Immunotherapy in Action
When immunotherapy works in cancer treatment, it can change everything. We see this in Superhuman Body, when young Emily Whitehead was cured with CAR T cell therapy—even though the six-year-old was at death’s door with Acute Lymphocytic Leukemia (ALL). Equally amazing stories are told all over the world—thanks to researchers helping the body in its fight against cancer.
These stories of hope always start with almost unimaginable suffering. For example, in Nottingham, England, John Dabell was first diagnosed with head and neck cancer on his daughter’s second birthday, in 2009. A tumor the size of a golf ball was growing inside his tongue; treatment began with a radical surgery of more than fifteen hours, including a neck dissection to remove all of his lymph nodes. Surgeons had to break his jaw to access the tumor and then remove most of his tongue. Next came thirty-five doses of radiation and six weeks of chemotherapy. He needed tubes to eat and breathe; his jaw was vulnerable to infections, bone damage, and deterioration. Still, John slowly recovered.
But eleven years later, it happened again. Another tumor in his throat. Stage four. John was told he didn’t have long to live. His chemotherapy regimen was stopped because of the COVID lockdown, and his cancer started to spread. John thought he was finally about to lose the battle. However, just in time he was given a round of radiation—and finally, his oncologist started John on a monthly cycle of immunotherapy.
“Understandably, many people dislike and even detest the battleground terminology associated with cancer,” John writes. “But in the case of immunotherapy, your body literally starts fighting back—and mine certainly did!” Little by little, he started to feel better—and, luckily, he’s been identified as an immunotherapy “super responder.” Now he hikes five miles per day, even on his monthly treatment days, where he sits for a one-to-two-hour infusion.
“Immunotherapy is keeping me alive,” he says. “It’s prolonging my life and dare I say it, it’s making me think that it could even cure me. My CT scans have shown that there is no evidence of disease, and that is wonderful.”[1]
Happily, stories like John’s are reported for many cancers. For example, just as CAR T has been a game-changer in the treatment of blood cancers like leukemia and multiple myeloma, other kinds of immunotherapy have worked for different tumor types. For example, survival rates for the most fatal form of skin cancer, melanoma, have increased from less than 10 percent to more than 50 percent.[2] And doctors at MD Anderson in Texas see patients with metastatic bladder cancer—who used to die within a year—receiving treatments for five years or more. Now, immunotherapy is also a standard treatment for lymphoma, cancers of the kidney, stomach, liver, head and neck, and both small-cell and non-small-cell lung cancers.[3]
Because of these successes, researchers are bolstered to improve and expand treatment options. Immunotherapy has made people think that someday cancer will be a thing of the past. Just a routine diagnosis with a routine treatment.
But today, even considering these amazing advancements, immunotherapy doesn’t always work. Understanding why requires first understanding the basics of our immune system.
How Does the Immune System Work, and How Do We Help It?
The primary job of the immune system is to recognize the difference between “self”—you—and “non-self.” Non-self can be a splinter, a parasite, viruses, bacteria—or even cancer—and the immune system is supposed to protect the body by forcing out or killing off invaders.
However, the immune system can go haywire in two ways. In autoimmune diseases, the system detects a “false positive,” misidentifying and killing off healthy cells. On the other hand, many cancers cause the system to detect a “false negative,” because it doesn’t recognize that rogue cells are growing out of control. Since the cancer is produced from our own bodies, our immune systems don’t “recognize” the cancer as non-self.
Helping the immune system to overcome these weaknesses can be thought of in three basic ways:
- Training the immune system to recognize a certain pathogen. This is what vaccines do. They introduce something into the body—perhaps a weakened form or portion of a germ, a toxin created by the germ, or genetic material from the germ—so that the body can develop defenses against that particular invader.[4] After the vaccine response is complete, the immune system remains hyper-alert and ready in case the germ shows up again. Please note: although we’re familiar with vaccines against viruses, unfortunately, cancer vaccines have not proven to be reliably effective. But that might be changing—more on vaccine advancements below.
