Emerging STING therapy combined with current standard could treat aggressive AML

CANCER DIGEST – May 12, 2024 – A new combination therapy may offer new hope to patients with an aggressive form of common leukemia, results of a laboratory study show.

The study conducted by researchers at The Walter and Eliza Hall Institute of Medical Research in Victoria, Australia tested the combination of a current standard therapy for acute myeloid leukemia (AML) called, venetoclax, and a new class of drugs called, STING agonists in a variety of cell lines including human AML cells. 

Because the STING-targeted drugs are currently in clinical trials and venetoclax is a current standard therapy for AML, the researchers led by Professor Andrew Wei are hopeful a clinical trial using the combination therapy could be launched soon. The study results were published in the April 25, 2024 journal Cancer Cell.

“While early clinical trials in solid cancers have suggested STING agonists are well tolerated in the body, these results offer exciting new hope for patients with the most resistant forms of leukemia,” said Prof Wei in a press release. “Given STING agonists are currently in clinical trials, we hope to conduct human studies using STING agonists in combination with venetoclax in the near future.

In their study, the researchers tested the combination of venetoclax with a STING agonist, a type of immunotherapy drug, against more aggressive and more difficult forms of AML. They found the combination treatment displayed a strong potential to kill AML cancer cells that had a mutation in a gene, called P53. 

P53 is a protein that plays a key role in keeping cells from dividing out of control as cancer cells do. When P53 is mutated the defective cell is at a much higher risk of becoming cancerous. P53 mutations are found in about half of all human cancers.

STING agonists detect and promote the immune system response to cancer cells. In normal cells that become damaged or too old, a process of cell death, called apoptosis, occurs. Cancer cells, however, mute that process by over producing a gene called BCL-2. When too much of this BCL-2 protein is present, the apoptosis mechanism is blocked. Venetoclax targets cells that produce too much BCL-2, resulting in restoring apoptosis allowing the cancer cells to self-destruct.

In aggressive cancers, however, the response may not be enough to kill all of the cancer. Adding a STING agonist gives the immune system an added boost in targeting remaining cancer cells.

“Within a cancer cell, venetoclax blocks the machinery of the cell that is keeping it alive," Assoc Prof Gemma Kelly, of WEHI’s Blood Cells and Blood Cancer division and co-author of the study, said in a press release. "In certain blood cancers where this response is sub-optimal, STING agonists can supercharge this effect to deliver cancer a deathly blow.” 

In the laboratory the combination of the two drugs resulted in highly effective eradication of AML cancer cells. In addition, the study provided evidence that adding STING agonists to other cancer therapies may be effective against other types of cancer as well.

The STING agonist used in this study is expected to enter clinical development for the treatment of AML later this year.

Sources: WEHI press release