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June 19, 2011

New approach to cancer vaccines proves successful for curing prostate cancer in mice

(a) Prostate weights of mice injected intraprostatically with PBS, VSV-GFP or ASEL, 2 or 10 d after injection (n = 3). (b–d) Histology of prostates 10 d after intraprostatic injection of PBS (b) or ASEL (c,d). Scale bars, 100 μm

University of Leeds researchers, funded by Cancer Research UK, have used a library of DNA to create a vaccine that could be used to treat cancer, according to a study published in Nature Medicine.

Before now, 'gene therapy' vaccines have often delivered just one gene to stimulate the immune system. It produces a protein, called an antigen, which activates the immune system to destroy cancer cells.

Nature Medicine - Broad antigenic coverage induced by vaccination with virus-based cDNA libraries cures established tumors



Effective cancer immunotherapy requires the release of a broad spectrum of tumor antigens in the context of potent immune activation. We show here that a cDNA library of normal tissue, expressed from a highly immunogenic viral platform, cures established tumors of the same histological type from which the cDNA library was derived. Immune escape occurred with suboptimal vaccination, but tumor cells that escaped the immune pressure were readily treated by second-line virus-based immunotherapy. This approach has several major advantages. Use of the cDNA library leads to presentation of a broad repertoire of (undefined) tumor-associated antigens, which reduces emergence of treatment-resistant variants and also permits rational, combined-modality approaches in the clinic. Finally, the viral vectors can be delivered systemically, without the need for tumor targeting, and are amenable to clinical-grade production. Therefore, virus-expressed cDNA libraries represent a novel paradigm for cancer treatment addressing many of the key issues that have undermined the efficacy of immuno- and virotherapy to date.

It has been difficult to develop successful cancer vaccines because each tumour has specific proteins and identifying the right antigens has been a huge challenge.

Scientists have also tried to boost the effectiveness of vaccines by using several genes to increase the chances of producing successful antigens. But a worry has always been that the immune system's response would be too strong for the body to handle.

But now researchers, working with the Mayo Clinic in Rochester, US, have solved this problem in experiments involving mice.

The team used doses of a vaccine made from a virus which contained a 'library' of DNA, containing multiple fragments of genes and therefore many possible antigens. This approach did not send the immune system into overdrive, which had been a concern. Instead the range of DNA meant the vaccine was able to target the tumour through many routes.

Importantly, the DNA library was harvested from the same organ as the tumour. This meant that the immune system 'self-selected' the cancer antigens to respond to and did not react against other healthy parts of the body. Also, the process of self-selection was triggered when the vaccine was injected into the bloodstream, an approach to vaccination that is far more practical than injecting directly into tumours.

The researchers delivered a library of DNA taken from healthy prostate tissue in mice. When delivered in a virus, the vaccine successfully treated mice with prostate cancer.

University of Leeds' Professor Alan Melcher, co-author of the study, said: "This is the first time we've been able to use a whole library of DNA in a viral vaccine successfully.

"The biggest challenge in immunology is developing antigens that can target the tumour without causing harm elsewhere.

"By using DNA from the same part of the body as the tumour, inserted into a virus, we may be able to solve that problem."

The vaccine was made by putting the DNA library inside a vesicular stomatitis virus (VSV), which stimulates an immune response that can then track down and kill tumour cells.

Professor Peter Johnson, Cancer Research UK's chief clinician, said: "This is an interesting and significant study which could really broaden out the field of immunotherapy research.

"Although the vaccine didn't trigger the immune system to overreact and cause serious side effects in mice, it will need to be further developed and tested in humans before we can tell whether this technique could one day be used to treat cancer patients."
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