic engineering, the team is reusing cancer cells to develop a treatment—killing cancer cells and stimulating the immune system to destroy primary tumors and prevent cancer.
Cancer vaccine is a hot research direction at present. Inactivated tumor cells can induce effective anti-tumor immune responses, while the effectiveness of this method is limited since it cannot kill tumor cells before inducing immune responses. Unlike inactivated tumor cells, living tumor cells have the ability to track and target tumors.
In this study, the Khalid Shah team took a unique approach. Instead of using inactivated tumor cells, they developed a bifunctional therapy based on living tumor cells with direct tumor-killing and immunostimulatory effects. These living tumor cells “trek” through the brain to return to their companion tumor cells.
Taking advantage of this property, the team used CRISPR-Cas9 gene editing technology to modify living tumor cells, by knocking out interferon-β (IFN- β)-specific receptors, to transform these tumor cells from IFN- β-sensitive 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 the long-term anti-tumor response of the immune system. Therefore, these genetically engineered tumor cells can not only kill tumor cells but be easily detected, labeled, and memorized by the immune system, so as to achieve the dual function of anti-cancer and preventing recurrence.
These therapeutic tumor cells (ThTC) can not only induce Caspase-mediated apoptosis and down-regulate the expression of platelet-derived growth factor receptor β in cancer-related fibroblasts, but activate anti-tumor immune cell transport and antigen-specific T cell activation signals, as well as eliminating advanced glioblastoma tumors in mice.
The team also tested the efficacy of this 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 living tumor cells, the team added a double safety switch consisting of herpes simplex virus thymidine kinase type 1 (HSV-TK) and rapamycin-activated Caspase9 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 various tumor mouse models. The research also showed that this bifunctional therapy armed with natural tumor cells rich in new antigens represents a promising solid tumor cell immunotherapy, which lays a foundation and direction for clinical transformation.