Humans are not mice. Their differences are both obvious and subtle. But they possess significant biological similarities. And Yale researchers have developed models of mice that could prove the key to creating individualized treatment for some of the deadliest diseases for women, such as breast cancer and uterine serous cancer (USC).
“The possibilities are enormous,” said Dr. Alfred Bothwell, a Professor of Immunobiology at Yale School of Medicine. “It’s an amazing time.”
Breast cancer is the most common cancer in women, affecting 220,000 women and killing 41,000. Uterine serous cancer spreads quickly and kills 70 percent of patients within five years.
Using a unique type of mouse developed at Yale, Bothwell and Therapeutic Radiology and Genetics Professor Joann Sweasy, Ph.D. have led WHRY-sponsored efforts to develop new ways to treat these and other cancers.
The Human Immune System and Cancer
A technique commonly used to test the effect of a drug on a cancer is to implant human tumors into mice to see if the drug might shrink the tumor. Researchers often find that a drug might shrink the tumor in mice but fail to have a similar beneficial effect when the drug advances to trials in human subjects.
The reason? The tumor does not exist in a vacuum. Dr. Alessandro Santin, Yale Professor of Professor of Obstetrics, Gynecology, and Reproductive Sciences, determined that the immune system of the animal fighting the cancer plays a role in tumor growth and responses to therapies.
“All of us have cells growing inside us that could become tumors, but our immune systems work to eradicate these aberrant cells before they become tumors,” Sweasy said. “This important concept has led the way to a new kind of cancer therapy.”
But first the researchers needed proof of their concept. And to get that proof, they needed a special kind of mouse.
Dr. Richard A. Flavell, Sterling Professor of Immunobiology and Chair of the department, developed a mouse with no internal immune system. These mice had none of the specialized white blood cells called lymphocytes that make proteins called antibodies to target antigens — potentially harmful outside substances such as viruses, bacteria, chemicals, and parasites.
Starting in 2009, Sweasy’s team used a pilot project grant from Women’s Health Research at Yale to implant human breast cancer cells into this new strain of immune-deficient mice. They then injected lymphocytes — called B and T cells — from the patients into the mice to reconstitute each patient’s individual immune system and see how the mice reacted to various treatments compared to mice without a human immune system.
When the researchers treated the mice with ionizing radiation — a standard therapy for breast cancer — they found the best results in mice receiving the treatment that also possessed the patients’ immune systems.
“The mice with the patients’ immune systems definitely had human lymphocytes in the tumor,” Sweasy said. “A clear sign that the patients’ immune systems were fighting the tumor.”
But immune systems can overreact.
Sometimes the body mistakes its own cells for dangerous invaders and attacks them, producing serious complications called autoimmune disorders. To protect against this type of self-inflicted damage, the body uses a series of immune checkpoints — molecules on immune cells that need to be activated in order to trigger an immune response.
And many times, cancerous tumors hijack this self-defense against collateral damage, avoiding destruction by acting like the body’s own harmless cells and inactivating the T cells that would otherwise fight invaders and harmful cancer cells.
But recently, Yale researchers have led the way in developing methods to block these checkpoints and release this natural anti-tumor immunity to fight cancer, a therapy dubbed immune checkpoint blockade.
Genetics and Cancer
Heredity of traits from generation to generation of almost all living things is conducted by deoxyribonucleic acid, or DNA, a self-replicating material that carries a genetic code directing the production of proteins, the building blocks of cells.
Cells occasionally undergo mutations, a permanent change in the sequence of DNA created through replication error or unrepaired damage.
Santin observed that 8 percent of patients with uterine serous cancer had thousands and thousands of mutations in their tumors when typically USC tumors only have hundreds of mutations. These hypermutations were likely due to a change in the proofreading function of a DNA-creating enzyme called DNA polymerase E (POL E).
Because of all of these mutations, proteins in a USC tumor cell look different, with the potential to act as what researchers call neo-antigens, which are foreign substances that the body has not previously encountered and identified. No longer blocked by a cancer-manipulated immune checkpoint, the T cells recognize the neo-antigens as foreign bodies and kill the tumor. Taking advantage of this dynamic, doctors can now inject neo-antigens into a patient who does not have the hypermutations to disrupt these immune checkpoints and let the body’s immune system do its job.
“Yale is the leader in this new therapy,” Sweasy said. “It’s what we’re known for.”
Dr. Santin discovered that patients with the POL E mutation do not appear to benefit from chemotherapy because the tumors are resistant to it. Instead, they would be better treated with immune therapy.
In 2014, Dr. Bothwell received a pilot project grant from Women’s Health Research at Yale to understand the mechanism of this protective effect, possibly leading to new therapeutic strategies.
“We are working to identify more precise biological targets to render tumors more detectable by the immune system,” Bothwell said. “We are only at the very beginning of being able to understand the consequences of what the mutations mean.”
As Bothwell’s team continues to make progress on his study’s goals, he envisions a future in which cancer patients receive personalized treatment based on their distinct tumor and the specific sensitivities of their own immune systems.
“My goal is to be able to put a tumor from a cancer patient as well as the human immune system from the same patient in a mouse,” he said. “Then test what particular therapies work for that particular patient.”
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