New Therapy Extends Breast Cancer Survival Rate, Prevents Recurrence

A new immunotherapy developed by researchers at Northwestern University dramatically extends the survival time of mice with triple negative breast cancer, one of the most aggressive and difficult-to-treat forms of breast cancer.

In a new study, the mice treated with the therapy, comprising two immunity-boosting drugs housed within a nanoparticle, underwent complete remission of the tumor for at least 100 days. All untreated mice died before day 30. None of the treated mice experienced adverse side effects or autoimmune responses.

The nanoparticle, called spherical nucleic acid (SNA), is a globular form of DNA that can easily enter and stimulate immune cells. Chad A. Mirkin of Northwestern, who led the study and invented SNAs, credits the shape and structure of nanoparticles for the success of immunotherapy.

“We have shown that the overall structural presentation of a cancer or immunotherapeutic vaccine, not simply the active chemical components, can dramatically affect its potency,” said Mirkin. “This finding is opening doors in an emerging field that we call ‘rational vaccination’ and could lead to treatments for many different types of cancer.”

The research will be published online during the week of July 13, 2020 in the procedures of the National Academy of Sciences.

Mirkin is a George B. Rathmann professor of chemistry at Northwestern Weinberg College of Arts and Sciences, director of the International Institute of Nanotechnology and a member of the Robert H. Lurie Comprehensive Cancer Center at Northwestern University.

How does it work

Typical immunotherapies consist of a tumor cell molecule (s) (called antigens) paired with a molecule (called an adjuvant) that stimulates the immune system. The most advanced forms consist of a cocktail of antigen molecules taken from a patient’s cancer cells (called lysates). The lysate trains the immune system to recognize its target (the tumor), and the adjuvant increases the body’s immune response to destroy that target. Doctors mix the lysate and the adjuvant in a cell culture and then inject the mixture into the patient.

Because therapy is a structurally ill-defined mix, Mirkin calls this the “blender approach.” The lysate and the adjuvant are not packaged together, making it difficult to ensure they reach the same goal.

“Statistically, you will get some cells that absorb both the lysate and the adjuvant,” said Cassandra Callmann, a postdoctoral fellow in Mirkin’s lab and the first author of the article. “But you will also get some cells that only receive one or the other. To maximize the potency of immunotherapy, you must jointly deliver to the same target cells and in the most effective form or structure possible.”

To overcome this challenge, Mirkin’s team packaged the lysate and adjuvant together within the nucleus of an SNA. In the study, they injected SNA under the skin of mice with triple negative breast cancer. SNAs traveled to the lymph nodes of the mice, entered the cells, and released their cargo. This caused an immune response within the cells to combat lysate.

Longer survival, prevention of recurrence

After treating nine mice with triple negative breast cancer, six experienced complete tumor remission for 100 days with no obvious side effects. Although the other three mice never reached remission, the new treatment suppressed their tumor growth, and the mice still lived longer than the control group.

“It is definitely prolonging survival,” Callmann said. “Even if not all of the mice were completely healed.”

Mirkin and his team also found that SNA-based immunotherapy protected mice from relapse. After the mice went into remission, the team tried to reimplant them with cancer, but the tumors did not grow.

When Mirkin’s team removed and examined the tumors from mice treated with therapy, the researchers found an increased number of cytotoxic T cells, a type of immune cell that attacks the disease, and a reduced number of immunosuppressive cells, which prevent the system from immune respond to fight disease

“If immunotherapy protects mice against cancer recurrence, then we can use this in a preventive context,” said Mirkin, a fellow at the Robert H. Lurie Comprehensive Cancer Center at Northwestern University. “Our study suggests that the therapy is providing ‘immune memory.'” That is something we are investigating at the moment. “

Interestingly, a stronger immune response occurred when the researchers incorporated oxidized tumor cells into the ANS. In making the lysate, the researchers treated the tumor cells with hypochlorous acid, which oxidizes and kills the cells. Other researchers have noted in previous clinical studies that oxidized cells create more powerful immunotherapies.

“We have confirmed that it is true,” Callmann said. “And we demonstrate that the immune system gives an even better response if the oxidized lysate is also packaged in an SNA.”

Exploring other cancers

Mirkin’s team first tested the new therapy on triple negative breast cancer tumors because cancer is one of the most difficult to treat. According to the Triple Negative Breast Cancer Foundation, this disease represents 15% -20% of all breast cancers. Cancer tests negative for three proteins (hence the name “triple negative”) produced in large amounts by other types of breast cancer. It resists the commonly used breast cancer drugs that target those three proteins.

“It is one of the most deadly and aggressive forms of breast cancer,” said Callmann. “There are many different types of mutations, and some of the cells mutate very quickly. There is an immediate need for new treatments that work.”

The researchers believe that, in theory, SNA-based immunotherapies should be an effective treatment for many types of cancer. Mirkin’s team plans to explore that next. Mirkin notes that he is encouraged that four ANS drugs are already in human clinical trials, including a variant of ANS used in this study in a type of immunotherapy for Merkel cell carcinoma. That structure was also invented at Northwestern and is in a phase 2 clinical trial conducted by Exicure, a clinical-stage biotech startup.