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Editorial
Cancer immunotherapy: new leads on an elusive goal
Emerging data increase optimism for mobilising immune cells against cancer
MJA 1998; 169: 570-571
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The prospect of
mobilising the body's immune defences against cancer
cells has been an elusive goal in cancer therapy for many decades. The
optimism held for this idea has fluctuated over the years, but there
are now concrete data emerging from a number of fronts that give good
reason to be optimistic about cancer immunotherapy in the medium
term. The new data on prospects for cancer immunotherapy were brought
together at a recent meeting in Canberra.* Australia has outstanding
researchers in this field, and this meeting was an opportunity to
assess the current hopes and limitations from multiple
perspectives.
One chief limitation to cancer immunotherapy has been the difficulty in finding good, cancer-cell-specific target antigens. Immunological tolerance to self antigens on healthy tissues has mistakenly been thought of as an absolute process, barring the prospect of ever getting immune cells to react against cancer cells unless antigens unique to the cancer could be found. Two new developments dispel this perceived limitation. Firstly, many of the cellular processes responsible for immunological self-tolerance are at last being illuminated, through new technologies to genetically engineer transgenic mice.1-4 Definitive work on the process of tolerance to tissue-specific antigens was presented by B Scott (University of Western Australia, Perth), W Heath (Walter and Eliza Hall Institute, Melbourne), F Alderuccio (Monash University Medical School, Melbourne), D Hanahan (University of California, San Francisco) and myself. The data show that tolerance to tissue-restricted antigens, such as proteins made only by specific epithelial, neuronal or endocrine cells, is acquired by regulatory processes that still allow circulation of T cells and B cells with tissue-reactive antigen receptors. If these regulatory processes can be defined and temporarily relaxed by specific drug antagonists, this potential reservoir of immune cells might, in principle, be called into action to destroy cancer micrometastases. One potential target for such antagonists is suggested by inherited mutations in a novel gene, Autoimmune Regulator (AIRE); mutations of AIRE cause a failure of tolerance to multiple endocrine tissues in patients with autoimmune polyendocrinopathy- candidiasis syndrome (N Shimizu, Keio University). Conversely, a potential immune agonist is the cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF), which is a potent inducer of immunity and appears essential for destructive autoimmunity in experimental diabetes mellitus (T Kay, Walter and Eliza Hall Institute, Melbourne). Notionally, such an immunotherapeutic course would follow after a primary tumour is surgically resected or debulked by radiotherapy or chemotherapy. The second development that opens the field of cancer antigen targets is coming from a clinical serum analysis technique called SEREX, which shows that tumours induce "autoimmune responses" much more frequently than has been appreciated.5,6 Autoantibodies against neuromuscular receptors have long been known to cause paraneoplastic syndromes of myasthenia gravis and Lambert-Eaton syndrome in patients with specific types of tumours such as thymoma or small cell lung carcinoma. Results obtained using SEREX show that patients who have any of a broad range of tumours are often making autoantibodies against various tissue-restricted antigens carried by the tumour cells (J Cebon, Ludwig Intitute, Melbourne; B Robinson, University of Western Australia, Perth). These results make it likely that immune defences can be mobilised against many tumours, but how effective will this be and how can they be improved? J Cebon summarised data suggesting that some patients with high antibody responses to tumours survive somewhat longer, but it is still uncertain that immune surveillance is a factor even in these cases, and it is clear that, ultimately, the tumour exceeds or escapes any immune surveillance.5 Genetically engineered mouse models of pancreatic cancer or skin cancer display spontaneous immune responses to cancer antigens,7,8 but augmenting these immune responses only delays tumour progression,9 and the extent to which the spontaneous immune responses restrict tumour growth appears quite limited (D Hanahan and D Daniel, University of California, San Francisco; C Parish, John Curtin School of Medical Research, Canberra). A review of individual case studies provides provocative examples of patients where squamous cell carcinomas or melanomas have spontaneously regressed, accompanied by vigorous immune cell responses to the tumour (G Halliday, University of Sydney).10 The potential for immune control of cancer cells is best illustrated by cancers of viral origin and by organ-specific autoimmune diseases. Only a small proportion of people infected with Epstein-Barr virus or human papillomavirus 16 develop lymphoma or cervical cancer, and there is clear evidence that this is due partly to effective immune responses against the viral antigens carried by the tumour cells (R Khanna, Queensland Institute of Medical Research, Brisbane; I Frazer, Princess Alexandra Hospital, Brisbane).8,11 The devastating destruction of pancreatic islet beta cells in type 1 diabetes mellitus, where no virus is known to be involved, is testimony that immune defences can be unleashed against common tissue antigens as well. Why do most tumours not remit despite ongoing immune responses? Several factors were clearly indicated at the meeting. Firstly, K Lafferty (John Curtin School of Medical Research, Canberra) reviewed recent studies in diabetes showing that vigorous immune responses can be "benign" (non-destructive) or "malignant" (destructive).12 Islet tissues can be heavily inflamed by a benign autoimmune response without any damage to beta cell mass because of poorly understood regulatory processes for self-tolerance.1,3,4 Genetic predisposition only allows a switch to malignant inflammation in certain individuals. As discussed above, the solution to this problem lies in charting the molecular pathways regulating tolerance and developing specific ways to interfere with them transiently. Secondly, tumour cells are genetically unstable and constantly evolving. In viral tumours, cancer cells escape immune surveillance by losing antigens or by losing the machinery needed to present antigens to T cells.11 Tumour instability is a serious problem for any single therapeutic approach, as it is for radiotherapy or chemotherapy, and successful application of immunotherapy will probably also depend on the tumour type and tailored combination with other measures. Thirdly, D Hanahan, B Robinson, G Halliday, and C Parish each drew attention to fragmentary evidence that secreted products from tumours -- such as activins -- and tumour influences on local vasculature and extracellular matrix may create suppressive or non-permissive environments for immune responses.13 It is conceivable that some of these products, such as transforming growth factor b, are key elements of normal mechanisms to prevent organ-specific autoimmunity. This is the least understood of all the obstacles facing immunotherapy. Counteracting such tumour products should not be an insurmountable barrier, but it may take considerable time and effort to define the molecular pathways involved and develop small-molecule antagonists against the best targets.
Christopher C Goodnow
* Autoimmunity workshop: the interface between autoimmunity and cancer immunity, sponsored by the John Curtin School of Medical Research, Australian National University. 11-13 September 1998. ©MJA 1998 |
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