21 June 2012
Being infected with a relative of Mycobacterium tuberculosis, the causative agent of TB, would probably not be the preferred cancer treatment option of many. Yet it is a therapy that has been over a century in its development and remains in use today to reduce tumour recurrence and progression in individuals with bladder cancer. This is because studies have shown that treating bladder cancer patients with mycobacteria in conjunction with chemotherapy is simply more effective than chemotherapy alone.
In research published this week in the international journal Cancer Immunology, Immunotherapy, Dr Joanna Kirman, Prof Franca Ronchese and colleagues applied 21st century technology to tease out the scientific basis for the anti-tumour effects observed with this age-old cancer therapy. In doing so, they have uncovered a new class of inflammatory immune cells that are induced in response to infection with mycobacteria. If these same cells are also responsible for the associated anti-tumour effects, then finding ways to induce them using synthetic parts of the mycobacteria rather than the whole organism, might just see mycobacterial immunotherapy returning to favour.
The potential of using bacteria to treat cancer has long been recognised. In the late 1800s American surgeon Dr William Coley made the remarkable observation that erysipelas (Streptococcus pyogenes) infection in cancer patients coincided with a shrinking of their tumours. Coley then used a crude mixture of killed bacteria called Coleys toxins, to activate the immune systems of his cancer patients. His theory being that the immune responses elicited by the bacteria were equally capable of destroying tumour tissue. Although Coleys results were encouraging, there were serious problems with this approach, mostly concerned with how sick his patients got as a result of their treatment.
Following on from these early observations, tumour immunotherapy with mycobacteria and their cell wall components has been used with varying degrees of success to treat melanoma and leukaemia as well as bladder, colon and lung cancers.
Although mycobacterial immunotherapy is clearly effective in eliciting local immune responses against solid tumours, its effectiveness in eliciting adaptive immune responses has been variable, says Dr Kirman.
It is the adaptive immune response that is needed for long-term protection against subsequent tumour growth or for cancers that might have spread to other sites in the body. Being able to elicit a strong adaptive immune response would also remove the need to have to administer the mycobacteria directly at the site of tumour growth, which is only possible for some forms of cancer.
In Dr Kirman and Prof Roncheses study, which was undertaken in collaboration with Malaghan Institute Group Leader Dr Jacquie Harper, lead author Fenella Rich chose to work with Mycobacterium smegmatis, a fast-growing non-pathogenic relative of TB.
In support of previous findings, Fenella found that when M. smegmatis was given adjacent to a tumour (in this case a thymoma) the rate of growth of the tumour slowed dramatically.
Although we found that M. smegmatis must be delivered adjacent to the tumour site to elicit a protective effect, the treatment did stimulate a CD8 T cell response that was systemic [spread throughout the body], says Dr Kirman.
Interestingly when we looked in the lymph nodes near to where M. smegmatis was given, we could detect a special type of antigen presenting cell that wasnt present in the absence of mycobacterial treatment.
We think these cells might be important for driving the anti-tumour response, she says.
This is the first time these inflammatory immune cells have been observed in context of mycobacterial immunotherapy, so Dr Kirman, Prof Ronchese and their teams hope to do further work to determine if, and how, these cells induce robust T cell mediated anti-tumour immune responses.
This knowledge will facilitate the identification of novel, safe and perhaps slightly more user friendly ways of harnessing the impressive immune-stimulating properties of mycobacteria for the treatment of cancer.
This work was supported by a research grant from the Cancer Society of New Zealand.
Rich FJ, Kuhn S, Hyde EJ, Harper JL, Ronchese F, Kirman JR (2012) Induction of T cell responses and recruitment of an inflammatory dendritic cell subset following tumor immunotherapy with Mycobacterium smegmatis. Cancer Immunol Immunother, 2012 Jun 20 [Epub ahead of print] Link to PubMed abstract.