Conjugated virus-like particles and uses thereof as anti-tumor immune redirectors
Disclosed is a new class of conjugated virus-like particles (VLPs). These conjugated VLPs bind a wide variety of tumors and comprise epitopes recognized by a prior T cell immune response already existing in a host. These epitopes are derived from pathogens or previous vaccinations (such as early childhood vaccines). This provokes the body's pre-existing cytotoxic immunity obtained through previous infection or previous childhood vaccination to be redirected to the tumor cells for the elimination of cancer, and form long-term anti-tumor immunity. The described conjugated VLPs are useful for tailoring a broad range of tumors towards a response from existing immunity circumventing the need to identify tumor antigens or generate tumor-specific immune responses. Importantly, the compositions and methods described herein broadens opportunities for treatment for all cancer types in subjects who previously had un-targetable cancers due to various technological and biological limitations of currently available immuno-therapeutic drugs.
1 . A method of treating cancer, which comprises administering to a subject in need thereof a pharmaceutically effective amount of a virus-like particle (VLP),
wherein:
the VLP in the order from amino terminus to carboxy terminus as a single peptide comprises:
at least one virus capsid protein, and
a fusion protein comprising:
a) at least one protease cleavage peptide sequence,
attached to
b) at least one recall protein comprising at least one epitope,
wherein the at least one protease cleavage peptide sequence is recognized by one or more tumor microenvironment protease selected from: cathepsins, kallikreins, serine proteases, caspases, matrix metalloproteinases, and disintegrin and metalloproteinases (ADAMs), and
wherein the fusion protein is 45 amino acids or less in length,
wherein the at least one recall protein comprises at least one epitope that is from 8 to 17 amino acids in length,
wherein the at least one epitope is at least one human T cell epitope, and
wherein the cancer is selected from the group consisting of: lung, oral, cervical, epithelial, ovary, breast, colon, and prostate.
2 . The method of claim 1 , further comprising:
detecting in the subject the presence of a preexisting immune response.
3 . The method of claim 2 , wherein detecting in the subject the presence of a preexisting immune response comprises:
obtaining a blood sample from the subject, and
assaying the blood cells for the presence of one or more populations of T cells specifically recognizing one or more epitopes from one or more childhood vaccines.
4 . The method of claim 1 , wherein the epitope is one that is from a childhood vaccine and elicits an immune response in the subject.
5 . The method of claim 4 , further comprising:
obtaining from the subject a tumor tissue sample; and
identifying in the tumor tissue a peptide sequence of one or more major histocompatibility (MHC) molecules expressed by one or more tumor cells in the tumor tissue sample.
6 . The method of claim 2 , wherein detecting in the subject the presence of a preexisting immune response comprises determining whether the subject was ever immunized or vaccinated against a pathogen.
7 . The method of claim 1 , wherein the epitope corresponds to an epitope present in the prior immunization or vaccination in the subject.
8 . The method of claim 3 , further comprising administering to the subject a boosting vaccine at least two weeks following administration of the VLP.
9 . The method of claim 3 , wherein the childhood vaccine is a shingles vaccine, a pneumococcal vaccine, a hepatitis vaccine, or a measles-mumps-rubella (MMR) vaccine.
10 . The method of claim 3 , further comprising administering one or more additional therapies to the subject selected from: Chimeric Antigen Receptor T-cell (CAR-T therapy, a vaccine, a check point inhibitor, an oncolytic virus, a neo-antigen vaccine, a neo-adjuvant, a chemotherapy, radiation, or surgery.
11 . A virus-like particle (VLP), comprising in order from amino terminus to carboxy terminus as a single peptide:
at least one virus capsid protein, and
a fusion protein comprising:
a) at least one protease cleavage peptide sequence, attached to
b) at least one recall protein comprising at least one epitope,
wherein the at least one protease cleavage peptide sequence is recognized by one or more tumor microenvironment protease selected from: cathepsins, kallikreins, serine proteases, caspases, matrix metalloproteinases, and disintegrin and metalloproteinases (ADAMs), and
wherein the at least one capsid protein exhibits tropism for a specific type of tissue.
12 . The VLP of claim 11 , wherein the at least one epitope is a viral epitope from vaccinia virus, varicella zoster virus, herpes zoster virus, rubella, hepatitis virus, influenza virus, measles virus, mumps virus, poliovirus, variola virus, rabies virus, dengue virus, Ebola virus, West Nile virus, yellow fever virus, zika virus, cytomegalovirus, or Epstein-Barr virus.
13 . The method of claim 1 , wherein the cancer is an epithelial cell cancer.
14 . The method of claim 1 , wherein the cancer is selected from the group consisting of: lung cervical, ovarian, breast, colon, and prostate.