Thursday, April 3, 2025
4/3/2025
Cold-responsive gene and drug delivery-potentiated cryoimmunotherapy - Project Summary/Abstract Breast cancer (BC) is the 2nd leading cause of cancer-related death in American women and metastasis is the major reason of BC-related mortality. Harnessing the immune system to battle cancer via immunotherapy has emerged as a powerful and potentially revolutionizing strategy for treating cancer metastasis. Although cancer immunotherapy strategies have shown success in treating hematological malignancies, their use for destroying solid tumors needs further improvement. The immunosuppressive tumor microenvironment (TME) is a key factor that contributes to the poor clinical outcomes of immunotherapy of solid tumors. Cryosurgery has been proposed as a promising strategy to modulate the TME. It is done by freezing to cause ice formation (i.e., frostbite) in tumor, which may lead to immunogenic cell death, shape an immune- active TME, and provoke antitumor immunity. Unlike hyperthermic therapy for which irreversible vascular stasis occurs during heating, there is a temporary (a few hours) reperfusion of the tumor after thawing a frozen tumor iceball. This enhances immune cell infiltration into the tumor after cryosurgery, compared to heating. However, cryosurgery alone is insufficient to activate a potent immune response against cancer via modulating the TME. Moreover, cryosurgery has been used in the clinic for treating cancer, especially BC. This is because it is minimally invasive with minimal cosmetic damage compared to surgical resection, and the hyperechoic frozen BC tumor iceball can be conveniently monitored in real time with medical ultrasonography. Unfortunately, a temperature of -20 °C or lower is needed for complete cell death, while the temperature in the periphery of a frozen tumor iceball is > -20 °C. This may result in incomplete tumor killing and cancer recurrence. Thus, combining cryosurgery with other therapies including immunotherapy has been studied to improve cancer killing in the peripheral region of a frozen tumor iceball. Although this is promising to kill localized tumor, an effective abscopal/immunization effect of cryoimmunotherapy against distant/metastatic tumors has not been reported and no nanomaterial has been used to enhance cryoimmunotherapy, until a recent study of us. In this study, we developed a cold-responsive nanoparticle (CRNP) that targets cancer cells actively and releases its payload (chemotherapy and immunotherapy agents) specifically into the cytosol in responsive to the cold temperature in the periphery of a frozen tumor iceball, for combining with cryosurgery. This induces a potent cryoimmune response against not only primary tumors with freezing but also distant and rechallenged metastatic tumors without cryosurgery (i.e., the abscopal and immunization effects). We hypothesize the efficacy and safety of the novel cryoimmunotherapy strategy can be further improved by 1), developing the CRNP to actively target both cancer cells and tumor vasculature and 2), delivering chemotherapy and immunotherapy agents that both perform their therapeutic function in the cytosol. The novel dual-targeting CRNP-potentiated cryoimmunotherapy may be invaluable for combating metastasis of BC and other cancers.
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