Genetic Engineering Publications - GEG Tech top picks

Researchers have reported promising results in a Phase I/II trial involving 37 patients with relapsed or refractory B-cell malignancies who were treated with a cord blood-derived natural killer (NK) chimeric antigen receptor (CAR), a cell therapy targeting CD19. Results showed an overall response (OR) rate of 48.6% 100 days after treatment, with one-year progression-free survival (PFS) and overall survival (OS) rates of 32% and 68%, respectively. The trial reported an excellent safety profile, with no cases of cytokine release syndrome (CRS), neurotoxicity or graft-versus-host disease. Another key finding of the trial was the importance of allogeneic cord blood donor selection criteria in the manufacture of CAR NK cells. Cord blood units cryopreserved within 24 hours of collection and those with a low content of nucleated red blood cells were associated with significantly better results. CAR NK cells generated from these units resulted in a one-year PFS rate of 69% and an OS rate of 94%, compared with 5% and 48%, respectively, for units with higher nucleated red cell content or longer collection to cryopreservation times. 

CAR T cells have shown some success in the clinic in treating certain cancers, such as relapsed leukemia. However, CAR T cells have not been successful in delivering solid tumors, in part because of problems with immune cell activation. Adding a molecular anchor to the key protein used to recognize cancer in cellular immunotherapies can make treatments much more effective. The researchers found that immune cells with the anchored protein increased cancer killing, regardless of their cell type or the type of cancer targeted. The concept of molecular anchoring is thus a new design for improving chimeric antigen receptor (CAR) based immunotherapies. Anchored CARs have increased survival in animal models of several tumor types, including lung, bone and brain cancers. CARs have shown promise in the clinic, but have not yet achieved widespread success in all tumor types. The findings were published in Nature Biotechnology.

Researchers have shown that a synthetic IL-9 receptor allows anti-cancer T cells to do their job without the need for chemo or radiation. T cells modified with the synthetic IL-9 receptor were potent against tumours in mice, as published in Nature. This group of researchers were interested in testing modified versions of the synthetic receptor that transmit other cytokine signals from the common gamma chain family: IL-4, -7, -9 and -21. Of the synthetic common gamma chain signals, the IL-9 signal was worth studying and unlike other cytokines, IL-9 signalling is not generally active in naturally ocurring T cells. The synthetic IL-9 signal gave the T cells a unique blend of stem cell and killer cell qualities that made them more robust in fighting tumours. In particular, the researchers targeted two types of difficult-to-treat cancer models in mice: pancreatic cancer and melanoma. They used T cells targeted to the cancer cells via the natural T cell receptor or a chimeric antigen receptor (CAR). In all cases, T cells engineered with synthetic IL-9 receptor signalling were superior and helped cure some tumours in mice when they could not do otherwise. 

CAR T-cell therapy and antibody treatments are two types of targeted immunotherapies that have revolutionized the fields of cancer care. However, there are still significant challenges in identifying cancer cell surface proteins as targets for immunotherapies. A research group at Lund University in Sweden is well on their way as they have developed a new precision medicine technology that allows for comprehensive mapping of the entire tumor cell surface antigen landscape in patients. The method developed by the research team, "Tumor Surfaceome Mapping, TS-MAP," allows direct analysis of all accessible tumor cell surface antigens in patient tumor tissue. In a close collaboration between neurosurgery, oncology and advanced proteomics in Lund, the researchers were able to identify several tumor cell surface antigens in fresh tissue from patients with aggressive brain tumors for which there is currently no effective treatment. An important advantage of the TS-MAP technology is that it provides a complete picture of the cell surface antigens displayed on the surface of the cancer cell, as well as information about specific cell surface antigens that have a high capacity to infiltrate cancer cells, and can destroy them from within. 

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.

Allogene Therapeutics develops allogeneic CAR T cell-based therapies for a range of hematological and solid cancers. Two candidates are being developed using Allogene's exclusive Allo CAR T platform : 

• - ALLO-316 is an AlloCAR T ™ anti-CD70 candidate in development for the treatment of renal cell carcinoma as well as several haematological cancers that express the CD70 cell surface antigen. CD52 is also disrupted in order to make CAR T cells resistant to this treatment. Allogene announced that the FDA has approved a phase 1 clinical trial in patients with advanced or metastatic renal cell carcinoma. This is the company's first clinical trial in solid tumours.  
• - ALLO-605 is a TurboCAR ™, under development for multiple myeloma, targeting B cell maturation antigen (BCMA), a cell surface protein universally expressed on malignant plasma cells. The company presented preclinical data that demonstrated improved cytokine secretion, polyfunctionality, improved in vitro serial killing activity, and improved anti-tumor activity and survival compared to CAR T cells targeting BCMA in a mouse model aggressive for multiple myeloma. Allogene revealed that it expects to file our first Investigational New Drug application for its new TurboCAR technology ™ in the first half of 2021. 

