Therapy for treating cancer with an intratumoral or intravenous administration of a recombinant MVA encoding 4-1BBL (CD137L) and/or CD40L
Inventors
Lauterbach, Henning • Hinterberger, Maria • Medina Echeverz, José
Assignees
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Publication Number
US-12390515-B2
Publication Date
2025-08-19
Expiration Date
Abstract
The invention relates to a composition and related methods for reducing tumor volume and/or increasing the survival of a cancer patient. The composition comprises a recombinant MVA encoding a Tumor Associated Antigen (“TAA”) as well as 4-1BBL and/or CD40L and can be administered to a subject in any suitable manner, including by intravenous and/or intratumoral administration.
Core Innovation
The invention relates to inducing an enhanced inflammatory response in a cancerous tumor by administering a recombinant modified Vaccinia Ankara (MVA). The recombinant MVA comprises a first nucleic acid encoding a first heterologous tumor-associated antigen (TAA) that is an endogenous retroviral (ERV) protein expressed in a tumor cell, and a second nucleic acid encoding a 4-1BBL antigen.
In one embodiment, the recombinant MVA includes a third nucleic acid encoding a CD40L antigen together with the ERV-derived TAA and the 4-1BBL antigen. The ERV-derived TAA includes HERV-K envelope protein or HERV-K gag protein, and the document describes ERV-related configurations and MVA-OVA constructs to demonstrate antigen-specific effects.
The document also describes that intratumoral or combined administration of these MVA constructs drives immune responses associated with tumor control, including increased inflammatory/TME cytokines, NK cell activation, and effector differentiation of antigen-specific CD8 T cells. rMVA-HERV-K-4-1BBL is described as mapping to HERV-K-specific T cell responses.
Claims Coverage
The document provides two independent claims covering methods for inducing an enhanced inflammatory response in a cancerous tumor using recombinant MVA encoding an ERV-derived TAA, 4-1BBL, and optionally CD40L. Across the independents, the core inventive features are the specified recombinant MVA gene content and the comparative enhancement of tumor inflammatory response relative to defined comparator administrations.
Intratumoral recombinant MVA encoding ERV TAA and 4-1BBL enhances tumor inflammation vs non-intratumoral dosing
Administering intratumorally to a subject a recombinant modified Vaccinia Ankara (MVA) comprising a first nucleic acid encoding a first heterologous tumor-associated antigen (TAA) that is an endogenous retroviral (ERV) protein expressed in a tumor cell and a second nucleic acid encoding a 4-1BBL antigen, wherein the intratumoral administration generates an enhanced inflammatory response in the tumor as compared to a non-intratumoral injection of a recombinant MVA virus comprising said TAA and said 4-1BBL antigen.
Recombinant MVA encoding ERV TAA, 4-1BBL, and CD40L enhances tumor inflammation vs 4-1BBL and CD40L alone
Administering to a subject a recombinant modified Vaccinia Ankara (MVA) comprising a first nucleic acid encoding a first heterologous tumor-associated antigen (TAA) that is an endogenous retroviral (ERV) protein expressed in a tumor cell, a second nucleic acid encoding a 4-1BBL antigen, and a third nucleic acid encoding a CD40L antigen, wherein the administration generates an enhanced inflammatory response in the tumor as compared to administration of a recombinant MVA, 4-1BBL antigen, and CD40L antigen by themselves.
Overall, the claim set ties enhanced tumor inflammatory response to recombinant MVA that encodes an ERV-derived TAA and 4-1BBL, with further enhancement when CD40L is additionally encoded, and compares the resulting tumor inflammation against defined non-intratumoral or component-only administration controls.
Stated Advantages
Enhanced inflammatory response in the tumor compared to a non-intratumoral injection of a recombinant MVA virus comprising the same TAA and 4-1BBL antigen.
Enhanced inflammatory response in the tumor compared to administration of a recombinant MVA, 4-1BBL antigen, and CD40L antigen by themselves.
Induction of immune responses associated with tumor inflammation, including activation of NK cells and expansion of antigen-specific CD8 T cells.
Improved tumor control outcomes, including reduced tumor volume and improved survival, compared with recombinant MVA lacking the 4-1BBL and/or CD40L encoding components or compared with the ligands alone.
Documented Applications
Inducing an enhanced inflammatory response in a subject’s cancerous tumor using intratumoral administration of a recombinant MVA encoding an ERV protein TAA and a 4-1BBL antigen.
Inducing an enhanced inflammatory response in a subject’s cancerous tumor using administration of a recombinant MVA encoding an ERV protein TAA, 4-1BBL, and CD40L, where tumor inflammation is greater than administration of 4-1BBL and CD40L components by themselves.
Cancer immunotherapy based on intratumoral and/or intravenous administration of recombinant MVA encoding an ERV-derived tumor-associated antigen together with 4-1BBL and optionally CD40L to enhance tumor inflammation.
Use of immune checkpoint antagonists, including anti-PD-1, together with the described recombinant MVA approach to enhance tumor control and/or ADCC.
Treatment strategies involving ERV-derived TAAs from HERV-K, including HERV-K env/gag/mel, expressed in tumor cells using recombinant MVA constructs.
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