Methods of Modulating Antigenicity to Enhance Recognition by T-Cells Unmasking Cancer Cells for Immune Attack

This patent describes methods and compositions for boosting the immune system’s ability to detect and destroy cancer cells by restoring molecular markers on the cancer cell surface that tumours have deliberately erased to avoid detection.

The Problem

Cancer cells are not passive targets. As they evolve, they actively suppress the immune signals that would otherwise flag them for destruction by cytotoxic T-lymphocytes (CTLs), the immune system’s dedicated tumour-killing cells. One mechanism tumours exploit is the overexpression of phosphatase enzymes. These enzymes strip phosphate groups from proteins on the cancer cell surface, removing a class of molecular flags known as phosphoneoantigens. Phosphoneoantigens are phosphorylated peptides unique to cancer cells that CTLs use as recognition targets. When a tumour dials up its phosphatase activity, it effectively wipes those flags from its surface and becomes invisible to T-cell surveillance. Existing immunotherapies, including checkpoint inhibitors, depend on the T-cell being able to see the tumour in the first place. If the antigen has been erased, even the best checkpoint blockade cannot restore an effective immune response.

What This Invention Does

The invention developed at Massachusetts General Hospital (The General Hospital Corporation) provides methods for increasing tumour antigenicity by inhibiting the cancer-associated phosphatases responsible for masking phosphoneoantigens. By decreasing phosphatase activity in cancer cells, the approach restores the level of phosphorylated tumour antigens on the cell surface, making those cells legible again to CTLs. The patent covers: methods of increasing phosphoneoantigen expression in cancer cells via phosphatase inhibition; methods of treating cancer in a subject by administering a phosphatase inhibitor; and combination strategies pairing phosphatase inhibition with immune checkpoint modulators, immunomodulatory cytokines, MDSC-suppressing agents, phosphoneoantigen vaccines, and adoptive T-cell therapies. The divisional application (of AU 2019271297) extends protection into Australia for this platform approach to cancer immunotherapy.

Key Features

• Phosphatase inhibition as the central mechanism. By targeting cancer-associated phosphatases such as alkaline phosphatase and related enzymes, the method chemically restores the phosphoneoantigen signal that tumours have suppressed. Inhibitors identified in the patent include ML095, thiophosphate, L-p-bromotetramisole, and several compound-library hits.
• Combination with checkpoint blockade. The method pairs naturally with anti-PD-1 antibodies (pembrolizumab, nivolumab, and others), anti-CTLA-4 antibodies, and bispecific checkpoint modulators. The rationale is that restoring antigenicity and relieving checkpoint suppression together are more effective than either alone, with the potential to reduce the dose of checkpoint inhibitor required.
• Cytokine and vaccine combinations. The invention also covers co-administration of interferons, interleukins (IL-2, IL-12, IL-15), and synthetic cytokine mimetics, as well as vaccination with the phosphoneoantigen itself together with an adjuvant to prime an antigen-specific T-cell response.
• Adoptive T-cell therapy compatibility. T-cells genetically engineered to express a T-cell receptor specific for the phosphoneoantigen can be combined with the phosphatase inhibitor, with the expectation that restoring antigen expression amplifies the therapeutic response.
• Quantified efficacy thresholds. Claims specify percentage increases in phosphoneoantigen expression and percentage reductions in phosphatase activity across a wide range, allowing the patent to cover a spectrum of clinical response magnitudes.

Who Is Behind It?

The applicant is The General Hospital Corporation, the legal entity of Massachusetts General Hospital in Boston, one of the leading academic medical centres and biomedical research institutions in the world. The named inventors are Mark Cobbold, Cyril Benes, and Feng Shi, researchers with backgrounds in tumour immunology and cancer biology. The Australian application is a divisional of AU 2019271297, indicating the underlying research dates from at least 2019. The Australian patent attorney is FPA Patent Attorneys Pty Ltd in Melbourne.

Why It Matters

Immune evasion through antigen downregulation is a well-recognised mechanism of resistance to both checkpoint immunotherapy and CAR-T cell therapy. A platform that restores antigen visibility, rather than simply blocking the brakes on a T-cell that cannot see its target, addresses a fundamental gap in cancer immunology. If the phosphoneoantigen hypothesis holds in clinical trials, phosphatase inhibition could become a pre-conditioning step before checkpoint blockade, potentially rescuing patients who are currently classified as checkpoint non-responders. For Australia, which has active clinical oncology research programmes and a substantial population receiving immunotherapy for melanoma, lung cancer, and other indications, this patent has both research and licensing relevance. The General Hospital Corporation is an active licensor of its IP portfolio through Partners HealthCare and its successors.

Related Concepts

This application sits within the field of tumour immunology, specifically the problem of antigen loss and immune evasion. Cancer cells frequently downregulate the surface markers that T-cells use to identify them, rendering checkpoint blockade and adoptive cell therapies less effective. Phosphatase inhibition as a strategy to restore these markers addresses the upstream cause of T-cell blindness rather than its downstream consequences.

The combination strategy described in this patent – pairing phosphatase inhibitors with checkpoint inhibitors, cytokines, and adoptive T-cell therapies – reflects a broader trend in oncology toward multimodal immunotherapy combinations, where each agent addresses a distinct barrier to effective anti-tumour immunity.

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AU 2026201823 was published in the Australian Official Journal of Patents on 2 April 2026 and is open for public inspection. Patent applications represent inventions that are sought to be protected and do not necessarily reflect commercially available products.