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Science Sub-Journal: Low-dose radionuclide targeted therapy to make cold tumors warmer and improve immunotherapy response
Low-dose radionuclide targeted therapy to make cold tumors warmer. Cancer immunotherapy, represented by immune checkpoint inhibitors, has completely changed the current status of cancer treatment by strengthening the patient’s immune system to fight cancer. However, some patients are resistant to current immunotherapies, while others have cancers characterized by immunological “cold tumors” that evade or suppress the patient’s immune response to cancer cells.
Many immune cells have gathered near the tumor tissues. Immune cells have fought desperately with cancer cells here. However, the way is high and the devil is high. Cancer cells have the upper hand. However, the outcome is still not there. When the dust settles, the battlefield is still “hot”.
In contrast to hot tumors, there are no or very few immune cells in the tumor tissue. The immune cells have never fought against cancer cells, and the battlefield has not even been ignited.
In the case of cold tumors, oncologists have developed external radiation therapy (EBRT). Patients undergoing EBRT will be placed in a carefully calibrated machine, with the radiation beam directly aimed at the tumor area.
EBRT can help turn “cold tumors” or resistant tumors into “hot tumors”, making them susceptible to immunotherapy.
For patients whose cancer has metastasized or spread to other parts of the body, EBRT usually cannot irradiate all tumor sites because the distant tumors may be too small, too large, and diffuse, so that the patient cannot tolerate so much radiation.
In these cases, radionuclide targeted therapy (TRT) may be an option. This treatment uses a radioactive element that is linked to cancer-targeting molecules and is administered by intravenous infusion to deliver radiation directly to cancer cells.
However, randomized clinical trials have not yet demonstrated whether this treatment can increase the systemic response of immune checkpoint inhibitors in metastatic tumors.
On July 14, 2021, a research team from the University of Pittsburgh School of Medicine and the University of Wisconsin-Madison published a study titled “Low-dose targeted radionuclide therapy renders immunologically cold tumors responsive to immune checkpoint blockade” in Science Translational Medicine. Paper, this paper is also the cover paper of the current issue.
Unlike traditional beliefs, a large dose of radiation is needed to kill cancer cells. The combination of low-dose radionuclide targeted therapy and immune checkpoint therapy successfully triggered the immune system to kill cancer cells and eradicate metastatic cancer in mice. This method has been proven to be very safe in dog experiments and may be used in clinical practice in the future.
First, the research team used PET/CT 3, 24, and 48 hours after intravenous injection of 86Y-NM600 (a therapeutic TRT that can chelate radioactive metals and deliver them to tumors for diagnostic imaging or radiotherapy). The imaging evaluated the uptake of NM600 in three mouse tumors and normal tissues. They found that compared with other normal tissues, the amount of uptake and retention in tumors increased over time.
Next, the research team used a small dose of 90Y-NM600 combined with immune checkpoint therapy to evaluate the anti-tumor function. Compared with 90Y-NM600 or anti-CTLA-4 alone, low-dose 90Y-NM600 combined with anti-CTLA-4 treatment significantly improved the anti-tumor response and increased survival. When combined with double antibodies (anti-CTLA-4 and anti-PD-L1), tumor mice appeared complete and long-lasting tumor-free period.
Although EBRT can safely deliver low-dose radiation to a large area or the whole body, it can lead to systemic lymphocyte failure and systemic immune suppression, thereby hindering the development of anti-tumor immunity. Therefore, the research team compared the therapeutic effects of targeted EBRT, whole-mouse EBRT, or systemic delivery of 90Y-NM600 on tumors.
The results suggest that low-dose tumor-targeted EBRT combined with immune checkpoint inhibitors or systemic delivery of 90Y-NM600 significantly enhanced tumor response, which depends on T cells, indicating that the tumor’s response to 90Y-NM600 + ICI is radiation and T Cell dependent.
Since large animals are closer to the environment in which the combined method was used in human clinical transformation, the research team tested the feasibility and safety of 90Y-NM600 in the treatment of tumors in dogs with extensive metastatic osteosarcoma and metastatic melanoma .
They did not observe clinically significant changes in laboratory tests, including alkaline phosphatase values and neutrophil, lymphocyte, platelet and red blood cell counts, indicating that this low-dose radiation combined with ICI therapy has a certain degree of safety.
The research developed a method to safely deliver low-dose radiation to solid tumors and any potentially metastatic tumors using 90Y-NM600.
This method can regulate the immune microenvironment, thereby promoting the response of “cold tumors” to immune checkpoint inhibitors and prolonging overall survival. It is very promising to be applied in clinical practice in the future.
(source:internet, reference only)