Genetic Engineering Publications - GEG Tech top picks

Researchers have bolstered the power of chimeric antigen receptor (CAR)-T cancer therapies, which use genetically altered T cells to seek out tumours and mark them for destruction. Now scientists have further engineered the cells to contain switches that allow control over when and where the cells are active. This helps them to infiltrate tumours and dodge immune-suppressing defences.

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. 

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. 

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.

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

A humanized chimeric antigen receptor (CAR) T-cell immunotherapy was seen successfully kill tumor cells and prevent further spread of colorectal metastatic cancer in mouse models of the disease.

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.  

Senescence is a hallmark of cellular ageing and contributes to many diseases. A new method enabling immune cells to target senescent cells might offer improved therapeutic options.

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

EMBL scientists have developed a new variant of the Sleeping Beauty transposase which could be used for genome engineering of stem cells and therapeutic T cells. As such it is extremely valuable for use in regenerative medicine and cancer immunotherapy. The underlying genome engineering procedures will in the future also reduce costs and improve the safety of genome modifications.

https://www.nature.com/articles/s41587-019-0291-z

A chimeric antigen receptor system that can integrate signals from multiple antigens
and fine-tune T cell activation in a cell-type-specific manner holds promise for enhancing
the safety and specificity of CAR T cell therapies for cancer treatment.