Checkpoint Inhibitors


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by William P. Meyers

What is a cancer checkpoint inhibitor?

In our human bodies the individual cells are supposed to serve the overall system. When a cell has problems that cannot be corrected, it is supposed to die. Sometimes it dies for internal reasons, but the immune system also polices cells and kills cells that it has determined to be faulty. A system has evolved that allows the immune system, in particular T-cells, a kind of lymphocyte or white blood cell, to determine which cells are friendly, and which cells should be destroyed.

Normally cells that are potentially cancerous are destroyed by the immune system. All cancer cells undergo changes that differentiate them from their neighbors, the most obvious change being the ability to multiply without inhibition. To really get going, however, a cancer needs to evade the immune system. One way it can do this is to keep the molecules on its cell membrane, the molecules the immune system can touch, in a state that says, effectively "I am a healthy cell, not a cancer."

Checkpoint proteins tell the immune system that a cell is healthy. There may be other molecules signaling that the cell is cancerous, but if there are enough checkpoint proteins on the cell surface, the immune system may overlook the "bad" signals. The best known example of a checkpoint protein is PD-L1 (for Programmed Death Ligand 1; its receptor is PD-1). The body needs PD-L1 to keep the immune system T-cells from attacking healthy cells. Cancer cells may upregulate (speed up the production of) PD-L1 as a protective mechanism. When PD-L1 activates the PD-1 receptor on the surface of a T-cell, the T-cell is signalled to destroy itself. If the T-cells are programmed to selectively attack cancer cells, that set of T-cells will be destroyed. The cancer wins.

Checkpoint inhibitors (also known as immune checkpoint modulators, or CPMs) are designed to lessen the effectiveness of checkpoint proteins. They could have a variety of mechanisms of action, but if effective they let the immune system see the other molecules on the surface of the cancer cells.

It appears that checkpoint inhibitors are a major reason why cancer immunotherapies don't work very well, so far.

Prior to the understanding of the role of checkpoint proteins, it was thought that cancers could be destroyed by mechanisms that teach the immune system to recognize particular molecules (antigens) on the surfaces of cancer cells. These molecules typically would not be found, or would be minimal, on the surfaces of healthy cells. The results would be destruction of the cancer cells with little in the way of side effects. In fact, the kind of side effects of traditional chemotherapy (including the risk of death, particularly in older, frail patients) have not been a very significant problem for the immune therapies. Their problem has been that they have not been cures. Like many cancer therapies, they help some patients, for a while, but in themselves (so far) have not been permanent cures for most patients.

If a CPM can expose cancers to the immune system without causing that same system to attack healthy tissue, it would be a major breakthrough in the war against cancer. It is possible that checkpoint inhibitors in themselves could act as single therapies. They could also be combined with immune therapies to aggressively attack cancers before they have time to mutate or otherwise develop a defensive response. Combining them with more traditional methods like surgery, radiation therapy, chemotherapy and especially the new therapies that are targeted at specific cancer mechanisms is also likely to be beneficial.

With genetic sampling of individual cancers, in the future (around, perhaps, 2025) a patient may be able to get a custom-crafted combination of therapies that rapidly and totally eliminates any particular cancer.

One checkpoint inhibitor, Yervoy (Ipilimumab) has already been approved by the FDA to treat melanoma (skin cancer) and is marketed by Bristol-Myers Squibb (BMS). Yervoy works by targeting CTLA-4, which is present on the surface of T-cellsa and acts to keep the immune system from becoming overly active. Some cancer cells use CTLA-4 expression to tell the immune system to ignore them. Yervoy is an artificial antibody that blocks T-cells from being stopped by CTLA-4. This, of course, can cause side effects, as the immune system will attack some healthy cells as well, but in the best case scenario the cancer is destroyed and CTLA-4 mechanisms return to normal when Yervoy is stopped. In clinical trials for metastatic melanoma about 20% of patients treated with Yervoy as a single agent remained alive over 3 years, as compared to an 8-months of life expectancy for standard care for the disease.

Dr. J. Joseph Yim, one of the developers of DNA-vaccine T-cell based cancer immunotherapies and CEO of Inovio, has stated that "checkpoint inhibitors alone are good but not good enough." He has explained that checkpoint inhibitors take the brakes off T-cells, while active immunotherapies press the accelerator on T-cells.

In addition to academic research and BMS, a number of biotechnology companies are working on bringing checkpoint inhibitors forward to patients. Merck, Roche, AstraZeneca's MedImmune division, Jounce Therapeutics and Agenus and other biotechnology companies all have potential checkpoint inhibitor candidates in the works.

Merck's anti-PD-1 therapy MK-3475 for melanoma, while not yet approved for commercial use by the FDA, does have an expanded access program approved, allowing more patients to try it in clinical trials [see approval notice below]. Roche's RG7446 is also in early clinical trials for solid cancers including lung cancer; it targets PD-L1. MedImmune has MEDI4736, Anti-PD-L1 MAb also in Phase I trials for solid tumors and melanoma.

Pre-clinical trials (with lab animal) have shown that combining PD-1 and CTLA-4 therapies has results that are statistically better than either therapy alone.

A word of caution, however. Cancer has been a very formidable foe for human science. While it is much better understood than it was even in the recent past, there may be other obstacles to a 100% cure beyond what we understand today.

Disclaimer: William P. Meyers owns shares of Inovio, Dendreon, and Agenus as of the time of writing this article.

More information:

New Drugs Free the Immune System to Fight Cancer by Jedd D. Wolchok, Scientific American, Volume 310, Issue 5

Merck Receives Accelerated Approval of KEYTRUDA® (pembrolizumab), the First FDA-Approved Anti-PD-1 Therapy [Press release September 4, 2014]

Agenus Presentation [June 5, 2014] (particularly slides 6 to 20)

the downside: Immune System, Unleashed by Cancer Therapies, Can Attack Organs