“In the past, we showed that tumor mutation burden associates with better response,2 which pinpointed neoantigens as the targets of immune checkpoint therapies. While MMR deficiency is associated with a better response, only 50% of MSI-positive patients responded. Our new study shows that even in MSI-positive patients, higher numbers of mutations still predict better outcome, showing that neoantigen quantity is still the driving force in MSI-positive tumors,” said Timothy Chan, MD, director of the translational oncology division at Memorial Sloan Kettering Cancer Center and lead author of the paper.

“This is very compelling, especially in the context of the exceedingly careful work that they’ve done in the mouse cell lines,” saidJames Eshleman, MD, PhD, professor of pathology at Johns Hopkins Medicine in Baltimore, Maryland.. “The paper says that it is frameshift mutations that the immune system is primarily responding to, which makes sense.” Dr Eshleman explained that the nature of these frameshift mutations means that they produce neoantigens that the immune system is likely to recognize as foreign.

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The researchers next looked at gene-expression analysis of the anti–PD-1-treated, MSI-high tumors from the B16F10 melanoma cells compared with control-treated MSI-tumors and the MSI-stable PD-1–treated tumors. They found an increase in expression of immune-related pathways, including genes involved in lymphocyte activation and function and cytokine signaling.

“From the mouse work it gives very good indication of why there’s heterogeneity in response, which is a very difficult question (to answer). In the clinical trials there is heterogenous response, so it tells us it’s more than just MMRD, which is one entire homogenous group,” noted Dr Eshleman.


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To validate these results in humans, the researchers looked at the MSI levels in patients from a previously published cohort3 of MMR-deficient or MMR-proficient gastrointestinal tumor patients treated with anti–PD-1 therapy, giving each one a “MSIsensor” score, which was a score assigned based on the result of a bioinformatics analysis quantifying the level of MSI by comparing tumor tissue with normal tissue.

The MMR-deficient tumors predictably had significantly higher MSI levels than the MMR-proficient samples, but crucially, patients who were clinical responders to the anti–PD-1 had higher levels of MSI and associated indel mutations than those who didn’t respond to the therapy.

This was further corroborated by looking at data from MMR-deficient colorectal and esophagogastric cancers in patients treated with immune checkpoint inhibitors.4,5 The researchers found a similar correlation between high MSI levels and clinical response in this cohort.

“The respective analysis of these cohorts is very compelling. The FDA’s package label [for prescribing anti–PD-1 therapies] — MSI-high of any organ or tissue type or MMR-deficiency of any tissue type — is very appropriate and will likely remain the recommendation for now and some time going forward,” said Dr Eshleman.

But what about immune checkpoint inhibitors which target CTLA-4 — is high MSI also likely to be a predictor of response with these agents?

“Yes, anything that activates CD8 T-cell dependent immune mediated killing should follow the general paradigms we have described. This is one of the things we find exciting; the genetic rules we are working out are fundamental principles governing how this whole class of therapeutics works,” said Dr Chan.

Dr Chan plans to do further prospective work in future cohorts to confirm the results, but does this work extend to other types of tumor not analyzed in the recent study?

“One of the conclusions from our work is that the immune infiltrate signals seen in MSI-positive tumors are applicable across nearly all cancer types. This should be a broadly applicable set of rules that apply to many cancer types,” concluded Dr Chan.

References

  1. Mandal R, Samstein RM, Lee KW, et al. Genetic diversity of tumors with mismatch repair deficiency influences anti–PD-1 immunotheray response. Science. 2019;364(6439):485-491.
  2. Samstein RM, Lee CH, Shoushtari AN, et al. Tumor mutational load predicts survival after immunotherapy across multiple cancer types. Nat Genet. 2019;51(2):202-206.
  3. Le DT, Uram JN, Wang H. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015;372(26):2509-2520.
  4. Janjigian YY, Sanchez-Vega F, Jonsson P, et al. Genetic predictors of response to systemic therapy in esophagogastric cancer. Cancer Discov. 2018;8(1):49-58.
  5. Yaeger R, Chatila WK, Lipsyc MD, et al. Clinical sequencing defines the genomic landscape of metastatic colorectal cancer. Cancer Cell. 2018;33(1):125-136.