Genetic Engineering Publications - GEG Tech top picks

CAR T cells have become an established treatment option for children with a rare form of relapsed or incurable leukemia. One of the key factors determining whether treatment will lead to lasting remission of leukemia is how long the CAR T cells live in the body. One team was able to study the cells of 10 children enrolled in a pioneering clinical trial (CARPALL) for up to five years after their initial CAR T cell treatment. This has enabled them to better understand why some of these CAR T cells remain in a patient's bloodstream, and why others disappear early, potentially allowing the cancer to recur. Using techniques that analyze individual cells at the genetic level to understand what they do, the scientists were able to identify a unique "signature" in long-lived CAR T cells. The signature suggested that long-lived CAR T cells in the blood transformed into a different state that allowed them to continue monitoring the patient's body for cancer cells. As part of the study, the researchers identified key genes in CAR T cells that appeared to enable them to persist in the body for a long time. These genes will provide a starting point for future studies to identify markers of persistence in CAR T-cell products as they are manufactured, and ultimately to improve their efficacy.

Many people are excluded from CAR T cell-based treatments because of its cost. One reason for the high cost is that the manufacturing process is complex, time-consuming and must be individually tailored to each cancer patient. So to address this challenge, the researchers created a biotechnology called Multifunctional Alginate Scaffolds for T cell Engineering and Release (MASTER) that is a biocompatible sponge-like material. To begin treatment, the researchers isolate the patient's T cells and mix these naive T cells with the modified virus. The researchers pour this mixture onto MASTER, which absorbs it. MASTER is decorated with the antibodies that activate the T cells, so the cell activation process begins almost immediately. Meanwhile, MASTER is surgically implanted into the patient. After implantation, as the T cells become activated, they begin to respond to the modified viruses, which reprogram them into CAR-T cells. MASTER is also imbued with interleukin factors that promote cell proliferation. After implantation, these interleukins begin to leach out, promoting rapid proliferation of CAR-T cells. In a proof-of-concept study involving lymphoma in mice, researchers found that this treatment was faster and more effective than conventional CAR-T cell cancer treatment. 

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.

The immunosuppressive nature of tumor microenvironment is considered one of the key factors limiting CAR-T efficacy. One negative regulator of Tcell activity is lymphocyte activation gene-3 (LAG-3). In this study, scientists successfully generated LAG-3 knockout Tand CAR-T cells with high efficiency using CRISPR-Cas9 mediated gene editing and found that the viability and immune phenotype were not dramatically changed during in vitro culture. LAG-3 knockout CAR-T cells displayed robust antigen-specific antitumor activity in cell culture and in murine xenograft model, which is comparable to standard CAR-T cells. This study demonstrates an efficient approach to silence immune checkpoint in CAR-T cells via gene editing.

Researchers have developed a universal receptor system that allows T cells to recognize any cell surface target, enabling highly customizable CAR T cell and other immunotherapies for treating cancer and other diseases. The new approach involves engineering T cells with receptors bearing a universal "SNAPtag" that fuses with antibodies targeting different proteins. By tweaking the type or dose of these antibodies, treatments could be tailored for optimal immune responses. The researchers showed that their SNAP approach works in two important receptors: CAR receptors, a synthetic T cell receptor that coordinates a suite of immune responses, and SynNotch, a synthetic receptor that can be programmed to activate just about any gene. In a mouse model of cancer, treatment with SNAP-CAR T cells shrunk tumors and greatly prolonged survival, an important proof-of-concept that sets the stage to test this approach in clinical trials in partnership with Coeptis Therapeutics, which has licensed the SNAP-CAR technology from Pitt. The discovery could extend into solid tumors and give more patients access to the game-changing results CAR T cell therapy has produced in certain blood cancers. With the addition of SNAP, the possibilities for customized therapies become almost endless.

Researchers at Seidman Cancer Center and Case Western Reserve University Hospitals have developed a new approach to CAR T cell therapy for B-cell cancers that triples targeted antigens on cancer cells. This approach promises to significantly reduce the potential for antigen escape currently found in CAR T therapies that target only CD19. The novel B-cell activating factor (BAFF) CAR T product developed here specifically binds to each of three receptors instead of one - BAFF-R, BCMA and TACI, providing more therapeutic options. At least two of these three receptors are found in almost all B-cell cancers, with some cancers expressing all three. Experimental results reported in Nature Communications show that BAFF CAR T is effective in killing several B-cell cancers. In addition, studies show robust in vitro and in vivo cytotoxicity exerted by CAR T BAFFs against mantle cell lymphoma, multiple myeloma, and mouse xenograft models of acute lymphoblastic leukemia. An Investigational New Drug application with the U.S. Food and Drug Administration will be filed in the coming weeks with Luminary Therapeutics and the team plans to initiate a clinical trial of BAFF CAR T therapy in patients with non-Hodgkin's lymphoma within the next few months. 

The "T-Cell Immunotherapy Market, 2018-2030 (3rd edition)" report features an extensive study of the current market landscape and the future potential of T-cell immunotherapies (focusing particularly on CAR-T therapies, TCR therapies and TIL therapies). One of the key objectives of the study was to review and quantify the future opportunities associated with the ongoing development programs of both small and big pharmaceutical firms.

Here scientists show that directing a CD19-specific CAR to the T-cell receptor α constant (TRAC) locus not only results in uniform CAR expression in human peripheral blood T cells, but also enhances T-cell potency, with edited cells vastly outperforming conventionally generated CAR T cells in a mouse model of acute lymphoblastic leukaemia.

In this study, the scientists evaluated a human application of T cells that were genetically modified using the Sleeping Beauty (SB) transposon/transposase system to express a CD19-specific CAR. They found that SB-mediated genetic transposition and stimulation resulted in 2,200- to 2,500-fold ex vivo expansion of genetically modified T cells, with 84% CAR expression, and without integration hotspots. Despite a low antigen burden and unsupportive recipient cytokine environment, CAR T cells persisted for an average of 201 days for autologous recipients and 51 days for allogeneic recipients. These results support further clinical development of this nonviral gene therapy approach.

In the report Kochenderfer et al discuss the efficacy of autologous T cells expressing a CD19-specific chimeric antigen receptor (CAR) in patients with relapsed diffuse large B-cell lymphoma.