.jpg?sfvrsn=31768537_2)
©Jakedan/ Dreamstime.com/ License: Royalty Free
We are seeing a renaissance of optimism about immunotherapy for cancer – after many years of disappointment. Patients with advanced and clinically intransigent lung cancers and melanomas, treated in early clinical trials with antibodies to immune checkpoint inhibitors PD-1 and CTLA-4, have been surviving longer than would previously have been expected 1,2. And other studies have demonstrated that patients whose tumours were infiltrated with lymphocytes show better outcomes 3.
Putting these observations together, the inference is that some tumours present neoantigens that are recognised by the immune system and that this reactivity can be boosted by releasing the checkpoint brakes on the immune system.
It’s particularly encouraging that genetically diverse or unstable cancers – lung cancer and melanoma 1,2,4, for example – appear to present the most neoantigenic enticement to the immune system. It’s likely that the majority of such antigens are generated by the same mutagenic exposures that are known to cause these cancers – cigarette carcinogens and UVB 4.
The idea is certainly appealing. A major challenge in cancer is the extensive intraclonal genetic diversity in cancers which, combined with changing phenotypes, can lead to therapeutic resistance and escape. The immune system is distinguished by its almost unlimited repertoire of antigen epitope recognition or functional diversity. To encourage a confrontation between one diversity-rich system and another is therefore an intriguing game plan.
Excitement about this tactic reached a peak early in March this year when Charles Swanton, Sergio Quezada and colleagues published a paper in Science 4, describing some very interesting and important work.
Press hyperbole was perhaps predictable and included this stonker of a front page headline in a well-known UK tabloid: ‘A cancer cure in just one jab?’ Just above this headline was another item: ‘Is this proof chimps believe in God?’ Credibility stretched to breaking point perhaps. But the headline detracts from the excellence of the science (in the cancer story) and the balanced conclusions the authors draw from it.
Their study compared the diversity of neoantigens and their clonal distribution (derived from genomics and bioinformatics) with clinical outcome. The results were striking. In adenocarcinomas of the lung (but not squamous cell carcinoma), better survival was associated with high numbers of neoantigens and the clonal distribution of those epitopes, i.e. when they are effectively in every cell. The potential functional correlates of this beneficial response were high level expression of programmed cell death ligand (PD-1L) pro-inflammatory cytokine IL-6 as well as expression of HLA class 1 and β2 microglobulin – all indicative of immune activation.
Other cohorts of patients were studied who had been treated with immune checkpoint blockers. In these cases too, overall survival was positively correlated with many and diverse neoantigens coupled with a clonal or homogenous distribution of those antigens. Of course it makes sense that an immune attack on cancer is more likely to succeed if all targeted epitopes are expressed on essentially all cells in the clone.
This is unquestionably exciting science. Quite what its clinical impact will be remains to be seen.
Should we consider bespoke generation of patient-derived T cell clones that, if expanded and reinfused, would provide sustained control? Or a parallel tactic could be to design vaccines or vectors expressing selected neoantigens for T cell activation 5. There are obvious advantages over more standard chemotherapy in these approaches, since the T cells will be long lived and cancer-specific. Leaving aside considerations of whether bespoke or ultra-personalised medicine of this kind is logistically and financially practical, is the idea likely to fly?
Immune checkpoint blockers are already showing positive results in some advanced lung cancers and melanomas 1,2, so a focus of further effort in this area is fully justified. Combining checkpoint blockage with T cell clones expanded in vitro or engineered vaccines might well extend the efficacy and duration of control.
Is there any downside to this? Well, yes, potentially there is. Checkpoint inhibition is a relatively blunt instrument for modulating such an adaptive, resilient and complex system as T cell recognition and response. Patients may suffer collateral damage from an unleashed immune system, which could include autoimmune conditions. T cell neoantigen targeting by itself probably suggests fewer concerns, other than perhaps a risk of a cytokine ‘storm’.
There is something else that could well limit the efficacy of boosting immunosurveillance to control of cancer – that old foe, resistance. T cell directed attack, although novel, is still quite like a conventional drug in so far as it has a specific, molecular target. It would be very surprising if genetically unstable advanced cancers didn’t include some cells that could downregulate that target or mutate it to invisibility.
But perhaps, in response to this concern, we could design vaccines or expand T cell clones so that they can ‘see’ multiple epitopes where the statistical probability of mutant escape is low? Well yes and no. ‘No’; if the effective epitopes and T cell recognition all operate via MHC (HLA) binding 5. That single or common target will provide very strong evolutionary selective pressure for the emergence of escape mutants. There is evidence for this from clinical situations where immune control of cancer is HLA-directed 6,7.
So what remains to be assessed is which complex, adaptive system is the most resilient – cancer clones or the immune system?
Perhaps the best prospects for this new wave of immunotherapy will be to combine it with drugs that operate through entirely separate pathways. In the meantime, we should ignore the hyperbole in the headlines and celebrate some excellent science that brings together genomics, clonal diversity and the versatility of the immune system.
References