When cancer escapes the immune system, our defenses are rendered powerless and are unable to fight against the disease. Chimeric antigen receptor T cells (CAR T cells) represent a promising immunotherapy strategy, developed with the aim of tackling tumors head-on. But the occurrence of relapse in some patients remains a challenge. Scientists at the Institut Pasteur have identified the precise function of CAR T cells in a bid to optimize future therapies.

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.

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.

Solid tumors generate anti-immune signals that deactivate CAR T cells, making treatment less effective. To solve this problem, scientists have combined CAR T cells with cytokine injection, which can cause significant unintended toxicities. Researchers replaced the extracellular domain of various cytokine receptors with leucine zippers to create constitutively active receptors. CAR T cells expressing one of these chimeric cytokine receptors had superior antitumor activity against several types of cancer in cell lines and mouse models compared with conventional CAR T cells. Although chimeric cytokine receptors give a constant "on" signal to CAR T cells, they do not induce non-specific proliferation of CAR T cells. The system thus limits the effect of cytokine signaling to modified cells only, reduces the risk of cytokine-related toxicity, and provides a signal that these CAR T cells should function effectively in a suppressive tumor microenvironment. 

Currently, too few CAR T cells become memory cells that persist and create more T cells in the long term. However, a group of researchers recently showed that the distribution of the c-Myc protein in a parental T cell may be important for this process and published this work in the journal Nature. The researchers knew that a daughter cell with more c-Myc became an effector cell. In this study, the team found that the protein complex cBAF (canonical Brg1/Brg-associated factor) interacted with c-Myc. Daughter cells with high concentrations of cBAF and c-Myc became effector T cells. The cBAF binds certain regions of chromatin, proteins on DNA. The discovery suggests that it can guide the fate of cells, what type of T cells they become, by controlling the expression of effector cell-related genes. The distribution of cBAF occurs in the first activated T cell that begins the adaptive immune response; therefore, the researchers realized that cell fate is decided early in the immune response. The researchers used the molecular information they discovered. They applied a cBAF inhibitor during CAR T cell activation to generate more memory T cells. In a preclinical model, T cells treated with an inhibitor-controlled tumor growth better than untreated cells. The treated cells also survived longer and in greater numbers.

Genetically modified immune cells successfully target specific cancer cells that may be responsible for the relapse of acute myeloid leukemia (AML). In a study published on 28 April in Nature Communications, the researchers developed a CAR T cell therapy (UCART123) targeting CD123, which is found on leukemia stem cells and enables T cells to seek out and attack cancer cells. When the team tested the UCART123 cells in a mouse model of AML, they found that the therapy effectively eliminated leukemia cells and prolonged survival. The scientists also devised a highly sensitive monitoring strategy to detect any residual cancer cells and assess the persistence of UCART123 cells. Finally, they demonstrated that UCART123 cells have specificity against leukemia cells, with minimal toxicity to normal blood cells in mice. The preclinical results led to a Phase 1 clinical trial testing UCART123 in patients with relapsed/refractory AML at several sites across the US, including New York-Presbyterian/Weill Cornell Medical Center. The results of the preclinical study suggest that UCART123 cells are highly selective and specific in targeting AML. 

A collaborative study led by the Monash Biomedicine Discovery Institute has discovered a new immune checkpoint that could be exploited for cancer treatment. The study shows that by inhibiting the protein tyrosine phosphatase PTP1B in T cells, the body's immune response to cancer can be mobilized, helping to suppress tumor growth. Indeed, this study showed that using a new drug candidate, the abundance of PTP1B in tumor-infiltrating T cells is increased, limiting the ability of T cells to attack tumor cells and fight cancer. These findings identified PTP1B as an intracellular brake, or checkpoint, reminiscent of the PD-1 cell surface checkpoint whose blockade has revolutionized cancer treatment. Furthermore, beyond the improved response to PD-1 blockade, the authors showed that inhibition of PTP1B also significantly improved the efficacy of cell-based therapies using CAR T cells. The authors demonstrate that deletion or inhibition of PTP1B can significantly improve the ability of CAR T cells to attack solid tumors in mice, including breast cancer.  

Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer and has the lowest survival rate of all common cancers. Only about 7% of people diagnosed with this type of cancer in the UK survive their cancer for 5 years or more. However, a new protein called CEACAM7 has been identified by researchers at Queen Mary University. It could be a new therapeutic target for the treatment of PDAC which is the most common type of pancreatic cancer. In this study, the researchers developed a novel CAR T cell therapy using part of an anti-CEACAM7 antibody from Professor Brad Nelson (British Columbia, Canada). They then modified the killer T cells and presented on their surface this new CAR protein that recognizes and binds to CEACAM7, directing the killer T cells to kill only the cells with CEACAM7. Using this protein as a target, the researchers were able to create a CAR T cell therapy that killed pancreatic cancer cells in a pre-clinical model.  

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