Putting the Brakes on Cancer: A Look into Immune Checkpoint Therapy

Written by Alexander Egipto and Edited by Ashima Seth

The fight against cancer is an ever-changing battlefield for researchers given its intrinsic quality to adapt to the physiological environment it is in. The 2018 Nobel Prize in Physiology and Medicine recognized a crucial development in re-enabling the body’s immune system to target cancer; researchers James P. Allison and Tasuku Honjo, working independently, studied two separate proteins that act to inhibit immune system function. By preventing the function of these molecular “brakes”, Honjo and Allison freed the immune system to act on the cancer cells present in the body [1].

One of the immune system’s most important functions is being able to differentiate between native cells and non-native cells in the body. This is accomplished through immune checkpoint molecules, or molecules that are involved in regulating the response of the immune system [2]. T-cells are a subset of white blood cells that primarily destroy infected cells – and in producing these checkpoint molecules, they show their capability for self-regulation.

The checkpoint molecules Allison and Honjo discovered, CTLA-4 and PD-1, can be seen as some of the first promising targets for instigating the immune system against cancer. Both proteins act to inhibit T-cells. CTLA-4 and PD-1 share many similarities: both are expressed by active T-cells, the molecules binding to T-cells determine whether or not they’re made, and both work to limit T-cell survivability and growth [3]. While both proteins can be viewed as “brakes” present in the immune system, they operate under mechanisms that are different enough to be viewed as separate points of medical treatment.

CTLA-4 is a protein typically active early on in a body’s immune response and is only expressed by T-cells. If the amount of CTLA-4 present on a T-cell’s surface is high, that T-cell will suffer decreased growth and survival rates [3]. PD-1 is usually active later on in a body’s immune response and is made by T-cells, as well as by other immune cells, when their receptors have been active too long. A key mechanism of tumor cells involves making the molecule that PD-1 binds to in order to increase its activity and ultimately decrease T-cell growth and survival [3]. While the discovery of these proteins was important, it was learning what happened in their absence that led to the development of key, lifesaving anti-cancer drugs.

The inhibition of these proteins has produced notable effects in cancer patients. Researchers were recently able to isolate a set of T-cell targets found in patients with melanoma, more commonly known as skin cancer. After treating these patients with ipilimumab, a drug that inhibits CTLA-4, the immune system was free to find cancer cells upon detecting the T-cell targets [4]. By finding this set of T-cell targets, Snyder and his research group have provided health professionals another avenue with which to verify the use of anti-CTLA-4 drugs on melanoma patients. Meanwhile, PD-1 blocking drugs have generated response rates as high as 70% in patients with a rare subtype of melanoma [5]. Unlike anti-CTLA-4 drugs, however, anti-PD-1 drugs have been observed to be better at specifically targeting tumors, have lower levels of toxicity, and appear to target a wider spectrum of cancers [6].
Since the discovery of these proteins, new checkpoint molecules such as LAG-3, Natural Killer cells of the immune system, and TIM-3 have been made the target of novel research [6]. Such new research will hopefully lead to the development of new drugs that can be used alongside what we have now to better continue our fight against cancer.

References:

6. Topalian S, Drake C, Pardoll D. (2015), Immune Checkpoint Blockade: A Common Denominator Approach to Cancer Therapy.
Cancer Cell, 27: 450-61.

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