Compositions and methods for immune-mediated cancer therapy

Inventors

Lee, Ruey-min

Assignees

Teclison Inc

Abstract

Disclosed herein are methods and compositions for enhancing an immune response to a solid tumor in a subject. In some embodiments, a method comprises: (a) administering to the subject a hypoxia-activated bioreductive agent (HABA); (b) inducing hypoxia by (i) administering a hypoxia-inducing agent to the subject or (ii) embolizing one or more blood vessels supplying the solid tumor; and (c) administering an immune checkpoint inhibitor prior to, simultaneously with, or subsequent to step (b) in an amount effective to enhance an immune response to the solid tumor, as compared to an immune response in the absence of the immune checkpoint inhibitor. Kits for use in the disclosed methods are also provided.

Core Innovation

The invention enhances an anti-tumor immune response in a subject in need thereof by combining administration of a hypoxia-activated bioreductive agent (HABA) that is tirapazamine with inducing hypoxia by trans-arterial embolization of one or more blood vessels supplying a liver tumor or microsatellite-stable metastatic colorectal cancer (mCRC-MSS) and a lung tumor. The method is directed to cancers including a cancer that has a liver tumor and a lung tumor, and a cancer that has mCRC-MSS and a lung tumor.

The combination of tirapazamine and induced hypoxia is required to induce necrosis of the liver tumor or the mCRC-MSS. The induced hypoxia is specifically carried out by trans-arterial embolization of one or more blood vessels supplying the relevant tumor, thereby creating conditions associated with hypoxia that enable the hypoxia-activated bioreductive activity of tirapazamine.

The method further includes administering an immune checkpoint inhibitor of programmed cell death protein 1 (PD-1) as an anti-PD-1 antibody, where the anti-PD-1 antibody is nivolumab or pembrolizumab. The combination of administering tirapazamine, inducing hypoxia, and administering the anti-PD-1 antibody is required to exhibit a synergistic effect, including a size reduction of the lung tumor greater than a corresponding size reduction achieved in the absence of the tirapazamine-and-hypoxia combination.

Claims Coverage

The independent claim defines a method to enhance an anti-tumor immune response using a three-part combination with tumor necrosis requirements and a lung tumor synergy criterion. The inventive features are concentrated in the core steps of HABA administration (tirapazamine), hypoxia induction via trans-arterial embolization, and PD-1 immune checkpoint inhibition with an anti-PD-1 antibody (nivolumab or pembrolizumab).

Across the independent claim, the coverage centers on a three-part regimen: tirapazamine as the hypoxia-activated bioreductive agent, hypoxia induction through trans-arterial embolization of blood vessels supplying the liver tumor or mCRC-MSS, and PD-1 immune checkpoint inhibition using an anti-PD-1 antibody that is nivolumab or pembrolizumab. The claim further requires that HABA plus induced hypoxia induces necrosis, and that adding the anti-PD-1 antibody produces a synergistic increase in lung tumor size reduction beyond hypoxia induction alone.

Stated Advantages

Documented Applications