Induction and enhancement of antitumor immunity involving Sindbis virus vectors expressing immune checkpoint proteins

Inventors

Meruelo, Daniel • Martinez, Alicia Hurtado • Pampeno, Christine • Scherwitzl, Iris

Assignees

New York University NYU

Abstract

Provided are polynucleotides and viral vectors, particularly, Alphavirus vectors such as Sindbis viral vectors, which encode an immune checkpoint protein, or a ligand binding portion of the checkpoint protein, or an immune checkpoint protein or ligand binding portion thereof fused to one or more immunoglobulin (Ig) domains, e.g., an Ig hinge region and an Ig heavy chain constant domain. Methods of treating a mammalian subject having a cancer or tumor are provided, in which the viral vectors, e.g., a Sindbis virus vector, encoding the immune checkpoint protein, a ligand binding portion thereof, or a checkpoint protein fusion protein as described, are administered to the subject, resulting in an anti-cancer or anti-tumor immune response, significant reduction in tumor growth in the treated subject and increased survivability.

Core Innovation

The invention provides polynucleotides and viral vectors, particularly Alphavirus vectors such as Sindbis virus vectors, engineered to encode immune checkpoint proteins, their ligand binding portions, or fusion proteins comprising immune checkpoint molecules and immunoglobulin domains. These constructs can express various checkpoint proteins, for example PD-1, PD-L1, CTLA-4, 4-1BB ligand (4-1BBL), or OX40 ligand (OX40L), or fragments thereof. In some embodiments, the immune checkpoint molecule is expressed as a fusion or 'minibody' with immunoglobulin hinge and heavy chain constant domains, and may also include linker sequences for enhanced flexibility.

The background section identifies the problem that many cancers evade immune surveillance and current therapies, including checkpoint inhibitors, are not always successful due to resistance and incomplete targeting of tumors. There is a profound need for new and improved anti-cancer therapeutic approaches that can stimulate an effective immune response and provide better eradication of cancer cells.

The invention's core methodology involves administering these Sindbis virus vectors encoding immune checkpoint proteins or their cognate ligand-binding fragments (including fusion forms) to mammalian subjects bearing tumors. The approach leads to the systemic expression of checkpoint proteins, which bind their ligands on tumor cells, blocking inhibitory interaction with T cell checkpoint proteins and thereby maintaining T cell cytotoxicity against cancer. Additionally, vectors can be constructed to encode tumor associated antigens (TAAs) or immunomodulatory sequences, either alone or in combination with checkpoint protein genes, further augmenting anti-tumor immune responses.

Experimental evidence provided in the patent demonstrates that treatment with Sindbis virus vectors encoding the extracellular portions of checkpoint proteins such as PD-1, OX40L, or 4-1BBL leads to significant reduction in tumor growth and increased survival in mouse tumor models. The invention’s strategy includes single and combined encoding of checkpoint proteins and/or TAAs by the same viral vector and allows administration alone or in combination with other therapies.

Claims Coverage

There are several inventive features claimed in the independent claims of this patent, primarily directed to viral vector-based therapeutic compositions expressing immune checkpoint proteins or ligand-binding regions fused to immunoglobulin domains, and related fusion protein constructs.

The claims broadly cover Sindbis virus-based compositions designed to express immune checkpoint proteins or their binding domains fused to immunoglobulin regions, establishing a platform for anti-tumor therapies utilizing engineered viral vectors.

Stated Advantages

Documented Applications