Given the findings and that HLA diversity has a natural role in fighting off foreign invaders, Dr Chan and colleagues are now exploring whether HLA diversity affects the likelihood of developing cancer in the first place. “The better the evolved efficiency of your HLA, the better you are able to fight cancer,” Dr Chan theorized. “It makes perfect sense, and to me, it’s very intuitive.”

Beyond HLA diversity though, another area immune checkpoint inhibitors may become more personalized is the way in which their side effects are managed. The fear is that management of immune-related adverse events (irAEs) with steroids, for example, may hinder the efficacy of the immune checkpoint inhibitor.

“Steroids are really a blunt instrument. They down-modulate many aspects of the immune system,” said Suzanne Topalian, MD, Bloomberg-Kimmel Professor of Cancer Immunotherapy at the Johns Hopkins University School of Medicine, Baltimore, Maryland, during an interview with Cancer Therapy Advisor


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In hope of elucidating the mechanism that might explain how irAEs arise — with the idea being that that knowledge could lead to identifying a more refined strategy for managing irAEs — Dr Topalian and colleagues turned to a patient who had metastatic melanoma.3

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The patient was enrolled in the rapid autopsy protocol at Johns Hopkins and was being been treated with anti-PD1 and anti–CTLA-4 therapy, which led to inflammatory side effects in multiple different organ sites. Over a 6-year span from the time of diagnosis to death, biospecimens were collected from the tumor sites, inflamed organ sites, and noninflamed organ sites. Biospecimens were compared to identify differences in the immune response seen at the tumor sites vs the inflamed organ sites.

Using TCR-Seq, the study researchers found that the T cells at the inflamed organ sites were different from those found at the tumor sites, suggesting that a distinct population of T cells may be responsible for the characteristic inflammatory side effects commonly seen with immune checkpoint inhibitors. 

The hypothesis had been that one of 2 possible mechanisms might explain how irAEs arise. One was a linked process in which the T cells that attack the tumor belong to the same population of T cells that attack normal tissues. The other was a parallel process, in which the T cells that attack the tumor belong to a different population of T cells that attack normal tissues. 

“Based on the difference between the tumor specimen T-cell receptor sequences and the inflammatory T-cell receptor sequences, at least for this 1 patient, it seems as if there is a parallel process going on,” Dr Topalian said. 

During an interview with Cancer Therapy Advisor, Shuming Chen, PhD, research associate in the Department of Surgery at the Johns Hopkins University School of Medicine and the Bloomberg-Kimmel Institute for Cancer Immunotherapy, cautioned that these findings are just preliminary observations and conclusions from a single patient. She presented the study findings during the 34th Annual Meeting & Preconference Programs of the Society for Immunotherapy of Cancer, or SITC 2019.3

The study also revealed that the genes IL1B and EP4, which give rise to proteins in the COX2 pathway, were upregulated in tissue from inflamed organ sites, offering potential therapeutic targets that could alleviate irAEs without compromising antitumor efficacy. Furthermore, evidence suggests that inhibiting proteins in the COX2 pathway may even have anticancer effects. For example, inhibition of IL-1B with canakinumab was associated with a reduction in lung cancer incidence and mortality.4

“We might be able to address 2 problems at the same time,” said Dr Topalian. “Maybe by using drugs that block the molecules IL-1B and EP4, we could reduce inflammatory side effects, and this might also have an anticancer effect.”

References

  1. Chowell D, Krishna C, Pierini F, et al. Evolutionary divergence of HLA class I genotype impacts efficacy of cancer immunotherapy. Nat Med. 2019;25(11):1715-1720. 
  2. Addeo A, Banna GL, Weiss GJ. Tumor mutation burden—from hopes to doubts. JAMA Oncol. 2019;5(7):934-935. 
  3. Chen S, Soni A, McMiller T, et al. Comparing anti-tumor and anti-self immunity in a patient with melanoma receiving immune checkpoint blockade. 34th Annual Meeting & Pre-Conference Programs of the Society for Immunotherapy of Cancer (SITC 2019): part 1. J Immunotherapy Cancer. 2019;7(282):abstract P285. doi: 10.1186/s40425-019-0763-1
  4. Ridker PM, MacFadyen JG, Thuren T, et al. Effect of interleukin-1β inhibition with canakinumab on incident lung cancer in patients with atherosclerosis: exploratory results from a randomised, double-blind, placebo-controlled trial. Lancet. 2017;390(10105):1833-1842.