When I started writing my blog, my first post in April 29 of 2017 was about the field of immunotherapy, and as an example of its application I selected the treatment of president Jimmy Carter who at the time had stage IV melanoma. President Carter was cured of his cancer, and went on to live several productive years before his health failed, and he was placed on hospice care in February of 2023. Carter has managed to live long enough in hospice to celebrate his 99th birthday. To honor of him, I will repost that first post with which I began my blog. The Cancer of Jimmy Carter and the Emerging Field of Immunotherapy ![]() I admire former president Jimmy Carter. Although by presidential standards his four years as president from 1977 to 1981 are viewed in a negative light, Carter in his post-presidential years has become a model of what it is to be dedicated to the betterment of humanity. Because of this I was sad last year when it was announced that Mr. Carter had the most advanced form of melanoma (stage IV), a skin cancer that had spread to his liver and brain. This cancer is very difficult to treat, so I thought to myself that this was the end of the road for President Carter. You can imagine how happy I was when I learned towards the end of the year that Mr. Carter had been treated and his cancer was in remission. This does not mean he is cancer-free, it just means that in the scans the doctors have performed they are not able to detect the cancer masses that they had previously found or any others. So how did this happen? Mr. Carter had several treatments. He had surgery to remove a cancer in his liver, and he had targeted radiation for the cancer in his brain. But more significantly, Mr. Carter was also administered a new form of therapy that targets the immune system. This therapy is the result of many years of research in many areas of science, and we will take a look today to see how all this came together to generate a new weapon for oncologists in the battle against cancer. Cancer occurs when the cells of the body undergo a transformation and start dividing uncontrollably. This characteristic is exploited by chemotherapeutic agents and radiation treatments. They affect mostly rapidly dividing cells. Unfortunately, our bodies also have many cells that proliferate rapidly in a controlled fashion such as many immune cells and the cells of the lining of the intestine. The same agents that kill the rapidly dividing cancer cells also kill the rapidly dividing healthy cells, and this leads to toxicities that in many cases limits the usefulness of these agents. Our immune system protects us from pathogens that enter our bodies. Early on in cancer research, scientists wondered whether the immune system could attack cancer cells. Initially it was thought that cancer cells were not targeted by the immune system because, unlike very different entities like viruses or bacteria, cancer cells were cells similar to normal cells. However, many cases were documented where the immune system did attack cancerous cells. As it turns out the immune system does detect cancer cells when they arise and eliminates the majority of them. Eventually cancer cells appear that escape destruction. These cancer cells have marginally survived the onslaught of the immune system, and they may be even be kept in check by it. However, the cells eventually divide and generate new cancer cells some of which are a bit more resistant to the attack of the immune system. Then finally, in an evolutionary process that may take years, a crop of cells emerges that has escaped detection by the immune system and goes on to divide out of control and generate full-fledged tumors. So how do cancer cells evade the immune system? ![]() The immune system cascade that results in the elimination of pathogens or cancer cells is a highly regulated process. And it has to be. The immune system must be able to differentiate self from non-self (e.g. bacteria from human cells). When this detection mechanism goes wrong we can have what are called autoimmune diseases like Lupus where the immune system attacks healthy cells. Also the body has to prevent the overactivation of the immune system and must thus have a mechanism to turn it off. To prevent the immune system from going rogue, its activation proceeds through a number of checkpoints that are controlled by specific receptors present in immune cells. When these receptors interact with specific ligands (molecules that bind to these receptors), the activation of immune cells is shut off. What successful cancer cells do to survive the immune system is that they express these ligands on their membranes thus preventing immune cells that come in contact with them from triggering the immune response. Therefore, scientists conjectured that this inhibition of the immune system by cancer could maybe be antagonized and permit the immune cells to attack the cancerous cells. But how could this be achieved? The answer was antibodies. Antibodies are proteins produced by cells of the immune system that bind with great specificity to those molecules against which they are made. Certain cells of the immune system regularly make antibodies against foreign bodies to flag them for removal. Scientist had learned to grow these cells and to coax them to make antibodies against specific molecules. So they proceeded to create an antibody against one of the molecules that controls an immune checkpoint called PD-1. This antibody blocks the PD-1 receptor on immune cells and prevents the ligands on the surface of the cancer cells from activating it thus blocking the immune response. One of these antibodies called “pembrolizumab” (marketed under the brand name: Keytruda) was the one administered to Jimmy Carter. Of course, Mr. Carter was given several treatments so we don’t know for sure what part of the effect was due to the antibody. Nevertheless, in clinical trials of patients with advanced melanoma pembrolizumab caused tumors to shrink in 21-33% of patients and reduced the risk of disease progression by 42-43%. In fact the administration of this antibody was much more effective than conventional chemotherapy. There are, however, two things that must be pointed out. The first is that only around a third of patients benefit from this immunotherapy. This is probably related to the fact that there are different checkpoints of the immune cascade that are exploited by cancer to avoid detection and the importance of these checkpoints to the survival of these cancers varies from one cancer to another. Second, as expected from blocking the inhibition of the immune system, there were side effects as a result of overactive immune cells, but it must be borne in mind that advanced melanoma is a lethal disease. Scientists are just now unravelling the immense complexity of immune system checks and balances and how they are exploited by cancer. A number of antibodies have been approved by the FDA or are being tested not only for immune system checkpoints but for other mechanisms that allow cancer to thrive like growth receptors or angiogenesis (the process that allows a cancer to create blood vessels to feed its cells). Researchers are even combining antibodies with conventional chemotherapeutic drugs which allows for targeted delivery with less side effects. The future of immunotherapy looks promising, and I feel optimistic about our chances of beating cancers like melanoma, especially with therapies that combine several approaches. As to President Carter, I hope that he fully recovers from his disease and continues his excellent work in favor of humanity. The images in this post are in the public domain. 2024 Postscript
By 2023 the Food and Drug Administration (FDA) had approved eleven immune checkpoint inhibitors for a wide variety of cancers. The FDA also approved six therapies based on chimeric antigen receptor (CAR-T) technology, where the patient’s immune cells are modified to fight cancer, and six therapies based on T-cell engaging bispecific antibodies, where the patient is infused with antibodies that bind cancer cells and flag them for destruction. These therapies have sparked a revolution in cancer treatment, but they have fared best when applied to blood cancers and cancers such as lung cancer or melanoma. However, immune therapies have faced significant challenges when applied as single agents to solid tumors. Because of this, scientists and clinicians are focusing on therapies that combine immunotherapies with other cancer treatments both new and old. With regards to president Carter, he is now the longest living ex-commander in chief, but there is no denying that he is soon approaching the end of his life. Wishing him to get well soon would be an empty gesture, but we can all make a commitment to remember his exceptional life and his example as a great American. 2025 Postscript President Carter died on December 29 of 2024. R. I. P.
