Combined immunotherapy in cancer treatment by boosting anti-tumor immune response
1. Tumor immune evasion is the main obstacle in cancer treatment. The aim of this project is to investigate tools to enhance the anti-tumor effect in the immune system through several different avenues. This will be done through validating immune-regulatory drugs which could potentially down-regulate Tregs to boost anti-tumor immunity through activation of effector Tcell functions in mice tumor models. We will test novel FoxP3 regulators on tumor growth, alone or in combination with immune checkpoint inhibitors to evaluate their efficacy on anti-tumor activity and immune response profiling. In addition, RIAD transgenic mice with blockade of PKA activity to regain the TCR activation in Tcells will be used as another combined cancer treatment. Through the experiments outlined in this FOTS application, we hope to identify potential FoxP3 regulator drugs for cancer patients alone or in combination with other immune therapies. In addition, we hope to determine the beneficial use of the CAR-RIAD combination in solid tumors.
2. The mice will be injected with tumor cells intradermally by applying anesthesia. FoxP3 regulator drugs and checkpoint inhibitors will be delivered with repeated intraperitoneal injections. For the harvesting experiments, we will do heart puncture to collect blood samples from mice under anesthesia. We will apply humane endpoint if the mice has weight loss >10% or tumor size reaches 10% of body weight. We have therefore evaluated the stress to be moderate.
3. If the FoxP3 regulator drugs works well on anti-tumor immunity regulation or the combined therapy benefit a lot in mice tumor growth inhibition and prolong survival rates, it implies good and effective anti-tumor treatments. Then we can design more efficient drugs according to these types of drugs which will be potential drug candidates for cancer patients alone or in combination with other immune therapies.
4.We apply for 2459 mice in total (including 1218 WT C57BL/6NTac mice, 928 RIAD mice, 29 C57BL/6J WT mice and 284 nude mice).
5. One of the FoxP3 regulators we are testing now is a FDA -approved drug, while the others are drugs with similar structures. We have discovered significant tumor growth inhibition of these drugs in our previous pilots in mice with PancO2 tumor model, with the perspective that it will reduce tumor growth in other models and the combined therapies could benefit more. The optimization of tumor cell numbers has been performed in our lab before which will reduce the numbers of mice needed for experiments. In the case of ulcerated or large tumors (more than 10% of body weight or volume>1.5cm3) that interfere with normal movement, or in the case of a body weight decrease by more than 10%, we will euthanize these mice.
2. The mice will be injected with tumor cells intradermally by applying anesthesia. FoxP3 regulator drugs and checkpoint inhibitors will be delivered with repeated intraperitoneal injections. For the harvesting experiments, we will do heart puncture to collect blood samples from mice under anesthesia. We will apply humane endpoint if the mice has weight loss >10% or tumor size reaches 10% of body weight. We have therefore evaluated the stress to be moderate.
3. If the FoxP3 regulator drugs works well on anti-tumor immunity regulation or the combined therapy benefit a lot in mice tumor growth inhibition and prolong survival rates, it implies good and effective anti-tumor treatments. Then we can design more efficient drugs according to these types of drugs which will be potential drug candidates for cancer patients alone or in combination with other immune therapies.
4.We apply for 2459 mice in total (including 1218 WT C57BL/6NTac mice, 928 RIAD mice, 29 C57BL/6J WT mice and 284 nude mice).
5. One of the FoxP3 regulators we are testing now is a FDA -approved drug, while the others are drugs with similar structures. We have discovered significant tumor growth inhibition of these drugs in our previous pilots in mice with PancO2 tumor model, with the perspective that it will reduce tumor growth in other models and the combined therapies could benefit more. The optimization of tumor cell numbers has been performed in our lab before which will reduce the numbers of mice needed for experiments. In the case of ulcerated or large tumors (more than 10% of body weight or volume>1.5cm3) that interfere with normal movement, or in the case of a body weight decrease by more than 10%, we will euthanize these mice.