- Engineering the immune system to fight a certain pathogen. This is what CAR T-cell therapy does. By inserting genetic material into the patient’s own blood cells, the cells bind onto cancer cells and kill them. CAR T is the type of immunotherapy Dr. Carl June developed—and which saved Emily Whitehead. In Emily’s case, her own T cells were engineered specifically to target leukemia. CAR T has been most successful in blood cancers, but not as effective when treating solid tumors.
- Interrupting or changing the usual behavior of immune cells that are not detecting cancer cells. This is what immunotherapy does. It is delivered as a medication that stimulates T cells to identify and kill cancer. However, unlike radiation and chemotherapy, immunotherapy isn’t a procedure or toxic drug that is introduced as an agent to shrink or kill the cancer. Instead, it interacts with the immune system so that a patient’s own cells—usually white blood cells called T cells—can do their usual work, but better. The T cells are stimulated to “see” and kill cancer cells.[5]
Why Does Immunotherapy Sometimes Fail?
Researchers have learned that not all cancers respond to immunotherapy in the same way. Some, including pancreatic cancer, prostate cancer, and glioblastoma, are resistant. According to Padmanee Sharma, MD, PhD, co-leader of MD Anderson’s immunotherapy platform, researchers are learning more about why some tumors are more difficult to treat. For example:
- Tumors can develop mutations or mechanisms that prevent T cells from penetrating the tumor.
- Tumors can “turn down” the T cells’ ability to detect the “non-self,” thereby dampening the anti-tumor immune response.
- Higher numbers of suppressive immune cells might be present in some tumors, which counter the activity of T cells.
- In advanced cancers, the sites of metastasis can have very different cellular environments than where the primary cancer developed. T cells may not function as well in those environments.[6]
Researchers at Washington University School of Medicine in St. Louis also have discovered something else about patients who live longer during the treatment of some stubborn cancers: Those with more dendritic cells do better. “If T cells are the players on a soccer field, dendritic cells are the coaches who get the players pumped up for the game and give them instructions. Without dendritic cells, T cells are subdued and aimless.”[7]
These dendritic cells actually are present in the tumors themselves, so researchers have been able to track their presence—and try to increase their numbers and responsiveness. With more dendritic cells, patients with various types of skin, lung, bone and soft tissue, breast, and cervical cancer respond better to immunotherapy.[8]
The Next Revolutions in Immunotherapy
After 100 years of effort, medicine has finally tapped into the immune system to change the world of cancer care—and recent successes in immunotherapy are encouraging. In fact, research trials are underway in thousands of medical facilities around the world. Arguably the most exciting developments are in “personalized” immunotherapy, where a patient’s T cells are transformed into a “living drug” that fights a particular kind of cancer for years. But there are other important types of immune cells too—and each one has its own set of mechanisms and targets.[9]
This focus on immunotherapy also has changed what’s possible in the use of cancer vaccines, which up to now have shown disappointing results. One exciting vaccine story comes from Elicio Therapeutics, a company created to translate research from Massachusetts Institute of Technology (MIT) laboratories into the treatment of actual patients. Christopher Haqq, now Elicio’s chief medical officer, joined the company in part because his father had a type of aggressive colorectal cancer that resists treatment. “His journey made me realize the enormous need for new therapy,” Haqq said.
