Targeted synergistic cancer immunotherapy
AssigneesThe Brigham and Women's Hospital, Inc., Children's Medical Center Corporation
InventorsJeffrey M. KARP, Rui KUAI, Jun XU, Wenmin YUAN, Dania ZHIVAKI, Jonathan C. KAGAN, Andrew BELLINGER
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Abstract
Reactive oxygen species (ROS) generated with noninvasive ultrasound and sonosensitizers, potently synergize with selected immunomodulators to hyperactivate dendritic cells and macrophages at desired locations and times within the body. Together with the tumor antigens provided by dying/dead tumor cells, these signals can result in activation of adaptive immune responses. This approach is useful for eliciting T cell responses within tumors present in any tissue of the body.
Claims52
A method of inducing cytokine secretion, the method comprising:
- a. contacting mammalian antigen presenting cells (APCs) with a sonosensitizer and an immunomodulator;
- and
- b. exposing the APCs of (a) to ultrasound radiation for a period of time sufficient to induce cytokine secretion by the APCs.
A method of inducing secretion of IL-1β in a mammalian subject comprising
- a. administering a sonosensitizer to the subject,
- b. administering an immunomodulator to the subject, and
- c. thereafter, exposing the subject to ultrasound radiation.
A method of eliciting secretion of cytokines from immune cells in a mammalian subject comprising:
- a. administering a sonosensitizer to the subject,
- b. administering an immunomodulator to the subject,
- c. thereafter, exposing the subject to ultrasound radiation.
A method of promoting T cell activation in a mammalian subject comprising:
- a. administering a sonosensitizer to the subject,
- b. administering an immunomodulator to the subject, and
- c. thereafter, exposing the subject to ultrasound radiation.
The method according to claim 32, wherein the lipophilic moiety is DOPE or cholesterol.
A method of treating a tumor in a subject comprising:
- a. administering a sonosensitizer to the subject,
- b. administering an immunomodulator to the subject, and
- c. thereafter, exposing the tumor to ultrasound radiation.
A kit for inducing secretion of cytokines that promote T cell activation in mammals, the kit comprising:
- a. a sonosensitizer comprising a cyanine, porphyrin, merocyanine, phthalocyanine, naphthalocyanine, triphenylmethine, pyrilium dye, thiapyrilium dye, squarylium dye, croconium dye, azulenium dye, indoaniline, benzophenoxazinium dye, benzothiaphenothiazinium dye, anthraquinone, naphthoquinone, indathrene, phthaloylacridone, trisphenoquinone, azo dye, intramolecular or intermolecular charge-transfer dye or dye complex, tropone, tetrazine, bis (dithiolene) complex, bis (benzene-dithiolate) complex, iodoaniline dye, bis (S, O-dithiolene) complex, or a combination thereof;
- and
- b. an immunomodulator comprising resiquimod (R848), PAPC, CpG, polyIC, poly-ICLC, 1018 ISS, aluminum salts, Amplivax, AS15, BCG, CP-870, 893, CpG7909, CyaA, dSLIM, GM-CSF, IC30, IC31, ImuFact IMP321, IS Patch, ISS, ISCOMATRIX, Juv Immune, LipoVac, MF59, monophosphoryl lipid A (MPLA), Montanide IMS 1312, Montanide ISA 206, Montanide ISA 50V, Montanide ISA-51, OK-432, OM-174, OM-197-MP-EC, ONTAK, PepTel®, vector system, imiquimod, gardiquimod, 3M-052, SRL172, beta-glucan, Pam3Cys, Aquila's QS21 stimulon, vadimezan, AsA404 (DMXAA), a STING agonist, or a combination thereof.
A pharmaceutical composition for parenteral administration to a subject comprising:
- a. a sonosensitizer comprising a cyanine, porphyrin, merocyanine, phthalocyanine, naphthalocyanine, triphenylmethine, pyrilium dye, thiapyrilium dye, squarylium dye, croconium dye, azulenium dye, indoaniline, benzophenoxazinium dye, benzothiaphenothiazinium dye, anthraquinone, naphthoquinone, indathrene, phthaloylacridone, trisphenoquinone, azo dye, intramolecular and intermolecular charge-transfer dye or dye complex, tropone, tetrazine, bis (dithiolene) complexe, bis (benzene-dithiolate) complex, iodoaniline dye, bis (S,O-dithiolene) complex, or a combination thereof;
- and
- b. an immunomodulator comprising resiquimod (R848), PAPC, CpG, polyIC, poly-ICLC, 1018 ISS, aluminum salts, Amplivax, AS15, BCG, CP-870, 893, CpG7909, CyaA, dSLIM, GM-CSF, IC30, IC31, ImuFact IMP321, IS Patch, ISS, ISCOMATRIX, Juv Immune, LipoVac, MF59, monophosphoryl lipid A (MPLA), Montanide IMS 1312, Montanide ISA 206, Montanide ISA 50V, Montanide ISA-51, OK-432, OM-174, OM-197-MP-EC, ONTAK, PepTel®, vector system, imiquimod, gardiquimod, 3M-052, SRL172, beta-glucan, Pam3Cys, Aquila's QS21 stimulon, vadimezan, AsA404 (DMXAA), a STING agonist, or a combination thereof;
- and
- c. a pharmaceutically acceptable carrier.
Dependencies are inferred from the claim text.