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Cell therapy landscape: Recent treatment advances and challenges

The first generation of cellular therapies, namely autologous CAR T-cell therapies, represent a new approach to providing cures in some patients for some of the most difficult-to-treat cancers, such as acute lymphoblastic leukemia and diffuse large B-cell lymphoma. These therapies have multiple challenges, however, including significant toxicity, limited effectiveness in solid tumors, a complex supply chain and difficulty in the scale up of manufacturing, but they illustrate the potential to use a cell as a medicine.

Rubius Therapeutics is developing a novel cell therapy platform by genetically engineering red blood cells to create an entirely new class of allogeneic cellular medicines, called Red Cell Therapeutics™. These Red Cell Therapeutics are designed to activate and expand the immune system to fight cancer by expressing co-stimulatory molecules and cytokines on the cell surface.

Activation of the immune system in patients with refractory cancers has proven effective in some settings with the development of checkpoint inhibitors. Taking a similar approach, immune agonists hold promise in oncology, however, the clinical development of these agents has been limited by both severe toxicity and low efficacy, leading to a narrow therapeutic window.

The RED PLATFORM®: Universal and reproducible process, scalable manufacturing

Rubius’ proprietary RED PLATFORM® was developed to harness both the unique properties of red blood cells and the creative potential of genetic engineering — utilizing cellular therapy to realize the promise of immune agonists. Red blood cells lack a nucleus, are unable to divide and have a biodistribution limited to the blood vessels and spleen. Together these properties can limit the toxicities generally associated with other immune boosting therapies in cancer.

Rubius Therapeutics uses donor-derived precursor cells that can give rise to any type of cell in the blood. The cells are genetically engineered using lentiviral vectors to insert genes that, in turn, produce therapeutic proteins. For every product candidate Rubius produces, the discovery and manufacturing process is the same. By modifying the initial manufacturing steps in which a gene or genes are added that encode biotherapeutic proteins within the cell or on the cell surface, Rubius is able to rapidly develop new Red Cell Therapeutics, resulting in a modular, reproducible platform across a number of potential therapeutic areas.

Realizing the potential of immune agonists through broad stimulation of innate and adaptive immunity

Stimulating, or boosting, the natural defenses of the immune system has been shown to be an effective way to treat cancer. Rubius Therapeutics is developing two distinct approaches to treat cancer by leveraging the immune system — first, through broad immune stimulation by combining agonist pathways, and second, through a more direct approach, called antigen-specific stimulation, which is designed to instruct the immune system to target specific types of cancer.

In the first approach, Red Cell Therapeutics are engineered to express combinations of co-stimulatory molecules and cytokines on the cell surface and are designed to activate and expand a patient’s NK and T cells to mount an anti-tumor immune response against the cancer. This approach has the potential to be an effective way to treat cancer and overcome resistance to existing immunotherapies.

Rubius’ lead oncology product candidate, RTX-240, is engineered to express the costimulatory molecule 4-1BB ligand (4-1BBL) and the trans-presented cytokine IL-15 (IL-15TP) on the surface of the red blood cell in their native forms. Because red blood cells are restricted to the vasculature and spleen, RTX-240 may have fewer side effects as observed with other agonist antibodies and recombinant cytokines that cause liver toxicity, potentially leading to a broad therapeutic window. RTX-240 is being evaluated in a Phase 1/2 clinical trial for the treatment of patients with advanced solid tumors and a second Phase 1 arm in relapsed/refractory acute myeloid leukemia. Rubius expects to present clinical results from the solid tumor Phase 1 study in early 2021.

Unlocking the potential of antigen-specific immunotherapy

With Rubius’ second approach to treating cancer, its Red Cell Therapeutics are engineered as artificial antigen-presenting cells, or aAPCs, and express specific tumor-related proteins to stimulate an immune response, known as tumor antigens, on the cell’s surface. These cell surface-bound antigens are designed to instruct only those cells of the immune system that have the ability to recognize and attack the tumor.

Rubius’ lead aAPC product candidate, RTX-321, is engineered to expresses a human papillomavirus (HPV) peptide antigen bound to major histocompatibility complex class I proteins, the costimulatory molecule 4-1BBL and the cytokine IL-12 on the cell surface to mimic human T cell-APC interactions. Based on preclinical data, RTX-321 is expected to have a dual mechanism of action by functioning as an aAPC to boost HPV 16 E7-specific CD8+ T cell responses and promote broad immune stimulation of both innate and adaptive immune responses. Rubius is currently screening patients in a Phase 1 clinical trial of RTX-321 in HLA-A*02:01 positive patients with advanced HPV 16-positive cancers, including cervical cancer, head and neck cancer and anal cancer.

Rubius Therapeutics also has earlier-stage programs in cancer and autoimmune diseases with a preclinical program in Type I diabetes. To learn more, visit