Emerging pipeline in solid tumor cancers
ACTR707 + Trastuzumab for HER2+ Cancers
ACTR707 was identified through a comprehensive high-throughput screening effort aimed at identifying constructs with properties that may function particularly well in a solid tumor setting (including increased proliferation, cytokine secretion, and persistence). Our first solid tumor program is ACTR707 used in combination with trastuzumab for the treatment of patients with cancers that overexpress HER2. Trastuzumab is a humanized monoclonal antibody that targets the HER2 cell surface receptor, and is currently approved to treat HER2+ breast cancers and HER2+ gastric cancers alone and in combination with chemotherapy. While HER2 is overexpressed in a subset of breast and gastric cancers, it is found at low levels on certain essential tissues within the body. In preclinical studies, we have shown antigen-specific killing of HER2-overexpressing cell lines with ACTR707 used in combination with trastuzumab, without observing cytotoxic effects in normal cells expressing low amounts of HER2.
We are currently testing the safety, tolerability, and anti-tumor activity of ACTR707 used in combination with trastuzumab in a Phase 1, multi-center, open-label clinical trial called ATTCK-34-01.
>> Learn more at clinicaltrials.gov
GPC3+ Solid Tumor Cancers
BOXR1030 is the first product candidate from the BOXR platform and is currently in preclinical development. BOXR1030 is engineered to specifically target tumor cells expressing an oncofetal antigen called glypican-3, also known as GPC3. This antigen is expressed in several solid tumor indications, including hepatocellular carcinoma and squamous cell lung cancer. A characteristic of these particular solid tumors is their enhanced metabolic activity, leading to depletion of free nutrients, like glucose, from their local environment. Nutrient competition within tumor microenvironments is a form of immune suppression, and can limit the ability of T cells to kill, proliferate, and exert anti-tumor activity.
In addition to GPC3 targeting, BOXR1030 contains the novel “bolt-on” enzyme called glutamic-oxaloacetic transaminase 2 (GOT2) that aims to improve intrinsic T cell function in the solid tumor microenvironment through enhanced metabolism. GOT2 plays a central metabolic role by linking multiple pathways involved in biosynthesis and cellular energy production. In our preclinical studies representing the immunosuppressive tumor microenvironment, GOT2 displayed pleiotropic effects on BOXR1030 T cells, dramatically improving anti-tumor activity beyond that achieved with traditional CAR-T cells.
Non-Hodgkin Lymphoma (NHL)
ACTR707 + rituximab
Antibody-Coupled T Cell Receptor (ACTR) is a single construct that we believe can be used in combination with a wide variety of tumor-targeting antibodies to pursue different antigens and cancer indications. ACTR leverages CD16, a receptor normally found on natural killer cells, to recognize a wide range of tumor cell-bound antibodies and drive cytotoxic T cell attack. Unlike CAR-T, in which a new synthetic receptor has to be created, manufactured, and tested for each new antigen, ACTR relies upon this same CD16 binding irrespective of tumor antigen or co-administered antibody. As a result, our ACTR construct needs to be engineered, manufactured, and preclinically validated only once, allowing for leverage across many ACTR-antibody combinations and enabling rapid expansion of our product candidate pipeline.
ACTR707 is a modified ACTR construct comprising the ectodomain of CD16 and a costimulatory domain (CD28). We are currently testing ACTR707 in a Phase 1 multi-center, open label clinical trial, ATTCK-20-03, in combination with rituximab, in patients with relapsed or refractory non-Hodgkin lymphoma.
>> Learn more at clinicaltrials.gov
BOXR Preclinical Solid Tumor Pipeline
Unum's BOXR platform was established over two years ago with the aim of discovering novel “bolt-on” transgenes that can be co-expressed with chimeric-targeting receptors to improve the function of T cells in the solid tumor microenvironment. Unum’s BOXR discovery capabilities broadly evaluate T cell phenotype through a rigorous, multi-stage screening strategy that simulates the tumor microenvironment. Unum has discovered and continues to enrich a library of master regulatory genes of T cell biology that regulate pathways essential for cell growth, proliferation, and survival under a variety of conditions. BOXR bolt-on transgenes identified in this platform can address a variety of immunosuppressive mechanisms of solid tumors, including metabolic competition, immune suppressor cells, and exhaustion due to chronic stimulation. Once discovered, BOXR transgenes may be incorporated into several different types of therapeutic T cells, including both ACTR T cells and CAR-T cells, to impart new functionality to T cells. BOXR platform objectives include expanding the scope of biological mechanisms and transgenes in its proprietary BOXR library, enabling BOXR bolt-on applications for a broad range of immune cell therapies, including both autologous and allogeneic approaches, and advancing new BOXR product candidates into the clinic.
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