A novel form of macrophage-based immunotherapy is effective at treating a broad spectrum of cancers, including colorectal cancer (CRC) and those at advanced stages, according to a ground-breaking study led by Georgia State immunology professor Yuan Liu. The researchers found that local radiation therapy (RT) cured colorectal cancer and two types of pancreatic cancer in SIRPα-deficient mice with advanced tumours. The findings are significant, given that colorectal and pancreatic cancers are often treatment-resistant with high mortality rates. The study, ‘Intratumoral SIRPα-deficient macrophages activate tumor antigen-specific cytotoxic T cells under radiotherapy’, was published in Nature Communications.
Liu's treatment works by leveraging macrophages, specialised white blood cells involved in the detection and elimination of cancer cells and other pathogens. Macrophages also activate T-cells which then attack and destroy cancer cells. Under normal conditions, this system works well to limit the growth of abnormal cells. However, cancer cells are tricky. Macrophages are vulnerable to cancer cells masquerading as healthy cells by co-opting mechanisms normal cells rely on that evade immune surveillance and detection. These mechanisms can profoundly increase cancer's ability to grow and resist traditional treatment.
This new immunotherapy alters macrophages by knocking out Signal-regulatory protein α (SIRPα), a receptor whose primary function is to prevent macrophages from engulfing and destroying healthy cells. Cancer cells often exploit SIRPα by expressing a marker (CD47) that disguises them as normal cells. In the animal study, published in Nature Communications, Liu and her team found that Sirpα-deficient macrophages initiate a robust immune response against cancer by triggering inflammation and activating tumor-specific T-cells.
The immune system is built to fight off invaders and aberrant cell growths like cancer, but cancer can also suppress and subvert the natural immune response by making it difficult for the body to recognise cancer cells as abnormal. While immunotherapy, which helps recruit the immune system to attack cancer cells, has revolutionised the treatment of tumours, the therapies only work for a limited number of patients.
"Scientists recognise that tumour-specific T-cells are the best weapon we have against cancer, but immunosuppression prevents them from doing their job," explained Liu. "Our treatment uses macrophages like a general to call up an army of T-cell soldiers to kill cancer."
The study demonstrates the treatment is effective - and does not destroy large amounts of healthy cells - when delivered locally to the tumour site in conjunction with RT, one of the cornerstone treatments for cancer.
"To kill the cancer without harming the patient, you need to localise the effects. We developed a method that is very effective while minimising the global adverse effects."
The mice in the study developed inflammatory immune responses, and in most cases the tumours stopped growing immediately after irradiation. Within four to 12 days, mice with small and medium tumours had cleared the cancer completely, without apparent long-term adverse effects, and the animals remained tumour-free for the remainder of the study. In general, mice that were cured of their cancer exhibited similar longevity (about 18 months) as healthy mice.
The treatment also prevented one of the major negative effects of RT, its tendency to drive a strong wound-healing response that can result in the regrowth of cancer, as the local immune response is suppressed to promote new tissue growth and repair at the site of the RT. This mechanism, however, was absent post-RT in the SIRPα-deficient mice (Figure 1).
The mice exhibited long-lasting immunity to the cancer, which Koby Kidder, a PhD student at Georgia State and co-author of the study, said is the result of an immune response robust enough to control the tumour cells throughout the body. Even when the cured mice were injected with new cancer cells, these cells failed to form tumours, suggesting the animals had acquired long-term immunity that prevented tumour recurrence.
"The reason we achieved such a high degree of efficacy is that we directly used the macrophage to mobilize other cells within the body," explained Kidder. "The mounting of a consummate anti-tumour immune response in concert with removing immunosuppressive factors (cells and cytokines) from the tumour microenvironment drastically affected the immune response. By removing SIRPα and combining it with radiotherapy, we elicited such a robust response it essentially cured the cancer."
The study demonstrates SIRPα is a master controller of immunity inside the tumour microenvironment, directing post-RT wound healing, strengthening immunosuppression, conferring treatment resistance and allowing the cancer to progress. In the absence of SIRPα, however, antitumor immune responses are significantly enhanced.
The treatment has the potential to become a "pan-cancer therapy," meaning it could be used to cure a broad spectrum of cancers, including those at advanced stages with metastasis. The study provides strong proof-of-concept for developing Sirpα-negative macrophage-based cell therapies, Liu added.
The cell therapy approach has already been tested against the entire NCI-60 cancer panel - made up of 60 various human tumour cell lines representing leukaemia, melanoma, lung, colon, brain, ovary, breast, prostate and kidney cancers - and has been found to be effective. The researchers are applying for approval of the therapy as an investigational new drug by the UFDA and hope to begin human clinical trials in 2022.
Liu has received grants from the National Cancer Institute, the Georgia Research Alliance and Biolocity to support this research.
"Currently, the treatments using immune therapy only benefit a small percentage of patients," Liu said. "This therapy has already proven effective in the laboratory and could be the key to fighting all types of cancer. This is basically a battlefield in the body, and if we are able to activate the proper delivery signals, our bodies win."
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