CTLA-4 Release the Kraken! Own Immune System May Be The Key to Thwarting Cancer... Vol 7 rel 11

Today James P. Allison and Tasuku Honjo have been awarded the Nobel Prize in chemistry for their discovery of a type of cancer treatment that harnesses a person's own immune system, the Nobel Assembly at Karolinska Institutet announced this morning (Oct. 1).

"By stimulating the inherent ability of our immune system to attack tumor cells this year’s Nobel Laureates have established an entirely new principle for cancer therapy," the Nobel Prize Foundation said in a statement.

James P. Allison (right) and Tasuku Honjo (left) 

were awarded the 2018 Nobel Prize in Medicine.

Credit: Sam Yeh/AFP/Getty Images

Allison, who is a professor at the University of Texas MD Anderson Cancer Center, Houston, was studying a protein called CTLA-4.  CTLA4 or CTLA-4, also known as CD152, is a protein receptor that, functioning as an immune checkpoint, downregulates immune responses. CTLA4 is constitutively expressed in regulatory T cells but only upregulated in conventional T cells after activation - a phenomenon which is particularly notable in cancers. It acts as an "off" switch when bound to CD80 or CD86 on the surface of antigen-presenting cells.  He realized that if he could release that "brake," the immune system would wreak havoc on tumors. Allison developed this idea into a new type of cancer treatment.

IN A NUTCELL

Preclinical data demonstrate that antibodies specific for CTLA-4 can restore an immune response through the increased accumulation, function, and survival of T cells and memory T cells. However, as the depletion of Tregs.14,20,21 Although inhibition of CTLA-4 can improve the antitumor response, it may also lead to immune attack of healthy cells.22 Novel approaches to enhance either the degree or specificity of immune activation with CTLA-4 blockade are under investigation.

CTLA4 STRUCTURE

One recent approach to regulate the degree of immune activity is to increase the depletion of Tregs. A specific type of CTLA-4 antibody with a modified Fc region, known as a non-fucosylated antibody, can bind to Tregs, identifying them for elimination by other immune cells.21,23,24 As shown in mouse models, the increased depletion of Tregs can improve cytotoxic T-cell activation and antitumor activity.25

Another approach aims to improve the specificity of CTLA-4 blockade by reducing antibody binding outside of the tumor microenvironment.27 Antibodies that have been masked with a protein, or pro-antibodies, can have the protein removed by enzymes that are either highly expressed by or only present on tumor cells. Pro-antibodies are therefore active primarily at the tumor site.23,26 Preclinical data indicate that limiting antibody binding to the tumor microenvironment may prevent immune attack of healthy cells, yet still enable an antitumor response

Meanwhile, Honjo, who is now a professor at Kyoto University in Japan, discovered a similar immune system-braking protein. Called PD-1, this protein, he found, functions as a T-cell brake but via a different mechanism than CTLA-4 uses. Honjo's research led to the clinical development of treating cancer patients by targeting that protein.

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Source(s)

• https://www.immunooncologyhcp.bmsinformation.com/antitumor-immunity/pathways/CTLA-4-pathway
• https://www.livescience.com/63717-nobel-prize-medicine-2018.html
• https://en.wikipedia.org/wiki/CTLA-4

So “Once more unto the breach, dear friends, once more;”

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