The MIT/Elicio team focused on improving cancer vaccines—and discovering why they had been so ineffective. Theoretically, in a cancer vaccine protocol, a patient could be injected with fragments of mutant proteins only expressed in cancer tumor cells—which would allow T cells to “learn to recognize them.” Therefore, the vaccine’s job would be to train the immune system to see and kill cancer cells. It’s been kind of a mystery why cancer vaccines haven’t been successful—until the team identified that they simply weren’t making it to the lymph nodes, where populations of “teachable” T cells are concentrated. After a lot of trial and error, the researchers finally found a way to get the T cells into the lymph nodes, and proved successful. And then the team took their work to the next level, by pairing a cancer-targeted vaccine with CAR T cell therapy. The combination allowed the CAR T cells to attack solid tumors more effectively than usual.[10]
In Elicio’s most recent trials for pancreatic and colorectal cancers, 84 percent of patients showed a significant increase in anti-tumor T cells, and 24 percent saw a complete elimination of residual tumors. Haqq felt that his dad’s story was actually making a difference for patients everywhere. “It gives me hope that we are on the right path to be able to help people just like my dad—and many others,” he said.[11]
Other combinations of therapies using CAR T cells—with chemotherapy, radiation, “killer” viruses, other forms of immunotherapy, and many more—are also proving effective.[12] For example, a team from Memorial Sloan Kettering Cancer Center in New York has reported that combining CAR T and immunotherapy medications—the ones that target the “false negative” response in T cells—is “poised to be the next frontier in immunotherapy,” especially for solid tumors.[13]
As research continues—and patients participate in more and more trials—the number of exciting new therapies will continue to increase. “I want patients to know that we are making advances every day. There are treatments that can offer cures, and we plan to deliver more,” Dr. Sharma says. “Together, we can unlock the promise of immunotherapy.”[14]
Resources
[1] John Dabell, “Immunotherapy is keeping me alive,” The Institute of Cancer Research (ICR website), posted online 13 June, 2023, https://www.icr.ac.uk/blogs/science-talk/page-details/immunotherapy-is-keeping-me-alive—john-s-story.
[2] Tamara Bhandari, “Cancer patients who don’t respond to immunotherapy lack crucial immune cells,” Washington University School of Medicine in St. Louis (website), posted online 16 February, 2023, https://medicine.wustl.edu/news/cancer-patients-who-dont-respond-to-immunotherapy-lack-crucial-immune-cells/.
[3] Clayton Bolt, PhD, “Why doesn’t immunotherapy work for everyone?”, MD Anderson Cancer Center, The University of Texas (website), posted online 30 September, 2020, https://www.mdanderson.org/cancerwise/why-doesnt-immunotherapy-work-for-everyone.h00-159385101.html.
[4] Medline Plus, “Vaccines,” National Library of Medicine (website), National Institutes of Health, accessed 6 May, 2024, https://medlineplus.gov/vaccines.html.
[5] National Cancer Institute (NCI), “Immune Checkpoint Inhibitors,” National Institutes of Health, NCI (website), Immunotherapy, reviewed online 7 April, 2022, https://www.cancer.gov/about-cancer/treatment/types/immunotherapy/checkpoint-inhibitors.
[6] NCI.
[7] Bhandari.
[8] Bhandari.
[9] Padmanee Sharma, MD, PhD, “What is the future of immunotherapy?” MD Anderson Cancer Center, The University of Texas (website), posted online 24 March, 2022, https://www.mdanderson.org/cancerwise/what-is-the-future-of-immunotherapy.h00-159538167.html.
[10] Bendta Schroeder, Koch Institute, “Hitchhiking cancer vaccine makes progress in the clinic,” MIT News (website), published online 15 February, 2024, https://news.mit.edu/2024/hitchhiking-cancer-vaccine-makes-progress-in-clinic-0215.
[11] Schroeder.
[12] Maysoon Al-Haideri et al, “CAR_T cell combination therapy: the next revolution in cancer treatment,” Cancer Cell International 22, Article number 365, published 24 November 2022, doi.org/10.1186/s12935-022-02778-6.
[13] Rachel Grosser et al, “Combination immunotherapy with CAR T Cells and Checkpoint Blockade for the Treatment of Solid Tumors,” Cancer Cell Volume 36, No. 5: published 11 November, 2019, doi:10.1016/j.ccell.2019.09.006.
[14] Sharma.