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10/5/2024 What Can’t You Accomplish When You Have God on Your Side? The Perils of Claiming the Support of the DivinityRead NowThis is not a political or religious blog, but I do deal with reason and related topics. And one such topic is the logic behind a claim often made in human history: God is on our side. So let me tell you what motivated me to write about this. I read what a person posted on X regarding the missile attack that Iran unleashed against Israel on October 1st 2024, which resulted in minimal casualties, because the vast majority were intercepted by Israel’s air defense system. The poster described the different air defense systems Israel employs as a technological wonder with unparalleled sophistication, but then went on to say that the chance that these systems would work in unison flawlessly are nonexistent. He also mentioned that the few missiles that were not intercepted landed in places where they caused minimal damage. This person then states that it is impossible to look at this objectively and not see the hand of God. Interestingly, the poster then acknowledges that some questions may be raised along the lines of where was God in the past when the Jewish people suffered such as during the October 7th 2023 attack by Hamas, which precipitated the current conflict, or the Holocaust. The poster agrees that these are valid questions that require a very serious nuanced conversation, but still he states that the low casualties in this attack is an obvious miracle: an an example of God in all his glory watching over his children (the people of Israel). Of course, people since time immemorial have claimed that God is with them during a struggle or an enterprise (sometimes out of conviction and sometimes as a propaganda tool). The power behind this claim is that the belief that one has the support of God has a huge effect on the human mind. After all, we are talking about “the creator”, “the big guy up there”, “alpha and omega”, "the one and only", “el numero uno”. What can’t be accomplished if you have the support of God? But notice that this question does not have any moral or ethical parameters associated with it. While the claim of divine support in some cases has allowed the people who make it to be motivated and determined to fight even when there is little hope, in other cases it has allowed the justification of ghastly crimes. For example, the Doctrine of Discovery issued by Pope Alexander VI in 1493 basically claimed that the new lands discovered to the west by Columbus were to be claimed and exploited by Christians and any barbarous nations were to be overthrown and brought to the faith. In the 1800s this doctrine gave rise to the concept of Manifest Destiny which was the belief that God called upon the people of the United States to expand westward, and which was used to justify the uprooting of Native Americans from their lands. Some people, like the poster whom I alluded to, witness a remarkable event, such as the neutralization of the missile attack on Israel, and they jump to the conclusion that God must have been behind it. But drawing this sort of conclusions from such remarkable events is unwarranted. I have written of how, for example, Hitler survived so many assassination attempts that he considered that God was on his side. There are such things as coincidences, even very remarkable ones. If enough people flip ten coins, one of them will get ten heads in a row. One thing that we have learned from history is that it has proven fiendishly difficult to figure out in a rational way what it is exactly that God wants and who he supports. Rather, more often than not, the two sides in a conflict wrap themselves in the mantle of divine support, and the victors then proceed to write their biased version of history. When I read what this poster wrote on X, the first thing that came to my mind is a passage from a book I read a long time ago. The book is entitled “Our Endangered Values: America’s Moral Crisis” written by ex-president Jimmy Carter in 2005. Part of the passage reads as follows: “There is a remarkable trend towards fundamentalism in all religions – including the different denominations of Christianity as well as Hinduism, Judaism, and Islam. Increasingly, true believers are inclined to begin a process of deciding: ‘Since I am aligned with God, I am superior and my beliefs should prevail, and anyone who disagrees with me is inherently wrong,’ and the next step is ‘inherently inferior.’ The ultimate step is ‘subhuman,’ and then their lives are not significant.” In this passage, Carter was talking about the danger of the rise of fundamentalism in religions, but the danger of a person, a group, or a country believing that THEY are favored by God is clearly spelled out. Claiming the support of God may make it easier for people to ignore or soften their adherence to their values resulting in the denigration of others who in their views are not supported by the divinity. Without judging upon matters such as the existence of God or who is right or wrong in the current conflict, it is my opinion that claiming the favoritism of God when it comes to the affairs of humans always complicates moral and ethical evaluations of actions to be taken or of those which have been already taken. This evaluation must be performed based solely on our values. And human rights, including the right to live, should be at the center of this analysis. Some people may even argue that this is what God would want us to do. The photograph of the painting “Benediction of God the Father” by Luca Cambiaso (1527-1585) taken by Daderot is in the public domain. |
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