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Publication Number
US-11548930-B2
Publication Date
2023-01-10
Expiration Date
Abstract
The present disclosure relates to, inter alia, a method for treating a tumor by intratumorally delivering an effective amount of a composition comprising an expression vector that comprises a first nucleotide sequence encoding a secretable vaccine protein, and a second nucleotide sequence encoding a T cell costimulatory fusion protein.
Core Innovation
The invention relates to treating a tumor in a subject by intratumorally delivering expression vectors encoding a secretable gp96-Immunoglobulin fusion protein that lacks the gp96 KDEL sequence together with a T cell costimulatory fusion protein. The intratumoral delivery is performed in vivo by injection, and the composition is delivered by electroporation. The T cell costimulatory fusion protein is OX40L-Ig, or a portion thereof that binds to OX40.
The method further includes administering an effective amount of a biological cell comprising expression vectors that encode a secretable gp96-Ig fusion protein lacking the gp96 KDEL sequence and a T cell costimulatory fusion protein that is OX40L-Ig, or an OX40-binding portion. The disclosed purpose of this administration is that the costimulatory protein enhances activation of antigen-specific T cells when administered to the subject.
The described rationale addresses converting less-immunogenic "cold" tumors to "hot" tumors. The approach combines intratumoral electroporation/injection of the secretable gp96-Ig and OX40L-Ig expression vectors with allogeneic vaccination using genetically manipulated biological cells expressing the same secretable vaccine and costimulatory constructs.
Claims Coverage
The independent claim includes 3 inventive features: intratumoral expression-vector delivery, allogeneic vaccination with biological cells expressing the same constructs, and costimulatory enhancement of antigen-specific T cells. Dependent claims refine the inventive method with additional limitations and embodiments, including quantified activation/proliferation increases, specifying PD-1 antibody, and narrowing component details such as Fc region tags and viral or virus-like particle incorporation.
Intratumoral expression-vector delivery with secretable gp96-Ig lacking gp96 KDEL and OX40L-Ig
An intratumoral delivery in vivo by injection of an effective amount of a composition comprising an expression vector encoding a secretable gp96-Immunoglobulin fusion protein that lacks the gp96 KDEL sequence and a T cell costimulatory fusion protein that is OX40L-Ig, or a portion thereof that binds to OX40, wherein the intratumoral delivery is delivered by electroporation.
Allogeneic vaccination with biological cells expressing secretable gp96-Ig lacking gp96 KDEL and OX40L-Ig
Further administering to the subject an effective amount of a biological cell comprising an expression vector encoding a secretable gp96-Ig fusion protein that lacks the gp96 KDEL sequence and a T cell costimulatory fusion protein that is OX40L-Ig, or a portion thereof that binds to OX40.
Costimulatory enhancement of activation of antigen-specific T cells
The method wherein the T cell costimulatory fusion protein enhances activation of antigen-specific T cells when administered to the subject.
Overall, the claim set covers a tumor treatment method that combines intratumoral electroporation/injection delivery of expression vectors encoding secretable gp96-Ig lacking the gp96 KDEL sequence and OX40L-Ig, or an OX40-binding portion, with additional administration of biological cells expressing the same constructs, where the costimulatory fusion protein enhances activation of antigen-specific T cells.
Stated Advantages
Enhances activation of antigen-specific T cells when administered to the subject.
Delivers a strategy to convert less-immunogenic "cold" tumors to "hot" tumors.
Induces CD8 cross priming and delayed tumor growth, and combining intratumoral electroporation with allogeneic vaccination enhances CD8 T-cell cross priming, antigen-specific expansion, and anti-tumor response.
Documented Applications
Proof-of-concept testing in mouse B16.F10-ova melanoma models, reporting CD8 cross-priming, delayed tumor growth, antigen-specific expansion, and an anti-tumor response.
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