Genetic Engineering Publications - GEG Tech top picks

Glioblastoma (GBM) is the most common and aggressive type of cancerous brain tumor in adults. People with GBM generally expect to live 12 to 18 months after diagnosis. Despite decades of research, there is no known cure for GBM, and treatments have only a limited effect on extending an individual's life expectancy. However, researchers have tested a technology that delivers CAR-T cells targeting two proteins commonly found in brain tumors: epidermal growth factor receptor (EGFR), estimated to be present in 60% of all GBMs, and interleukin-13 receptor alpha 2 (IL13Rα2), which is expressed in over 75% of GBMs. While CAR-T cell therapy for blood cancers is usually administered intravenously, the researchers administered these dual-targeted CAR-T cells intrathecally, by injection into the cerebrospinal fluid, so that the modified cells could reach the tumors more directly in the brain. Magnetic Resonance Imaging scans taken 24 to 48 hours after administration of dual-targeted CAR-T cells targeting EGFR and IL13Rα2 revealed a reduction in tumor size in all six patients, and these reductions were maintained up to several months later in a subgroup of patients. 

Immunotherapy, particularly CAR T-Cell cancer therapy, extends the lives of many patients. But sometimes the therapy randomly migrates to places it shouldn't go, sneaking into the lungs or other non-cancerous tissue and causing toxic side effects. However, a team of researchers has discovered the molecule responsible for guiding T cells to tumors, setting the stage for scientists to improve the revolutionary treatment. Their discovery of the crucial migration control gene that expresses ST3GAL1 is the result of "unbiased genomic screening": researchers used a state-of-the-art CRISPR technique to edit thousands of genes expressed in T cells, then tested the migration control capabilities of these genes, one by one over a period of nearly four years, in mouse models. The next step is to find a drug that can manipulate the key T cell protein, ST3GAL1. If the study progresses as planned, such a drug could be added to the CAR T-cell regimen to ensure that the T cells reach their targets

In the new study, Dr. Sykulev and colleagues in Takami Sato's lab engineered CAR-T cells to recognize an antigen on melanoma cells called high molecular weight melanoma-associated antigen (HMW-MAA). Melanoma cells express varying amounts of HMW-MAA on their cell surfaces. In their research, the researchers evaluated the extent to which CAR-T cells killed melanoma cells. They found that CAR-T cells effectively killed melanoma cells expressing high levels of HMW-MAA, but not those with lower levels of the antigen. The researchers then tested how well another type of immunotherapy, known as TCR-T cells that uses T cells engineered to express a specific T-cell receptor, killed the target cells. When the researchers treated melanoma cells with TCR-T cells, they found that the treatment readily killed tumor cells, even in melanoma cell lines that expressed far less HMW-MAA antigens than needed for CAR-T. The comparison thus revealed that TCR-T is superior to CAR-T therapy for melanoma.

Axi-cel CAR T therapy targets the CD19 molecule on large B-cell lymphoma cells. The ZUMA-7 trial demonstrated that axi-cel reduced the risk of disease progression, need for retreatment or death by 60% compared with standard therapy. Despite these positive results in terms of event-free survival and overall survival, some patients did not respond well to treatment or relapsed rapidly after treatment. Researchers analyzed tumor gene expression patterns from patient samples and determined that a B-cell gene expression signature and CD19 protein expression were significantly associated with improved event-free survival for patients treated with axi-cel but not with standard therapy. Patients with lower tumor cell levels of CD19 showed gene expression patterns associated with immunosuppression. These observations suggest that the tumor immune environment may play an important role in regulating axi-cel treatment and outcome. Furthermore, biomarkers associated with improved axi-cel treatment outcomes decreased as patients received more treatments, suggesting that receiving axi-cel as part of earlier treatment lines is essential to ensure better patient outcomes.

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.

According to Jing Pan's article in the Journal of Clinical Oncology titled: Donor-derived CD7 chimeric antigen receptor T cells for T-cell acute lymphoblastic leukemia: first-in-human phase I trial, CAR T cells are reported to be remarkably effective in patients with B-cell acute lymphoblastic leukemia (ALL) but have not been successful to date in patients with T-cell ALL (T-ALL). Now, data from Pan and colleagues demonstrate the safety and impressive short-term efficacy of allogeneic donor-derived anti-CD7 CAR T cells in an early phase clinical trial involving patients with relapsed and/or refractory T-ALL.