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Researchers from Cellectis investigate how external signals in the tumor microenvironment could control the cell-surface expression and specificity of engineered CARs.
Beyond challenges related to expansion and persistence of T-cell therapies, there are also challenges related to overall toxicity, specificity, and safety of T-cell therapies. Advances have been made to arm T-cell therapies with suicide switches or marker genes to prevent on-target, off-tumor activity. Bispecific T-cells, which often have an inhibitory CAR recognizing antigens on normal tissues and an activating CAR to recognize tumor antigens, are also in development.
A new, locally effective CAR-T construct was the focus of a
published on Jan. 23, 2017 in Scientific Reports. Researchers from Cellectis engineered T cells to respond to variation in oxygen levels, enabling the immune cells to remain inactive in normoxic conditions and become active in low-oxygen (hypoxic) settings, such as the conditions that are characteristic of the tumor microenvironment.
The cells were created to contain an oxygen-sensitive subdomain of hypoxia-inducible factors 1-alpha (HIF1α), a protein that degrades in normal oxygen environments and stabilizes (i.e., becomes active) in the presence of low oxygen levels. The subdomain acts as a sensor to control T-cell response, making the construct safer to normal tissues. Thus, the construct’s cytolytic ability is directly tied to level of oxygen in the local environment.
Although off-the-shelf, gene-edited chimeric antigen receptor T-cell therapies (CAR-T therapies) are ideal for the manufacture of cell therapies at large scale, and are associated with a lower risk of graft-versus-host disease in patients upon adoptive transfer, there hasn’t been much action on the regulatory front for these universal cell therapies-until now. Cellectis
that an investigational new drug application (IND) for its T-cell candidate targeting CD123 was filed with FDA, and according to the company, it is the first allogeneic CAR-T being investigated in human clinical applications in the United States.
The universal CAR-T (UCART) UCART123 will enter into Phase I trials during the first part of 2017. Cellectis will test the agent’s efficacy to target CD123, the membrane biomarker that is typically overexpressed on the cells of patients with acute myeloid leukemia (AML), blastic plasmacytoid dendritic cell neoplasm (BPDCN), and other hematologic malignancies.
Sources: Scientific Reports, Cellectis