Engineered Cells, T Cell Immune Modulating Antibodies and Methods for Using the Same Dual-Targeting CAR-T Cells That Secrete Immune Modulators for Triple-Negative Breast Cancer

This patent from the Dana-Farber Cancer Institute covers an advanced CAR-T cell platform in which engineered immune cells simultaneously carry a chimeric antigen receptor targeting two cancer cell antigens and express a secreted antibody that modulates the surrounding immune environment.

The Problem

Triple-negative breast cancer (TNBC) is one of the most aggressive and difficult-to-treat breast cancer subtypes, defined by the absence of estrogen receptor, progesterone receptor, and HER2 expression. Because these three receptors are the targets of the most effective breast cancer therapies, TNBC has no approved targeted treatments and relies on chemotherapy, which produces high rates of relapse and resistance. Immunotherapies including anti-PD-L1 checkpoint blockade have shown some benefit in TNBC, but response rates remain modest. CAR-T cell therapy, which has transformed treatment of some blood cancers, has struggled in solid tumours including breast cancer. Two of the core challenges are: antigen escape (tumours down-regulate or lose a single target antigen to escape single-target CAR-T cells) and the immunosuppressive tumour microenvironment, which inactivates T cells even after they successfully infiltrate the tumour. A CAR-T cell platform that addresses both simultaneously would represent a meaningful advance in solid tumour immunotherapy.

What This Invention Does

The Dana-Farber invention engineers T cells to carry two functional payloads. The first is a chimeric antigen receptor (CAR) with an antigen-recognition domain specific for two antigens simultaneously on the surface of cancer cells: C-X-C chemokine receptor type 4 (CXCR4) and Claudin-4, both of which are overexpressed in TNBC. The CAR uses single-chain variable fragments (scFvs) targeting each antigen, combined with signalling and co-stimulatory domains including CD28, 4-1BB, and CD3-zeta intracellular domains. Targeting two antigens reduces the probability of antigen escape, since the tumour would need to simultaneously lose both surface markers. The second payload is a polypeptide, such as a minibody or other antibody fragment, that is secreted by the engineered cell into the tumour microenvironment. The secreted antibody is designed to modulate the immune system locally, for example by blocking inhibitory checkpoint signals or engaging additional immune effectors. The combined system arms the T cell to find and attack the tumour while simultaneously remodelling the suppressive environment that would otherwise blunt its activity.

Key Features

• Dual-antigen CAR targeting CXCR4 and Claudin-4. Both targets are overexpressed in TNBC. Targeting two distinct antigens substantially reduces the probability that the tumour escapes by down-regulating a single surface marker, a key limitation of first-generation single-antigen CAR-T approaches.
• Secreted immune-modulating antibody. The engineered cell expresses and secretes an antibody or antibody fragment into the local tumour environment, providing an autonomous immune-modulatory function that operates in concert with the direct killing activity of the CAR-T cell.
• Flexible vector architecture. The CAR construct and the secreted antibody construct can be expressed from the same or different expression vectors within the same cell, allowing modularity in the engineering approach and potential optimisation of relative expression levels.
• Multiple antibody format options. The secreted polypeptide payload can take the form of monoclonal antibodies, bispecific antibodies, minibodies, scFvs, or multi-specific antibody fragments, giving design flexibility to address different immunosuppressive mechanisms in different tumour contexts.
• NIH-funded research origin. The invention was made with support from NIH Grant T32-CA207021, reflecting its academic research origin and the public investment in its development.

Who Is Behind It?

The applicant is Dana-Farber Cancer Institute, Inc., the Harvard Medical School-affiliated cancer research centre in Boston, one of the world’s leading institutions for cancer immunotherapy research. The named inventors are Wayne A. Marasco, Quan Karen Zhu, and Emily Kuiper. The application is a divisional of AU 2019235900, which claims priority from US Provisional Applications 62/643,040 (filed 14 March 2018) and 62/657,151 (filed 13 April 2018). The Australian patent attorney is Spruson and Ferguson in Sydney.

Why It Matters

Triple-negative breast cancer affects a disproportionate share of younger women and carries a worse prognosis than hormone-receptor-positive subtypes. In Australia, where breast cancer is the most commonly diagnosed cancer in women, TNBC represents a significant unmet clinical need. A CAR-T cell approach that addresses the two principal mechanisms of failure in solid tumour immunotherapy — antigen escape and immunosuppressive microenvironment — would mark a meaningful step beyond current checkpoint inhibitor combinations. Dana-Farber’s dual-payload engineering platform is at the frontier of the next generation of adoptive cell therapies, and this Australian patent positions the Institute’s IP for licensing to commercial cell therapy developers operating in the Australian and Asia-Pacific markets. The CXCR4/Claudin-4 dual-targeting design is also potentially applicable beyond TNBC to other tumour types that overexpress these markers, broadening the commercial scope of the technology.

Related Concepts

This invention sits at the intersection of CAR-T cell therapy and antibody engineering. CAR-T approaches have transformed outcomes in blood cancers, but solid tumours present additional barriers – notably antigen escape and the immunosuppressive tumour microenvironment – that Dana-Farber’s dual-payload design explicitly targets.

The triple-negative breast cancer subtype targeted here is defined by the absence of oestrogen receptor, progesterone receptor, and HER2 expression, leaving chemotherapy as the primary systemic option. Next-generation platforms that combine dual antigen targeting with local immune modulation represent a significant step toward effective solid tumour immunotherapy.

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AU 2026201842 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.