Methods for reducing side effects of immunotherapy
Inventors
Chang, Esther H. • Harford, Joe B. • Kim, Sang Soo
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-12274784-B2
Publication Date
2025-04-15
Expiration Date
Abstract
This invention provides methods to overcome the current limitations of immune checkpoint immunotherapy to provide more effective methods of treating cancer. In embodiments this invention provides a means of using of p53 gene therapy to augment immune checkpoint inhibition by combining antibodies targeting immune checkpoint molecules with SGT-53, a nanomedicine carrying a plasmid encoding human wild-type p53. This invention provides means of increasing tumor immunogenicity, enhancing both innate and adaptive immune responses, and reducing tumor-induced immunosuppression, sensitizing otherwise refractory tumors to anti-immune checkpoint antibodies. In other embodiments this invention also unexpectedly reduces immune-related toxicities that are seen with immunotherapies.
Core Innovation
The invention provides a method of treating a cancer in a patient using a transferrin-receptor-targeted cationic liposomal complex together with an immune checkpoint modulator. The complex comprises a cationic liposome and an anti-transferrin receptor single chain Fv (TfRscFv) complexed with the cationic liposome, where the TfRscFv is not chemically conjugated and does not comprise a lipid tag. The complex also includes a nucleic acid encoding p53 and is administered intravenously only as the transferrin-receptor-targeted cationic liposomal complex in combination with the immune checkpoint modulator.
The method delivers the nucleic acid encoding p53 via the transferrin-receptor targeted cationic liposomal complex to immune cells in the patient, and administers the immune checkpoint modulator to immune cells in the patient. The approach enhances an innate anti-tumor immune response triggered by immune cells of the patient and enhances an adaptive immunity response triggered by the immune cells of the patient.
The invention addresses cancer immune evasion and immunosuppression, including limitations associated with immune checkpoint modulation. The document states combining tumor-targeted cationic liposomal gene therapy that increases tumor immunogenicity with immune checkpoint modulators to trigger innate and adaptive anti-tumor immunity while reducing tumor immune evasion and immunosuppression.
The document further states an unexpected reduction of immune-related toxicities, including fatal xenogeneic hypersensitivity from repeated anti-PD-1 in syngeneic models.
Claims Coverage
The independent claim defines a cancer-treatment method with five main inventive elements: a transferrin-receptor-targeted cationic liposomal complex carrying nucleic acid encoding p53, intravenous administration of the complex together with an immune checkpoint modulator, delivery of p53 nucleic acid and the checkpoint modulator to immune cells, enhancement of innate anti-tumor immunity, and enhancement of adaptive immunity.
Transferrin-receptor-targeted cationic liposomal complex with p53 nucleic acid
Providing a transferrin-receptor-targeted cationic liposomal complex comprising a cationic liposome; an anti-transferrin receptor single chain Fv (TfRscFv) complexed with the cationic liposome but not chemically conjugated and wherein the TfRscFv does not comprise a lipid tag; and a nucleic acid encoding p53.
Intravenous co-administration with an immune checkpoint modulator
Administering intravenously only the transferrin-receptor-targeted cationic liposomal complex in combination with an immune checkpoint modulator to the patient.
Immune-cell delivery of p53 nucleic acid and checkpoint modulation
Delivering the nucleic acid encoding p53 via the transferrin-receptor targeted cationic liposomal complex to immune cells in the patient and the immune checkpoint modulator to immune cells in the patient.
Enhancement of innate anti-tumor immune response
Enhancing an innate anti-tumor immune response triggered by the immune cells of the patient.
Enhancement of adaptive immunity response
Enhancing an adaptive immunity response triggered by the immune cells of the patient.
Anti-PD1 immune checkpoint modulator
The method is administered using an immune checkpoint modulator that is an anti-PD1 antibody.
Combination with selected chemotherapeutic agents and/or radiation
Administering the transferrin-receptor-targeted cationic liposomal complex together with an immune checkpoint modulator and a selected chemotherapeutic agent and/or radiation therapy for treating cancer, where the chemotherapeutic agent is cisplatin, carboplatin, docetaxel, gemcitabine, paclitaxel, vinorelbine, or pemetrexed.
Broad inhibitor checkpoint modulator selection
Implementing the method using an immune checkpoint modulator that is an inhibitor selected from A2AR, B7-H3, B7-H4, BTLA, CTLA-4, IDO, KIR, LAG3, PD-1, PD-L1, PD-L2, TIM-3, VISTA, TIGIT, CD47, or SIRPalpha.
Treatment of specified cancer types
Characterizing the cancer as one of specified cancer types, including primary or metastatic brain tumor, breast cancer, neuroendocrine tumor, melanoma, pancreatic cancer, prostate cancer, head and neck cancer, ovarian cancer, lung cancer, bladder cancer, kidney cancer, liver cancer, vaginal cancer, urogenital cancer, gastric cancer, colorectal cancer, cervical cancer, liposarcoma, angiosarcoma, rhabdomyosarcoma, choriocarcinoma, retinoblastoma, and multiple myeloma.
Reduction of xenogeneic hypersensitivity reaction
Additionally treating by reducing a xenogeneic hypersensitivity reaction.
Overall, the claim set centers on using a transferrin-receptor-targeted cationic liposomal complex with an anti-transferrin receptor TfRscFv and nucleic acid encoding p53, administered intravenously together with an immune checkpoint modulator to immune cells, to enhance both innate and adaptive anti-tumor immunity, with refinements including specific checkpoint modulator selections, optional chemotherapeutic and/or radiation combinations, enumerated cancer types, and reduction of xenogeneic hypersensitivity.
Stated Advantages
Enhances an innate anti-tumor immune response triggered by the immune cells of the patient.
Enhances an adaptive immunity response triggered by the immune cells of the patient.
Reduces a xenogeneic hypersensitivity reaction.
Documented Applications
Treating a cancer in a patient using transferrin-receptor-targeted cationic liposomal p53 nucleic acid in combination with an immune checkpoint modulator.
Treating cancers including primary or metastatic brain tumor, breast cancer, neuroendocrine tumor, melanoma, pancreatic cancer, prostate cancer, head and neck cancer, ovarian cancer, lung cancer, bladder cancer, kidney cancer, liver cancer, vaginal cancer, urogenital cancer, gastric cancer, colorectal cancer, cervical cancer, liposarcoma, angiosarcoma, rhabdomyosarcoma, choriocarcinoma, retinoblastoma, and multiple myeloma.
Interested in licensing this patent?