For many years, the focus of cancer treatment has been to kill or destroy cancer cells with chemotherapy and radiation. But new research from the Duke Cancer Institute is shifting how doctors view cancer and approach treatment decisions.
As part of our ongoing Conversations in Cancer video series, Diane Reedy-Lagunes, MD, a medical oncologist at Duke Health, talks to Nicholas DeVito, MD, a Duke researcher and immunologist who treats colon and other gastrointestinal (GI) cancers. His research suggests that for an increasing number of GI cancers, including colorectal cancer, certain types of immunotherapies–-namely checkpoint inhibitors–-may one day replace harsh cancer treatments and their toxic side effects as first-line therapy.
Duke Health experts discuss the use of checkpoint inhibitors in fighting cancer.
What Is the Difference Between Chemotherapy and Immunotherapy?
Dr. DeVito: Chemotherapy kills fast-growing cells in the body, but often causes strong, sometimes debilitating side effects that can build up over time.
Immunotherapy trains the body to recognize and fight cancer cells and has more manageable and less harmful side effects.
My research focuses on immunotherapy that blocks the correct immune checkpoints and suppressive cells that trick the body into thinking the cancer should stay.
Explain Your Novel Way of Talking About Cancer
Dr. Devito: I think of cancer as a "neo" organ that grows and fights the immune system every day. Most of the time, the immune system wins, thanks to dendritic cells, which identify which cells belong in the body and teach T-cells which cells to target.
Cancer occurs after mutations develop in a tissue, and also when it finds a way to evade the immune system. When immune cells attack a cancer cell, it responds by using a "checkpoint" protein-such as PD-1, PD-L1, or CTLA-4-that disguises it as a healthy cell. Cancers can also bring in defensive immune cells to make them even harder to detect. As a result, the immune system no longer fights it, and the tumor grows unchecked.
When you view cancer through this lens, you stop thinking only about killing cells and start focusing on how to retrain the immune system to reject tumors.
Help Us Understand How Checkpoint Inhibitors Work
Dr. DeVito: Immune checkpoint inhibitors help the immune system recognize and attack cancer cells by blocking those "checkpoint" proteins--PD-1, PD-L1, and CTLA-4--that trick the immune system into thinking they are healthy and belong, and permit T-cells to destroy these cells.
Immune checkpoint inhibitors first showed clinical success in melanoma. In that type of cancer, often the only thing holding back the immune system is PD-1, so if you block PD-1, you eliminate the cancer. Checkpoint inhibitors are now used to treat other cancers, including lung and bladder cancer.
But they aren't successful in all cancers. For example, they are not successful in a common subtype of metastatic colorectal cancer called microsatellite-stable colon cancer. This means there are other mechanisms suppressing the immune system.
That is why it’s not enough to just bring in more T-cells. Some cancers require that we choreograph all the fighting cells and the ones defending the cancer to build a more accurate immune response. We want to understand what makes immune checkpoint inhibitors work better in some cases, and what suppresses the immune system in others.
What Did Your Research Show?
Dr. DeVito: Our trial studied 15 patients with stage 4, microsatellite-stable colorectal cancer that does not involve the liver, bone, or brain. It is often treated with multiple chemotherapies in combination with targeted therapies. In our trial, immunotherapy was given before any chemotherapy, which was only given as a backup, if needed.
We were able to delay chemotherapy by at least 8 months, and only 4 pts out of the 14 with responses had to start chemotherapy. In 2 patients, the tumors shrank by at least 30 percent. These patients were never supposed to respond to therapy.
In a cancer where there’s no FDA-approved immunotherapy, we’ve taken a late-line therapy with promising data and moved it to the front line.
Does Your Research Play a Role in the Rising Incidence of Colon Cancer in Young People?
Dr. DeVito: The participants in our trial are mostly around age 50. Several of the patients are under the age of 45, including the one with the most remarkable response, who is only 30 years old.
Think about being diagnosed with a metastatic cancer at that stage in life. You would want a tolerable therapy with good disease control for a long period of time. That is not sequential lines of chemotherapy. The fact that we're seeing colon cancer rise in young people is evidence that we need better, more durable therapies, and we should be giving them first rather than waiting.
With more young people being diagnosed with colon cancer, we need to change the way colon cancer is treated rapidly. This trial is meeting that challenge by developing therapeutics we can offer to patients in hopes of getting a good response, or if not, then to delay their chemotherapy.
How Was Your Trial Different from a Typical Clinical Trial?
Dr. DeVito: Often, an investigational drug is tested in trials after all standard-of-care options have been exhausted. But are you really giving that drug a fair shot? You're seeing a tumor that may have been treated with several different chemotherapy regimens. There are so many differences between patients, and we don't know how the cancer may have evolved because of those treatments. We have no idea how many drugs have been thrown out because they didn't work as a fourth- or sixth-line treatment.
By treating patients with immunotherapy first, as we did in this trial, you get to see how the tumor changes in response to that therapy only. You can measure the signals that are very clean, and you can assess the benefit quickly. We have a well-controlled dataset of these patients, and it gives us a unique window into how the immune system changes over time. We know because there are no other variables, like previous treatments, convoluting our results. We have a scientific rationale for our logic to give immunotherapy earlier, and why we think the field should move in this direction.
How Was Your Trial Funded?
Dr. DeVito: It was supported by a nonprofit organization called Gateway for Cancer Research, which is funded by a patient who thought cancer treatments were too focused on killing cancer and not on the patient. I am extremely grateful for their support of this ground-breaking trial.
Could Your Work Apply to Other Cancers?
Dr. DeVito: I hope my work in colon cancer and being bolder and more dynamic leads others to consider giving immunotherapy first and saving chemotherapy as a backup plan.
I hope more people want to learn about treating cancer with immunotherapy in this setting to build on incremental, but durable success. This could be done for other cancers that I do not treat, from ovarian cancer to glioblastoma.
Creativity is what’s needed; that’s the bottom line.
And we need patient-first trials that are forward-thinking like this. I can't emphasize enough that the most validating aspect of this work is that we recruited in half the time we expected to, and it's purely driven by patients. They want this approach and know the standard of care isn't good enough.
