The Presidential Distinguished Senior Research Scholar award recognizes Curiel’s interdisciplinary approach to thinking about cancer as an infection and his research on its root causes.
His pending publication of several key discoveries in ongoing cancer research uncover how cancer cells manage to survive in the human body. This discovery should help doctors devise more effective treatments of almost any cancer.
The road to Curiel’s cancer treatment discovery started with research, and in particular, how he became both a medical practitioner and a top tier scientist.
Curiel cross-trained as both an infectious disease consulting physician and as an oncologist, which complemented his initial training as an immunologist working on the opportunistic infections of AIDS patients. Additionally he became a researcher and co-founded the first cancer training program to double train doctors in infectious diseases and cancers, funded by the National Institute of Allergy and Infectious Diseases (NIAID) and the National Cancer Institute (NCI).
This interdisciplinary approach turned out to be important as cancer treatment shifted to focus on cancer immunotherapy. Curiel had thought he would leave his infectious disease research behind to focus more on cancer and autoimmunity.
As it turns out, cancer, chronic infections, and the immune system are all intrinsically interrelated — and that understanding is what drives the paradigm shift in cancer research.
Cancer: Mirror Image of Autoimmunity
Around 2009, Curiel started thinking about the common qualities cancer and autoimmune diseases share.
“It’s been known for a long time that chronic infections and cancers have lots of similarities, but I was thinking that cancer and autoimmunity are also similar in having mirror image immune outcomes,” he said.
One way to understand how cancer and autoimmunity share common qualities is to think about why women tend to have more autoimmune diseases, such as lupus or Hashimoto’s disease, than men.
Curiel asked, “What can women do that men cannot do? They have babies.”
Women suppress their own immune systems for nine months as the fetus gestates. This temporary suppression is the reason women are able to give birth to healthy babies without their immune system attacking the developing fetus.
“Babies grow faster than any cancer,” Curiel said.
When a person has an infection, the immune system is activated to fight off the invading cells, triggering an inflammatory response. That swollen spot where you cut yourself is your body’s way of fighting off the bacteria in the wound, with white blood cells surrounding and killing the bacteria.
Once the infection is stopped, the immune system switches off to avoid lasting damage from chronic inflammation. The immune system is always turned on for people suffering from autoimmune diseases. Uncontrolled inflammation plays a role in many major diseases, including cancer, heart disease, diabetes, and Alzheimer’s disease.
In a patient with cancer, the immune system does not turn on to fight the invasive cells because something is suppressing the immune response.
T-Reg Cells: Link between Cancer and Immune Function
The link between fighting an infection, autoimmunity, and cancer is the body’s ability to trigger the appropriate immune response, either by turning it on or off: On to fight infections and cancer cells, off when the infection or cancer is eliminated and to stop autoimmunity.
“I identified a common element in both cases – regulatory T cells, commonly called T-regs,” Curiel said.
Cancer immunotherapy focuses on stopping the development of immune tolerance to the proteins produced by tumor cells, or blocks this tolerance in an established tumor. In immune-based therapy for autoimmune diseases, the treatment approach focuses instead on re-establishing immune tolerance after these mechanisms have broken down, leading to chronic inflammatory disease.
In both cases, T cells are key actors and must be either coaxed into acting when they are inhibited locally – as in cancer – or prevented from acting to stop the chronic damage from the body’s immune system attacking itself in autoimmunity.
“In cancer you have too many T-regs and in autoimmunity you don’t have enough of them,” Curiel said.
T-regs control this balance between too much or not enough immune response.
“We’ve made cool discoveries in the differences in male and female immune response,” Curiel said. “I thought I was streamlining my lab operations (by focusing on cancer and leaving behind infectious disease research).
“I discovered instead that understanding the mechanisms behind both infectious diseases and autoimmunity was a key to cancer immunotherapy research.”
Discovery Pinpoints How Cancer Survives the Immune Response
The common thought before the T-reg cell discovery was that a person got cancer when the body did not produce enough killer cells to fight off the cancer cells. Cancer treatment used to focus on giving patients more “good stuff with transfers of killer T cells, dendritic cells, or magic antigens,” Curiel said.
