Recently several news media reported a sensational news of all 14 people (stage2,3 rectal cancer patients) — and counting in Memorial Sloan Kettering clinical trial have their cancers disappeared by immunotherapy.
Immunotherapy drug used Dostarlimab (Jemperli(R))- PD-1 immune check point inhibitor which was developed by GlaxoSmithKline .
PD-1 immune check point inhibitor immunotherapy drugs have been available since 2014 when FDA had approved Nivolumab (Opdivo) by Bristle Meyers Squibb for metastatic melanoma, and for bladder cancer Pembrolizumab (Keytruda) by MERCK had been approved by FDA in 2017.
What's special about the clinical trial is that the patients were chosen not based upon high expression of PD-L1 on cancer cells which have been patients selection criteria for Pembrolizumab (Keytruda) for the use of bladder cancer, but based upon if tumors have a specific genetic makeup known as mismatch repair-deficient (MMRd) or microsatellite instability (MSI).
In colorectal cancer, tumors with no MMRd has about 70 gene mutations (low mutation load) , but tumors with MMRd has about 1,700 different gene mutations (high tumor mutation load). (2015 Dr. D.T. Le and others). As it has been known the efficacy of immunotherapy is associated with high mutation load, already in 2015 PD-1 immune check point inhibitor immunotherapy drugs was showing its effectiveness to colorectal cancer, tumors with MMRd. The immune-related objective response rate and immune-related progression-free survival rate were 40% (4 of 10 patients) and 78% (7 of 9 patients), respectively, for mismatch repair–deficient colorectal cancers and 0% (0 of 18 patients) and 11% (2 of 18 patients) for mismatch repair–proficient colorectal cancers. In this study, Pembrolizumab (Keytruda) was used. Subsequently, FDA approved Pembrolizumab (Keytruda) a first-line treatment for colorectal cancer patients whose tumors have a microsatellite instability high (MSI-H) or mismatch repair deficiency ( MMR-D or dMMR ) biomarker .
So, it is not so surprising to see PD-1 immune check point inhibitor immunotherapy worked for rectal cancer patients. The surprising factor is that all patients thought the number is small 14 so far that every patients tumors have disappeared with PD-1 immune check point inhibitor immunotherapy.
In terms of bladder cancer and its relation to mismatch repair-deficient (MMRd) , I have found that a study was published already in 2001. A write up in Urotoday.com - June 19, 2020 says about the Mismatch Repair Deficiency in Urothelial Carcinoma of the Bladder.
A study found 5 or 1.1% of 448 muscle invasive bladder cancers was found to have MMRd. Perhaps because such small percentage of bladder cancers are found to have MMRd, MMRd has not been used as biomarker for the treatment of bladder cancer in general.
In terms of colorectal cancers, 97% do not have MMRds and 3% have MMRds according to Dr. Scott Kopetz of MD Andersons Cancer Center. It seems that MMRds are checked as biomarker often in colorectal cancers.
About mismatch repair-deficency (MMRd)
Cancer is caused by accumulation of multiple gene mutations. It is known that mismatch repair-deficient (MMRd) can cause hundreds of different gene mutations.
Our body makes errors in DNA duplication process as a part of cell division.
There are 37 trillion cells in our body. Those 37 trillion cells go on a cell division process to renew at certain interval. Inside each cell, there is a DNA. NIH site defines DNA as the molecule inside cells that contains the genetic information responsible for the development and function of an organism. DNA molecules allow this information to be passed from one generation to the next. DNA is made up of a double-stranded helix held together by weak hydrogen bonds between purine-pyrimidine nucleotide base pairs: adenine (A) paired with thymine (T), and guanine (G) paired with cytosine (C). Also called deoxyribonucleic acid.
www.cancer.gov/publications/dictionaries/genetics-dictionary/def/dna
DNA is comprised of 3 billion base pairs of adenine (A) paired with thymine (T), and guanine (G) paired with cytosine (C), or 3 billion pairs of A-T and G-C. The problem is our body makes errors during the cell division process, which mismatch pairs such that instead of paring A&T, it pairs A&G, A&C,T&G and T&C. The error does not happen often but with 3 billon base pairs in each DNA and with 37 trillion cells in our body, mismatch errors are happening more than we think. But, our body has evolved and now our body has lability to repair those mismatched base pairs during DNA duplication process. But, some are missing proteins to repair the errors.
When those proteins are missing, it is called mismatch repair-deficient (MMRd).
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