It has been suggested for over 50 years that there is an immune reaction to cancer, but such speculations were countered by the rejoinder that, if the immune system was any use, it would have stopped the cancer in its tracks at its outset.
However, there were occasional observations of spontaneous regressions of cancer masses – particularly in melanoma and kidney/renal cancer. Furthermore, there was every reason to believe that the multiple mutations of genes that are present in cancers (and the cause of the cancer) and the deranged protein effector molecules downstream from the mutated genes would be recognised by the immune system as new antigens and therefore engender an immune reaction comparable to the rejection of a kidney transplant from another person, whose genetic make-up differs from the recipient.
In recent years, it has become obvious that cancers are antigenic and that the immune system is trying to react and reject the cancer, but the cancer puts up a ‘smokescreen’.
Let me explain: in foetal life, when the immune system is being laid-down, the normal tissues of the body are screened and declared normal (not to be rejected) and this is the establishment of ‘self-tolerance’ of normal tissues which thereafter protects them. Occasionally, this self-tolerance goes wrong and auto-immune diseases occur (e.g. Hashimoto’s thyroiditis, systemic lupus erythematosus etc.) but, in general, self-tolerance prevents normal tissues being attacked by the immune system. Now: it appears that the smokescreen projected by many cancers mimics the expression of self-tolerance features, which fools the immune system to believe they are normal tissues such that it ignores rather than attacking the cancer.
The immune lymphocytes express a PD (programmed Death) receptor and this appears to be one key check-point, determining whether the immune system attacks or ignores. If the cancer expresses the programmed death ligand (PDL-1), then the interaction between the lymphocyte PD receptor and the PDL-1 on the cancer signals to the immune system not to attack.
The introduction into Oncology of PD inhibitors (notably so far: pembrolizumab and nivolumab) and latterly PDL-1 inhibitors (atezolizumab, durvalumab) has added a completely new dimension to therapy – so much so that, in certain cancers (e.g. lung cancer, melanoma) immunotherapy with these agents is first line therapy. In other cancers (e.g. kidney cancer, triple negative breast cancer, head and neck cancer, MMR deficient colorectal cancer, bladder and kidney cancer) this checkpoint inhibitor therapy is a completely different but effective ‘fall-back’ therapy (from alternative chemotherapy in tripple negative breast cancer, or SMART drug therapy in kidney cancer) for resistant metastatic disease, and is establishing its role here. Immunotherapy is changing the face of modern Oncology.
However, there is a risk of side effects, notably creating auto-immune disease (see above) in normal tissues (hepatitis, pneumonitis, rash, gastroenteritis, myocarditis etc.) – a minority risk with this type of therapy, which is otherwise well-tolerated by patients. Long-lasting remissions of the cancer have been induced in all these cancer types by such checkpoint therapy. The author has an elderly man who has been in remission from a small cell lung cancer that had become resistant to chemotherapy, for now over 18months – this would not have occurred before the introduction of this type of immunotherapy.
How does the Oncologist predict whether the immunotherapy would work against the cancer? The first and best known method is to assess the strength of expression of PDL1 on the cancer cells – expressed as a percentage of cells expressing this ligand. The second method relates to the mutagenicity of the cancer (i.e. how many mutations are present in the cancer cells – as this relates to its antigenicity). In colon cancer, it was found that some cancers (mainly those of the caecum and ascending colon) carry DNA repair faults (mismatch repair [MMR] deficiency) more than other colorectal cancers. It was subsequently discovered that this MMR deficient subgroup of the disease was the only subgroup that would respond to checkpoint inhibitor immunotherapy. This is (almost) proof-of-concept for ‘hypermutation’ being a predictor for immunotherapy efficacy. Indeed, testing for MMR deficiency is now a routine test for assessing the potential of immunotherapy usefulness across the board in Oncology.
Another inhibitory signal produced by lymphocytes to modulate the immune response is CTL4 (Cytotoxic T-lymphocyte antigen 4) and inhibition of this by drugs (e.g. ipilumumab, tremelimumab) allow cytotoxic (‘cell lethal’) immune attack to commence. Although CTL4 inhibition currently plays second fiddle to PD1/PDL1 inhibitors, the foregoing demonstrates the complexity of the subject (glass half empty group) or the fantastic opportunities for future therapy (glass half full group).
So, the relatively recent knowledge of the ‘smokescreen’ put up by cancer in ‘blunting’ any immune rejection/reaction and its inhibition in therapy, has brought an important new dimension to Oncology therapy and is set for further development and even more success as the mechanisms are unravelled.
The response of a brain metastasis to immunotherapy – Left panel: before therapy and right panel: after three months of immunotherapy – showing shrinkage (as distinct from growth – had there been no therapy)
Nick Plowman MD is one of the world’s leading cancer specialists and Director of The Oncology Clinic, Harley Street. For more information visit www.canceradvice.co.uk