Metastatic Immunity

In 2013, cancers represented more than one third of the top-fifteen causes of all-age mortality in the UK, irrespective of gender. Despite intensive efforts, for some cancers survival rates have scarcely improved for decades. Described by oncologist turned Pulitzer prize-winning author Siddhartha Mukherjee as the Emperor of all Maladies, it is not one disease, but many. Part of its fearsome reputation stems from the fact that after successful treatment, many cancers may return, sometimes even decades later. Since traditional chemotherapy works by killing cells in the process of division, some quiescent cancer cells can be missed. Without a process of ongoing disease prevention, cancer can recur in the same area or metastasise to reappear elsewhere in the body. Worst of all, upon recurrence, the cancer may have evolved resistance to the previously effective treatment.

Of course, human beings already benefit from a process of ongoing disease prevention — our immune system. The idea of creating some kind of vaccination against cancer has drawn immunologists into the world of oncology for decades. Indeed, the notion that activating immunity could play a role in cancer treatment probably began in the 1890's, when William Coley first documented his attempts to use the streptococcus bacterium to shrink otherwise inoperable tumours. The promise of immunotherapies over standard treatments is that once sensitised to specific antigens, immune T-cells remain on guard from that point onwards; their potential to detect and destroy rogue cells at some later date could prevent relapse and radically extend the duration of post-treatment survival.

Immunotherapies are, however, fraught with risk. Both autoimmune disease and cytokine release syndrome (or even fatal cytokine storm reactions such as were found during the Spanish influenza pandemic) are ever-present dangers. A healthy immune system depends crucially on distinguishing between healthy and unhealthy tissue, between pathogen and self. It is these very distinctions that prove complex in cancers, where mutations of our own cells are augmented by evolved mechanisms to remain undiscovered.

One approach coming of age at the present time is around the use of engineered T-cells. Chimeric antigen receptor-modified (CAR) T-cells are immune cells extracted from a patient and modified to target specific proteins found on the surface of their cancerous cells. The CAR T-cells are replicated and injected as a treatment, an approach showing exciting results, including complete remission for the majority of patients in this leukemia trial. This technique is equally applicable to other blood cancers, however use with solid cancers remains less successful and is subject to ongoing research.

Another focus in this field is around the class of drugs known as immune checkpoint inhibitors. Their ability to 'take the brakes off' the immune response disables mechanisms cancers use to evade attack. Different types of inhibitor have demonstrated individual efficacy, and combination therapies involving multiple approaches have demonstrated the potential for impressive periods of progression-free survival in cases of metastatic melanoma. However, even with that success it was noted that more than a third of patients needed to discontinue treatment due to the severity of the adverse effects.

The next stages in this battle are likely to involve focusing the immune response more effectively at tumour cells to avoid high rates of collateral damage in other bodily systems. Cancers grow in complexity as they evolve, and targeting the immune response at specific antigens present throughout a tumour rather than on antigens present only on a minority of tumour cells holds promise. Combining this very specific immune-system excitation with checkpoint inhibition may unlock a new generation of personalised treatments with far greater effectiveness.

If evidence were needed that excitement around immunotherapy is burgeoning, it might be taken from the frequency with which the oncologically rare c-word (cure) turns up in the media. Sometimes, the media furore even precedes the availability of the published research, which can make it difficult to draw firm conclusions. Such exuberance is unsurprising, and any treatment contributing to the survival of a US president is always going to hit the headlines. What is clear however, is that medics now have new tools in the armoury for the fight against cancer, and that these tools are evolving at an unprecedented pace. It seems likely we will see further progress against previously intractable cancers in coming years.

References

Ford, A.M., Mansur, M.B., Furness, C.L., van Delft F.W., Okamura, J., Suzuki, T., Kobayashi, H., Kaneko, Y. and Greave, M. (2015) Protracted dormancy of pre-leukemic stem cells. Leukemia (2015) 29, 2202–2207; doi:10.1038/leu.2015.132

Coley, W.B. (1894) Treatment of inoperable malignant tumors with the toxines of erysipelas and the bacillus prodigiosus. Transactions of the American Surgical Association. v.12 1894.

Caspi, R.R. (2008) Immunotherapy of autoimmunity and cancer: the penalty for success. Nat Rev Immunol. 2008 Dec; 8(12): 970–976. doi: 10.1038/nri2438

Dai, H., Wang, Y., Lu, X., Han, W. Chimeric Antigen Receptors Modified T-Cells for Cancer Therapy. J Natl Cancer Inst. 2016 Jan 27;108(7). pii: djv439. doi: 10.1093/jnci/djv439.

Maude, S.L., Barrett, D., Teachey, D.T., Grupp, S.A. Managing cytokine release syndrome associated with novel T cell-engaging therapies. Cancer J. 2014 Mar-Apr;20(2):119-22. doi: 10.1097/PPO.0000000000000035

Maude, S.L., Frey, N., Shaw, P.A., Aplenc, R., Barrett, D.M., Bunin, N.J., Chew, A., Gonzalez, V.E., Zheng, Z., Lacey, S.F., Mahnke, Y.D., Melenhorst, J.J., Rheingold, S.R., Shen, A, Teachey, D.T, Levine, B.L, June, C.H, Porter, D.L, Grupp, S.A. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med. 2014 Oct 16;371(16):1507-17. doi: 10.1056/NEJMoa1407222

Zhang, B.L., Qin, D.Y., Mo, Z.M., Li, Y., Wei, W., Wang, Y.S., Wang, W., Wei, Y.Q. Hurdles of CAR-T cell-based cancer immunotherapy directed against solid tumors. Sci China Life Sci. 2016 Mar 11.

Larkin, J. et al. (2016) Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma, N Engl J Med 2015; 373:23-34July 2, 2015 DOI: 10.1056/NEJMoa1504030

Quezada, S.A., Swanton, C. et al. (2015) Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade, Science 03 Mar 2016; DOI: 10.1126/science.aaf1490

Stephen Richards
(Mar 16, 2016)
Reading Coley's paper was interesting for many reasons. His description of successful treatments sounded almost miraculous, which immediately makes the modern mind somewhat suspicious. Coley published his case-note data at the end of the paper, though, and claimed that these were all his cases, i.e. that he hadn't selectively excluded deaths or treatment failures. However, even more interesting than all of this was the discussion published after the paper, with several physicians reporting that they tried - and failed - to reproduce Coley's results. There could be many reasons for this, including Coley unconsciously selecting cases that were more likely to respond to his treatment. Since modern oncologists don't recommend injecting tumours with bacterial toxins, Coley's method obviously wasn't reliable enough for this to become a standard treatment.

The really fascinating aspect is seeing evidence-based medical science in action: open publication, peer review and discussion, then (failed) attempts to reproduce the results. I was left wondering: where is the equivalent for actuarial methodologies used in pricing and reserving?

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Gavin Ritchie is the IT Director of Longevitas