Thursday, June 30, 2022

The immune system has myriad effects on the etiology and treatment of cancer. I have intended to write about some of them, but the recent attention garnered by a study from Memorial Sloan-Kettering published in the New England Journal of Medicine on the use of immunotherapy for rectal cancer provides a stimulus to address at least one aspect of the topic.

Specifically, we will address the use of the immune system for therapeutic purposes. There are multiple approaches that have been and are utilized for this—interferon, interleukin, various types of vaccines and so-called CAR-T cell therapy—but when most people refer to immunotherapy nowadays, they are usually speaking about a class of drugs called checkpoint inhibitors. The immune system has responsibility for controlling both the identification and elimination of potential external threats (bacteria, viruses, etc.) as well as internal threats, like abnormal cells, including malignant cells. This is the same process by which the immune system rejects transplants or unmatched blood transfusions and what it identifies as “other.”

Lymphocytes are able to recognize same vs. other and normal vs. abnormal.

So one may ask, “If the immune system is functional and working, why do cancers ever arise?” It turns out that cancer cells have developed so-called immune checkpoints, proteins that are able to fool the immune system into thinking that the cancer cell is normal and part of the normal landscape; these proteins can shut off the immune response. Think of it as foreign soldiers who intermingle with the native population so the army cannot recognize them as enemies—they speak the language and know the culture and customs. The main protein molecules recognized to do this are CTLA4, PD-1 and PD-L1, among others. The pharmaceutical industry has developed new drugs, mainly antibodies, that are used to reverse this process that are known as checkpoint inhibitors, the first of which was ipilimumab (Yervoy), approved in 2011. Other common drugs in this class are pembrolizumab (Keytruda) and nivolumab (Opdivo).

The success of these agents has been most dramatic for metastatic melanoma, which was previously untreatable but can now be nicely controlled with these drugs for extended periods. Likewise, many lung cancers respond, as do a variety of other cancers to varying degrees. The other good thing is that, compared to conventional chemotherapy, the side effect profile of the checkpoint inhibitors is relatively much easier. They are not a cure-all—they are one more excellent weapon that works for some things and does not work for others. The Nobel Prize in Medicine in 2018 was awarded to the scientists who discovered the underlying checkpoint mechanisms leading to these therapeutic advances, James Allison of MD Anderson Cancer Center and Tasuku Honjo of Kyoto University.

So what about colorectal cancer (CRC)? For this we have to address another topic, which is how DNA replication occurs in the cell. When DNA is copied, millions of nucleotide bases are copied by the responsible enzymes and there is surprising quality and fidelity in how good the replication process is—otherwise there would be huge numbers of errors and mutations. But understandably some errors do occur—so-called mismatches. The cell nucleus has an outstanding quality control mechanism by which it checks for such errors and corrects them so as to minimize the number of errors that slip through—there is a mismatch repair (MMR) enzyme. It is extraordinary how elegant the whole system is!

It turns out that a certain fraction of colorectal cancers are MMR-deficient—they lack the enzyme that repairs the mismatches and hence these tumor cells have more mutations than tumors that are MMR-proficient. It is these tumors that are sensitive to checkpoint inhibitors and only these. For advanced metastatic CRC, the percentage that are MMR-deficient is about 4-5%. If treated with, for example, pembrolizumab (Keytruda), about 50% will respond and have a long duration of response; a decent proportion will have complete remission (disappearance) of tumor. I have several patients in my practice in this category who have had complete disappearance of tumor for more than three years and are, in effect, cured.

For localized nonmetastatic CRC, approximately 15% should be MMR-deficient. This was the category of patients who were in the study reported from Memorial—12 rectal cancer patients were treated with a new checkpoint inhibitor and all 12 went into complete remission and remained in remission for up to two years. Since it is a new drug, perhaps it is better than the reported experience with metastatic disease; this was unusually good.

In the absence of immunotherapy, the conventional treatment for these patients would be chemotherapy and radiotherapy followed by surgery. Nowadays about 20% go into complete remission after conventional chemotherapy/radiotherapy and the trend has been in many of them to hold off on surgery. If one adopts this watchful waiting approach (this is controversial), about 15-25% will recur and subsequently require surgery. Thus, while the results of the Memorial trial are impressive and promising, time will tell if late recurrences are also likely to occur.

Alfred I. Neugut, MD, PhD, is a medical oncologist and cancer epidemiologist at Columbia University Irving Medical Center/New York Presbyterian and Mailman School of Public Health in New York.

This article is for educational purposes only and is not intended to be a substitute for professional medical advice, diagnosis, or treatment, and does not constitute medical or other professional advice. Always seek the advice of your qualified health provider with any questions you may have regarding a medical condition or treatment.

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