May 1 2021 Aileen Ryan

We knew that immunotherapy finally had a breakthrough when James Allison and Tasuku Honjo received the Nobel Prize in Physiology or Medicine in 2018 for “discovery of cancer therapy by inhibition of negative immune regulation.”

Prior to this, our focus in oncology therapy centered on chemotherapy to block the proliferation of cancer cells, and radiation to selectively kill tumor cells, both of which also adversely impacted other rapidly growing cells in the body. More recent advances are targeted agents that inhibit pathways by which cancer cells proliferate. Unfortunately, for the majority of these agents, while they are effective in stopping or delaying the cancer, the cancer cells adapt and find ways to bypass these pathways in their search for dominance.

The discovery by Drs. Allison and Honjo of the ability of tumor cells to shut down our immune system, which would have prevented the cancer from proliferating and taking hold in our bodies, was revolutionary in changing our views of how cancer grows and metastasizes, and how our bodies fight cancer. It also revolutionized our approaches to the treatment of cancer.

The origins of this work go back to the 1990’s when, in mouse models, antibodies that targeted a cell surface marker on T cells called cytotoxic T-lymphocyte antigen 4 (CTLA-4), were shown to stimulate an immune response that resulted in the killing of the tumor cells that had been transplanted into the mice. Another marker, Programmed Death-1 (PD-1), was subsequently identified. This molecule was expressed not only by immune cells, but also by certain cancer cells. It had the ability to prevent our immune system from killing cancer cells. Interestingly, CTLA-4 and PD-1 work by different mechanisms. The modulation of these pathways, whereby tumor cells work to evade the immune system and therapeutics are developed to stop this immune suppression, has come to be known as immune checkpoint inhibition. Monoclonal antibodies that targeted CTLA-4 and the PD-1 pathways were quickly developed by the pharmaceutical industry and entered into clinical trials. To date, many have been approved for a multitude of cancer indications ranging from solid tumors to hematological malignancies, including a number of cancers which have proved to be “chemo-resistant” and, as a result, extremely difficult to treat. At present, there are additional targets in preclinical and clinical development.

Many significant advancements have been made since the research in the 1990’s. However, advancements are often accompanied by challenges. Find out more about the hurdles encountered while developing CTLA-4 and PD-1 targeted treatments in the next installment of this series.

Many significant advancements have been made since the research in the 1990’s. However, advancements are often accompanied by challenges.

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