Two medications, Daurismo and Venclexta, have passed the final rounds of review by the US Food and Drug Administration (FDA) and been approved for patients with acute myeloid leukemia (AML). These drugs are intended for use in patients who are not candidates for intensive chemotherapy. Intensive chemotherapy is not recommended for patients over the age of 75 or those with certain health conditions due to the severe side effects that it causes.

Daurismo, marketed by Pfizer, was tested in clinical trials in combination with a low-dose of the chemotherapy drug, cytarabine. Known as a hedgehog inhibitor, Daurismo is a targeted medicine that interferes with the hedgehog-signaling pathway. The hedgehog-signaling pathway is involved in cell differentiation and growth, and problems in this pathway can cause out-of-control cell growth and lead to certain types of cancers, such as AML. Daurismo was tested in a randomized clinical trial of approximately 100 people. Patients who received Daurismo in addition to cytarabine lived an average of four months longer than those who only received the chemotherapy.

The drug Venclexta is already available to patients with chronic lymphocytic leukemia, but the FDA expanded its approved indications to include AML after two non-randomized clinical trials. These trials measured the number of AML patients who went into complete remission, meaning there were no traces of cancer in the body, and how long they stayed in remission.

In the first trial, 37 percent of patients achieved complete remission after receiving Venclexta along with the chemotherapy drug azacitidine and stayed in remission for an average of 5.5 months. In the same study, 54 percent of patients who received Venclexta and decitabine, another chemotherapy drug, went into complete remission that lasted for an average of 4.7 months. In the other trial, 21 percent of patients achieved complete remission for an average of six months when Venclexta was used with cytarabine. Venclexta was developed by AbbVie and is marketed by AbbVie and Genentech USA Inc (Roche).

Both medications were reviewed under special FDA procedures that are used to speed up the approval process for medicines to treat serious illnesses without adequate alternatives. They were also granted orphan drug designation, which provides modest financial incentives to companies to encourage the development of drugs for rare diseases.

A study by investigators at the Dana-Farber Cancer Institute suggests that neoantigens could play a role in treating glioblastomas. Patients in this study received a personalized vaccine that led to longer survival compared to most patients with glioblastomas, suggesting that selectively stimulating these tumors could be the key to curing them.

Glioblastomas are malignant brain tumors that are usually slow growing but can become aggressive. By the time these tumors are discovered, they are typically Grade IV, meaning they grow rapidly, have bizarre cellular appearances and easily infiltrate nearby brain tissue. They are also capable of forming new blood vessels (angiogenesis), which allows them to absorb more nutrients and continue growing. In addition to their location and rapid growth, glioblastomas are “cold” tumors, meaning they contain very few immune cells. Immune cells are recognized by the body as cells requiring action; since these tumors contain very few of those cells, the immune system does not respond properly.

To combat the lack of immune cells, David Reardon, clinical director of the Center for Neuro-Oncology at Dana-Farber, performed a study with a neoantigen vaccine for glioblastomas, published in Nature. The vaccine used in the study was a personalized ‘neoantigen’ serum that caused an immune response against glioblastomas. Like other cancers, glioblastomas contain DNA mutations that cause cells to reproduce rapidly and create tumors. Some of these mutations, including those in glioblastomas, cause cancer cells to display peptide molecules — or neoantigens — on the cell’s surface. Neoantigens are not present on healthy cells, making them relatively easy targets for the immune system.

To attack the tumor cells, researchers created personalized vaccines by removing and analyzing tissue from tumor and healthy cells in the patient. Once they identified which neoantigens were present in the tumor, proteins from the neoantigens were synthesized in a laboratory to form the base of the vaccine. After being administered, the vaccine encourages the body to create T-cells that migrate to the brain tumor, causing inflammation around the cancer cells. Then, the neoantigens in the serum “teach” the patient’s immune system how to detect and attack tumor cells.

The eight patients in the study received vaccines containing between seven and twenty neoantigen peptides. All of the patients ultimately died from their tumors, but they survived longer than average for glioblastoma patients. Reardon is encouraged by the results of this preliminary study.

“The next step is to add an immunotherapy drug called a checkpoint inhibitor, aimed at freeing the immune response from molecular ‘brakes’ so that the T-cells can react more strongly against the tumor,” Reardon said.

The combination of a neoantigen vaccine with a checkpoint inhibitor should lead to a stronger immune response and potentially extended survival without tumor spread and thus, the possibility of a cure.