Genetic Engineering Publications - GEG Tech top picks

The race to the clinic is reviving for a ready-made alternative to autologous CAR-T cell therapy, even as concerns about chromosomal abnormalities persist. The Advanced Regenerative Medicine Therapy designation, which makes the therapy eligible for accelerated approval, will also help remove a veil that has hung over standard CAR-T cell therapies since October, when the FDA put all trials of competitor Allogene Therapeutics on hold following the detection of a chromosomal abnormality in a patient who received ALLO-501A in a Phase 2 trial. The FDA's green light for CRISPR Therapeutics dispels broader concerns that the agency views this type of genotoxic safety event as an intractable problem for the entire class of allogeneic CAR-T therapies. Today, many companies are eliminating loci associated with the MHC-I to avoid host T cell recognition of transplanted CAR-T cells. Companies also equip their T cells with a variety of safety switches and performance enhancers.

However, as the complexity of the assembly increases, the risk of off-target effects also increases. This may be important from a safety perspective, given that most cancers lack unique antigens. Achieving rapid remission and re-dosing if necessary, can minimize the toxic effects that CAR-T cells can have on healthy tissues expressing the targeted antigen.

Currently, most people with cancer could be treated with CAR T cell therapy but they don't benefit from it. The main reason is that this treatment is difficult to produce. The average delay between donation and receipt of therapy is more than three weeks. For people with rapidly proliferating diseases, such as acute leukemia, this may be too long to wait. The current technique requires a person's own cells, but the use of cells from healthy donors could allow more people to benefit. However, donor T cells can identify the body of the person receiving the treatment as foreign and attack it, triggering Graft-Versus-Host Disease, which can be fatal, or the foreign T cells can be eliminated by the person's immune system before they can attack the cancer. To counter these problems, biotech company Allogene Therapeutics of southern San Francisco, California, has genetically engineered T-cells to remove a protein known as CD52 from their surfaces. Antibodies that help destroy the cells that carry the surface protein are then administered to the person, depleting his or her own white blood cells that could otherwise kill the modified CAR T cells. And to protect against GVHD, the T-cell receptor on the modified cells can be altered, preventing them from attacking the person's own cells.