Genetic Engineering Publications - GEG Tech top picks

Graft-versus-host disease occurs when a donor's cells attack the recipient's tissues, usually following a bone marrow or stem cell transplant. In a recent study, a new technique involving the combination of Chimeric Antigen Receptors (CARs) with Mesenchymal Stromal Cells (MSCs), resulting in modified stem cells known as CAR-MSCs, was used to specifically target a protein linked to graft-versus-host disease, but also to inflammatory bowel diseases such as ulcerative colitis and Crohn's disease. In mouse models, when stimulated by the specific protein for which they were designed, CAR-MSCs showed an enhanced ability to reach the inflamed area, better control inflammation and improve outcome and survival. This was mediated by a change in the genetic signature of CAR-MSCs, the proteins they released and receptor expression. These preliminary results pave the way for future applications of this technology, paving the way for improving the versatility of the therapy to treat various diseases across the autoimmune spectrum.

The network of blood vessels in the tumour microenvironment remains one of the most difficult blockages for cell therapies to penetrate and treat solid tumours. However, a new study published in Nature Cancer explains that researchers at Penn Medicine found that combining CAR T cell therapy with a PAK4 inhibitor drug allowed modified cells to work their way through and attack the tumour, leading to significantly improved survival in mice. The genetic reprogramming of tumour endothelial cells lining the walls of blood vessels is caused by an enzyme known as PAK4. Penn's team discovered that PAK4 inhibition reduces abnormal tumour vascularization and improves T cell infiltration and CAR T cell immunotherapies in mouse models of glioblastoma. An experiment with T-RCA cell therapy led by EGFRvIII and a PAK4 inhibitor showed a nearly 80 percent reduction in tumour growth compared to mice that received CAR T cell therapy only five days after infusion. The targeting of PAK4 may therefore provide a unique opportunity to recondition the tumour microenvironment and improve T-cell-based cancer immunotherapy for solid tumours.   

The researchers report a first-in-human phase I clinical trial to test the safety and feasibility of multiplex CRISPR-Cas9 editing to engineer T cells in three patients with refractory cancer. Two genes encoding the endogenous T cell receptor (TCR) chains, TCRα (TRAC) and TCRβ (TRBC) were deleted in T cells to reduce TCR mispairing and to enhance the expression of a synthetic, cancer-specific TCR transgene (NY-ESO-1). Removal of a third gene encoding PD-1 (PDCD1), was performed to improve anti-tumor immunity. Adoptive transfer of engineered T cells into patients resulted in durable engraftment with edits at all three genomic loci. Though chromosomal translocations were detected, the frequency decreased over time. Modified T cells persisted for up to 9 months suggesting that immunogenicity is minimal under these conditions and demonstrating the feasibility of CRISPR gene-editing for cancer immunotherapy.

Three studies reveal that the presence in tumours of two key immune components — B cells and tertiary lymphoid structures — is associated with favourable outcomes when individuals undergo immunotherapy.

Mass General investigators have created a new method that could make immune therapy more effective again brain tumors and expand its use against other types of solid tumors.

Their study is published in the journal Nature Biotechnology.

For 17 years, Thomas Blankenstein has been working on his Berlin-based start-up T-knife and is finally going to be able to test his T-cell receptor (TCR) cancer immunotherapy. To make this immunotherapy, they replaced the TCR genes of a mouse with those of a human and inserted genes to encompass both the human TCR repertoire and human major histocompatibility complex (MHC) molecules. They eliminated genes from related mice, generating mouse lines carrying human genes, and then subjected them to a succession of crosses to bring all the genes together in a single mouse, the HuTCR mouse. Designing transgenic mice with such efficient humanized TCRs has been very difficult and laborious. However, TCR-T cells are capable of more extensive signaling and killing than CAR-T cells. The engineered TCRs integrate seamlessly into the signal transduction pathways of T cells: there are ten subunits in a TCR versus one subunit in a CAR, they have ten immunoreceptor tyrosine activation motifs versus three in a CAR, and they are associated with more co-stimulatory receptors: CD3, CD4, CD2. In addition, unlike CARs that only bind to antigens on the cell surface, TCRs can target intracellular as well as extracellular tumor antigens.

Treatments based on immunotherapy give hope to many people with cancer that they will finally be cured. However, some treatments can be very expensive, have side effects, or may only work on a small number of people. That's why researchers at the University of Chicago's Pritzer School of Molecular Engineering have developed a new therapeutic vaccine using a patient's own tumor cells that have been modified to secrete vascular endothelial growth factor and then irradiated so that the cells are dead before being reinjected. This vaccine would therefore train the patient's immune system to detect and eradicate cancer because, according to clinical trials, it stops the growth of melanoma tumors in mouse models. In addition, an immunological memory is set up thanks to the vaccine and leads to long-term effects because the vaccine would destroy the appearance of new tumor cells 10 months after the injection. The injection of the vaccine is done like a traditional vaccine. The advantages of this vaccine are that it would be more effective, less expensive and much safer.

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.

Researchers at Cardiff University have discovered a new type of killer T-cell that offers hope of a “one-size-fits-all” cancer therapy.

The study was published in Nature Immunology.

https://www.nature.com/articles/s41590-019-0578-8

Cellectis established a preclinical proof-of-concept for its new CAR T therapy in a study published in Nature Communications. 

A team of researchers from the University of Pennsylvania have received the go-ahead from a US National Institutes of Health (NIH) panel for the first test that proposes using CRISPR gene editing technology in humans to treat cancer. The NIH's Recombinant DNA Advisory Committee delivered a positive recommendation for the study, which proposes to combine gene editing and immunotherapy. If the US Food and Drug Administration (FDA) approves the trial, it will become the first to involve CRISPR–Cas9 technology in human trials. The study will be funded by the Parker Institute for Cancer Immunotherapy, established with a $250 million gift from internet billionaire Sean Parker (Nat. Biotechnol. 34, 583, 2016). The institute's president and CEO Jeffrey Bluestone said that the study protocol, entitled “Phase 1 Trial of Autologous T Cells Engineered to Express NY-ESO-1 TCR and Gene Edited to Eliminate Endogenous TCR and PD-1,” will enroll 18 people with melanoma, myeloma and sarcoma at Penn's Abramson Cancer Center, MD Anderson Cancer Center in Houston, and the University of California, San Francisco. The protocol will entail removing a subject's T cells and re-infusing them a month later after genetic alterations have been made—including one that makes the cells responsive to PD-1, which some cancers use to evade the immune system. The idea is to enhance the T cells' function while reducing the risk of autoimmunity. Before enrollment can begin, the FDA must give its approval.