Induction and enhancement of antitumor immunity involving virus vectors expressing multiple epitopes of tumor associated antigens and immune checkpoint inhibitors or proteins
Inventors
Meruelo, Daniel • Martinez, Alicia Hurtado • Pampeno, Christine • Scherwitzl, Iris
Assignees
Publication Number
US-12116412-B2
Publication Date
2024-10-15
Expiration Date
2038-03-05
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Abstract
Provided are polynucleotides and viral vectors, e.g., alphavirus or Sindbis viral vectors, encoding multiple, e.g., two or more, epitopes of at least one tumor associated antigen, in which each epitope is separated by a processing or enzyme cleavage site. The encoded epitopes may be the same or different. Also provided are polynucleotides and viral vectors, particularly, alphavirus or Sindbis viral vectors, encoding an immune checkpoint protein, or a ligand binding portion thereof. The immune checkpoint protein or ligand binding portion thereof may be fused to immunoglobulin domains, e.g., an Ig hinge domain and an Ig heavy chain constant domain. Methods of treating subjects having a cancer or tumor, e.g., a TAA-expressing tumor, with the described viral vectors are provided. Treatment of subjects with the vectors, the checkpoint inhibitor molecules and/or other immunomodulatory components, generate an anti-cancer or anti-tumor immune response resulting in increased survivability of tumored subjects and epitope spreading.
Core Innovation
The invention provides methods and compositions involving the use of Sindbis virus vectors encoding polypeptides derived from tumor-associated antigens, specifically NY-ESO-1, in combination with immune checkpoint inhibitors such as anti-PD-1 antibodies. These compositions and regimens are designed for the treatment of subjects with cancer. The Sindbis virus vector delivers the NY-ESO-1 polypeptide, resulting in the induction and enhancement of antitumor immunity.
The core problem addressed is the frequent ineffectiveness of existing cancer treatments due to tumor immune evasion, incomplete tumor remission with oncolytic viruses, and resistance to immune checkpoint inhibitors. Tumors often evade detection and destruction by the immune system, and many patients develop resistance to checkpoint blockade therapies. There is a need for improved anti-cancer agents that can both elicit robust immune responses and overcome immune resistance mechanisms.
In response, the invention features the administration of a Sindbis virus encoding an NY-ESO-1 polypeptide together with an anti-PD-1 antibody, resulting in elimination of established tumors expressing NY-ESO-1. The method exploits both direct immunogenic effects from the viral vector and checkpoint blockade to synergistically trigger enhanced immune-mediated tumor cell destruction, addressing both tumor antigenicity and immune suppression.
Claims Coverage
The independent claim covers a therapeutic method utilizing a combination of a Sindbis virus encoding an NY-ESO-1 polypeptide and an anti-PD-1 antibody for treating cancer.
Combination of Sindbis virus encoding NY-ESO-1 polypeptide and anti-PD-1 antibody for tumor elimination
The claim specifies administering to a subject having cancer: - A Sindbis virus that encodes an NY-ESO-1 polypeptide. - An anti-PD-1 antibody. The combination is defined by the elimination of an established tumor that consists of cancer cells expressing the NY-ESO-1 polypeptide. This inventive feature relies on the co-administration of these two agents and their coordinated action to treat tumors expressing the specific antigen.
The claim coverage is directed specifically to combined therapy using a Sindbis virus encoding NY-ESO-1 and an anti-PD-1 antibody for the treatment of cancers characterized by NY-ESO-1 expression, with the result being the elimination of established tumors.
Stated Advantages
Enables elimination of established tumors composed of cancer cells expressing NY-ESO-1 polypeptide.
Generates an anti-cancer or anti-tumor immune response resulting in increased survivability of tumored subjects.
Circumvents resistance and immune evasion mechanisms seen with prior checkpoint inhibitors or oncolytic viruses.
Induces epitope spreading that broadens the anti-tumor immune response.
Documented Applications
Treatment of subjects having cancer, specifically tumors expressing NY-ESO-1 polypeptide, by administering a combination of Sindbis virus encoding NY-ESO-1 and anti-PD-1 antibody.
In vivo elimination of established cancers/tumors in mammalian subjects, including use after tumor establishment.
Methods of inducing or enhancing anti-tumor immune responses that result in increased survival and tumor clearance.
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