Systems and methods for histotripsy immunosensitization
Inventors
Xu, Zhen • CHO, Clifford Suhyun
Assignees
US Department of Veterans Affairs • University of Michigan Ann Arbor
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Publication Number
US-11813485-B2
Publication Date
2023-11-14
Expiration Date
2041-01-28
Abstract
Systems and methods for histotripsy and immunotherapy are provided. In some embodiments, histotripsy can be applied to a target tissue volume to lyse and solubilize the target tissue volume to release tumor antigens. In some embodiments, an immune response of the treatment can be evaluated. In other embodiments, an immune therapy can be applied after applying the histotripsy. In one embodiment, the lysed and solubilized cells can be extracted from the tissue. The extracted cells can be used to create immune therapies, including vaccines.
Core Innovation
The disclosure provides systems and methods for histotripsy immunosensitization, wherein histotripsy is applied to a target tissue volume to mechanically lyse and solubilize tumor cells to release tumor antigens. This process induces immunogenic cell death and stimulates immune responses against the treated tumor. The histotripsy treatment is designed to disrupt tumor cell membranes without generating thermal damage or protein denaturation, thus preserving antigenicity.
Histotripsy immunosensitization is intended not only for local tumor ablation but to potentiate systemic immune responses, including effects on distant tumors of the same phenotype. The treatment volume and location within the tumor are determined to maximize immune responses while minimizing complications. The system can also evaluate the immune response post-treatment and apply immune therapies such as checkpoint inhibitors to enhance therapeutic effects.
The problem being solved addresses limitations of current cancer immunotherapies and ablative treatments. Conventional immunotherapies like checkpoint inhibition have limited efficacy in non-immunogenic cancers and carry risks of autoimmune complications. Thermal ablations like HIFU cause protein denaturation and incomplete induction of immunogenic cell death. Histotripsy offers a non-thermal, mechanical method to liberate soluble tumor antigens and induce strong immunogenic cell death, overcoming immune evasion of tumors and enhancing responsiveness to immunotherapy.
Claims Coverage
The patent includes multiple independent claims focusing on methods of histotripsy treatment and immunosensitization, immune response evaluation, immune therapy application, and creation of immune directed therapies or vaccines.
Targeted histotripsy treatment to increase tumor antigen release
Identifying at least one target tumor, determining treatment volume and location to increase cell response of releasing tumor antigens, and applying histotripsy treatment to mechanically lyse and solubilize tumor cells to release tumor antigens.
Histotripsy application for treatment resistant tumors
Applying histotripsy to tumors previously treated with or resistant to radiation therapy or immunotherapy to release tumor antigens and enhance immune response.
Evaluation of immune response after histotripsy
Assessing immunological cell death and immune activation through imaging modalities (CT, MRI, PET), tissue or liquid biopsy, and biomarker analysis post histotripsy treatment.
Combined histotripsy and immune therapy administration
Applying immune therapies such as checkpoint inhibitors, immunostimulatory therapies, cancer vaccines, oncolytic viruses, neutralizing immune inhibitors, and activating cytokines following histotripsy to enhance immune response.
Harvesting lysed tumor cells for immune directed therapies and vaccines
Extracting tumor cells lysed by histotripsy, preparing immune directed therapies including cell therapies or cancer vaccines, and administering them via various delivery routes including oral, systemic, intratumoral, or loco-regional injections.
Robotic positioning and treatment planning for histotripsy
Using a robotic positioning system to place the histotripsy focus within the tumor, conduct cavitation threshold testing at multiple locations, derive a treatment plan based on thresholds, and automate treatment delivery with immune response evaluation.
The independent claims collectively cover methods and systems for targeted histotripsy treatment to mechanically disrupt tumors and release antigens, particularly in treatment-resistant cases, alongside immune response evaluation, combination with immunotherapies, creation of immune directed therapies or vaccines from lysates, and integration with robotic and imaging systems for optimized treatment planning and delivery.
Stated Advantages
Histotripsy provides non-thermal mechanical destruction of tumors preserving antigenic protein integrity, enabling more effective immune sensitization compared to thermal ablation methods.
The technique induces immunogenic cell death resulting in robust regional and systemic tumor-specific immune responses, including the potential for abscopal effects on distant tumors.
Histotripsy can sensitize tumors resistant to existing immunotherapies, thereby enhancing their therapeutic efficacy.
The use of real-time imaging and robotic positioning allows precise targeting, controlled ablation volume, and patterning, reducing complications and improving treatment outcomes.
Harvested histotripsy-lysed tumor cells can be used to create personalized cancer vaccines or immune directed therapies, providing a new modality for immunotherapy.
Documented Applications
Treatment of tumors located in organs including liver, kidney, spleen, pancreas, colorectal, bowel, stomach, esophagus, breast, lung, head, neck, thyroid, skin, nervous tissue, hematological malignancies, sarcomas, primary and metastatic lesions, and brain tissue.
Treatment of tumors previously treated with radiation therapy or immunotherapy, especially those resistant or non-responsive to such treatments.
Combination therapy administering immune therapies such as checkpoint inhibitors after histotripsy treatment to maximize systemic immune responses.
Creation of cancer vaccines from lysed tumor cells harvested post histotripsy for use as personalized immunotherapeutics.
Use in laboratory and bench settings for producing tumor homogenates or lysates for direct or combinatory immune therapies.
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