August 2013

CHOP Researchers Advance New Anti-Tumor Immunotherapy Approach

Immunotherapy

By carefully adjusting the function of crucial immune cells, Children’s Hospital investigators may have developed a completely new type of cancer immunotherapy, which involves harnessing the body’s immune system to attack tumors. To accomplish this, they had to thread a needle in immune function, shrinking tumors without triggering unwanted autoimmune responses.

The new research, performed in animals, is not ready for clinical use in humans. However, the approach, which makes use of a key protein to control immune function, lends itself to further study using candidate drugs that employ the same mechanisms.

“This preclinical study demonstrates proof of principle that using a drug to regulate the function of a special, immunosuppressive subset of so-called T-regulatory (Treg) cells safely controls tumor growth,” said the study’s leader Wayne W. Hancock, MD, PhD, chief of the Division of Transplant Immunology. “It really moves the field along towards a potentially major, new cancer immunotherapy.”

Dr. Hancock and his colleagues published the study recently in Nature Medicine.

“There’s a basic paradox in immunology: why doesn’t the immune system prevent cancer in the first place?” said Dr. Hancock. The answer is complicated, he adds, but much of it involves a delicate balancing act among elements of the immune system: while immunity protects us against disease, an overly aggressive immune response may trigger dangerous, even life-threatening, autoimmune reactions in which the body attacks itself.

In the current study, Dr. Hancock focused on a subtype of immune cells called Foxp3+ T regulatory cells, or Tregs. Tregs were already known to limit autoimmunity, but often at the cost of curtailing immune responses against tumors. “We needed to find a way to reduce Treg function in a way that permits antitumor activity without allowing autoimmune reactions,” Dr. Hancock said.

The investigators showed that inhibiting the enzyme p300 can affect the functions of another protein, Foxp3, which plays a key role in controlling the biology of Tregs. By deleting the gene that expresses p300, the researchers safely reduced Treg function and limited tumor growth in mice. Notably, they also achieved the same effects on p300 and Tregs in mice by using a drug that inhibits p300 in normal mice.

Dr. Hancock plans to pursue further investigations into targeting p300 in immunotherapy. The preclinical findings offer encouraging potential for being translated into the clinic, said Dr. Hancock, who added that pharmaceutical companies have expressed interest in researching this approach as a possible cancer therapy.

The antitumor study, down-regulating Treg function, is the flip side of another part of Dr. Hancock’s Treg research. In a 2007 animal study, also in Nature Medicine, he increased Treg function with the goal of suppressing the immune response to allow the body to better tolerate organ transplants. In the current study, decreasing Treg activity permitted the immune system to attack an unwelcome visitor — a tumor. In both cases, he relied on epigenetic processes — using groups of chemicals called acetyl groups to modify key proteins — but in opposite directions.

“This is the yin and yang of immune function,” Dr. Hancock noted.

Share This

Print