Because cancer cells are programmed to survive and multiply, Curiel discovered, they generate T-reg cells that turn off the killer T cells, which defend a person’s body “infected” with cancer.
“We were able to show using ovarian cancer as a test case that women had lots of killer cells against ovarian cancer,” Curiel said. “What we found was that something was turning the killer T cells off.
“We started in 2003 with a study that showed how off the shelf drugs available then can kill those T-reg cells in the cancer,” Curiel said. “Our most highly cited paper from Nature Medicine showed how T-reg cells for the cancer prevented the body’s immune defenses from working.”
The Blockade of PD-L1 improves myeloid dendritic cell?mediated antitumor immunity study showed that blocking the PD-L1 protein prevents cancer cells’ T-reg cells from turning off a person’s T-reg cells — and consequently, their immune response to fight off the cancer.
“This discovery should work for the treatment of almost any cancer,” Curiel said. “We no longer have to think about developing drugs for breast or colon cancer. Instead, we develop drugs to kill off T-regs and that way, we kill cancer’s immunity. That’s what launched our revolution.”
Understanding how cancer infects the body has improved with the new concept of immune checkpoints, which a cancer cell uses to turn off a person’s immune response. Pioneered by Jim Allison, the executive director of immunotherapy at the M. D. Anderson Cancer Center, researchers now know that cancers affect many of your body’s immune checkpoints and leaves them on, to fool your immune system into thinking it’s time to stop fighting infections.
In Curiel’s pivotal 2003 study, his team looked at the immune checkpoint in ovarian cancer, which they uncovered was promoting the production of a person’s harmful T-reg cells to prevent the fight against the cancer.
“The checkpoint inhibitors are what have won the early battles — these are the revolutionary immunotherapy drugs you’re hearing about, the antibodies that block these checkpoints so a person’s immune system keeps fighting off cancer,” Curiel said. “These are the hot drugs coming on the market. Jim Allison developed the first drug to be approved for this use, anti-CTLA4.”
CTLA4 (cytotoxic T-lymphocyte-associated protein 4) is a protein receptor that functions as an immune checkpoint, which downregulates or reduces immune responses in T-reg cells.
It is this revolutionary cancer treatment drug that Curiel believes will garner Allison, known as the “Texas T Cell mechanic,” a Nobel prize. In 2013, Science magazine named cancer immunotherapy the breakthrough of the year, citing Allison’s work.
Curiel explained, however, that a drug blocking T-regs alone isn’t enough — a combination approach that targets the different ways cancer cells function is needed for better patient outcomes.
Redefining How Major Cancer Drugs Work
“We’ve identified and published novel mechanisms for these checkpoint antibodies and used this as the basis of our new trials,” Curiel said.
More of Curiel’s work underway now will be published later this year.
The discoveries to be announced in late 2017 will provide more details on the immune checkpoints, uncovering how combination therapies can be used for more effective cancer treatment. Cancer immunotherapy gives a person the ability to inhibit T-reg cells and promote killer T cells that can recognize and fight off cancer, providing a lifetime of cancer protection against recurrence.
That means patients may no longer need to tolerate multiple rounds of chemotherapy or worry about cancer returning.
“The biggest news is the redefining of how major cancer drugs work, adding lots of important details to why some people don’t respond who should and why some people we didn’t think could respond in fact do,” Curiel said. “We’re testing these concepts to see what is useful and how well it will work in humans. It turns out that these (immune) checkpoint antibodies do lots of things no one really knew about.”
Talking to Curiel there is a sense of excitement, of his team getting close to understanding exactly how cancer cells infect a person and how the immune response does or does not work to fight off cancer. These discoveries can also be applied in treating autoimmune diseases as well as aging — the damage to the body from a lifetime of chronic inflammation.
This type of research is expensive, however, especially once the concepts are tested in human trials.
“If there’s a donor willing to write a check for oh, $15 million to $30 million, we could help solve this problem. Of course, we’ll settle for less,” Curiel said with a smile.