Immunotherapy

Eradication of systemic B-cell tumors by genetically targeted human T lymphocytes co-stimulated by CD80 and interleukin-15. Brentjens, R.J. et al. Nature Med. 3, 279–286 (2003)

T cells have been engineered to recognize specific tumour antigens, but co-stimulatory signals are needed to activate their cytolytic activity, localize them to tumours and prevent apoptosis. Brentjens et al. generated mouse autologous T cells that recognized a B-cell leukaemia antigen, and activated the cells, ex vivo, with modified antigen-presenting cells. They showed that these T cells migrated to the bone marrow of mice and eradicated established B-cell tumours. Using a similar approach, the authors transduced human autologous T cells and showed that they were able to destroy tumour cells in patients with chronic lymphocytic leukaemia.

Early Detection

Inactivation of hMLH1 and hMSH2 by promoter methylation in primary non-small cell lung tumours and matched sputum samples. Wang, Y.-C. et al. J. Clin. Invest. 111, 887–895 (2003)

Wang et al. performed a genetic and epigenetic analysis of 77 resected primary non-small-cell lung tumours, and found that 70% had lost expression of the mismatch-repair genes hMLH1 or hMSH2. Promoter methylation of hMLH1 occurred in 56% of tumours, and seemed to be the main mechanism of gene deregulation. This methylation pattern was detected in sputum samples, making it a potential diagnostic marker for lung cancer.

Tumour Supressors

Mutated APC and Asef are involved in the migration of colorectal tumour cells. Kawasaki, Y. et al. Nature Cell Biol. 5, 211–215 (2003)

The adenomatous polyposis coli (APC) tumour suppressor has many functions, including signal transduction and cytoskeletal organization. Kawasaki et al. examined the interaction of APC with the RAC-specific guanine nucleotide exchange factor, ASEF, and showed that truncated APC stimulates ASEF-mediated activities, such as motility and E-cadherin-associated cell adhesion.

Vascular leak syndrome

Genetic engineering of an immunotoxin to eliminate pulmonary vascular leak in mice. Smallshaw, J. E. et al. Nature Biotechnol. 10 Mar 2003 (doi:10.1038/nbt800)

Vascular leak system (VLS) is often a dose-limiting side effect of immunotoxins and cytokines used to treat relapsed lymphoma or myeloma. The authors previously identified a disintegrin-like amino-acid motif common to both these biological therapies. Smallshaw et al. have now mutated this motif in a ricin toxin A chain immunotoxin, and have shown that it is more effective than the non-mutated toxin but did not cause VLS in mouse models.