Research Suggests New Immunopreventive Approach To Tackling Cancer
By Deborah Borfitz
January 18, 2024 | The lifetime probability of being diagnosed with an invasive cancer is estimated to be roughly 40% for both men and women, and there’s a strong possibility that they are all, in some sense, preventable. Scientific evidence suggests that the body’s immune system copes with the “internal danger” of tumor development the same way it deals with the external threat of infectious diseases, according to Haval Shirwan, Ph.D., a professor in the department of pediatrics and molecular microbiology and immunology in the University of Missouri (MU) School of Medicine.
Were it not for the immune system, the estimated rate of lifetime invasive cancers would be 100%, and individuals would develop cancer at early ages, he says. Simply put, cancer represents an immune system failure and that implies preventing it is a matter of identifying and rectifying the deficiency.
His optimism stems from years spent researching an immune checkpoint stimulator (SA-4-1BBL) that recently showed the potential to prevent lung cancer caused by a potent carcinogen in cigarettes known as NNK, as well as reducing the number of nodules on cancerous tumors. Results of the preclinical study published in Cancer Immunology, Immunotherapy (DOI: 10.1007/s00262-023-03507-2).
The molecule works as a single agent by triggering an immune surveillance mechanism that patrols the body for cancer cells and efficiently eliminates them, Shirwan explains. It contains a portion of a naturally occurring immune stimulant protein that has been modified using recombinant DNA technology.
He and his colleagues wanted to use the molecule as a standard vaccine component, much as adjuvants are used to boost the effectiveness of vaccines against infectious diseases such as COVID. After submitting an Investigational New Drug application to the Food and Drug Administration in hopes of starting first-in-human testing, the agency requested that SA-4-1BBL be further tested in preclinical models to ensure it would not be regarded by the body as foreign and generate anti-drug antibodies, rendering it ineffective, says Shirwan.
In doing that experiment, researchers stumbled upon the unexpected finding that the molecule was just as effective by itself in the control group as it was in combination with a vaccine. The result was so surprising that they had four other people in the lab successfully repeat the experiment on their own, he says.
It has long been known that the immune system protects the host from invasion by infectious agents. “Our data shows that [it] ... naturally also protects us against cancer,” says Shirwan.
Antitumor Protective Effect
The preclinical study was funded by a Department of Defense grant awarded to study co-author Esma Yolcu, Ph.D., a professor in the department of pediatrics and molecular microbiology and immunology in the MU School of Medicine. Her hypothesis, she says, was that the SA-4-1BBL molecule might boost the immune system of smokers enough to prevent them from ever getting lung cancer.
As it was a short-term Idea Award, with limited funds available for distribution, Yolcu decided to borrow the treatment regimen used in previous studies by Shirwan. It involved exposing an inbred strain of mice that tends to develop carcinogen-induced tumors to weekly injections of a NNK (a nicotine-derived compound) for two months. During this ongoing exposure, they also received two treatments with the novel immune checkpoint stimulator.
When compared to a control group of mice who didn’t receive SA-4-1BBL treatment, the molecule significantly reduced the formation of lung tumors—and the antitumor protective effect was dependent on the presence of T cells and natural killer (NK) cells, Yolcu reports. The molecule also significantly reduced the number of lung tumor nodules during the NNK exposure period, which was validated by sectioning the lung and checking for even microscopic evidence of them.
It is possible that nodule formation might have been 100% eliminated with a few more rounds of treatment with SA-4-1BBL, she adds. With additional funding, she hopes to test that theory.
Predator and Prey
Despite tremendous effort and breakthrough innovations, cancer remains a pandemic-scale problem, says Shirwan. In the U.S, where it is the second leading cause of death, an estimated two million people were newly afflicted in 2023.
Chemotherapy and immunotherapy are the standard cancer treatments but often don’t work and have many adverse effects on the quality of patient life, he continues. The efficacy rate of immunotherapies is typically no more than 30% for a given tumor type.
One of the most effective types of immunotherapies used in the clinic is immune checkpoint inhibitors, which block the proteins on the surface of immune cells from binding with their partner proteins on tumor cells. This prevents the “off” signal from being sent to T cells so they can do their job of destroying the cancer.
“Cancer develops with the immune system... [and] there is constant interaction between the two,” explains Shirwan. Disease occurs when the immune system fails to keep pace with cancer and becomes its prey.
That being the case, Shirwan, Yolcu and their team set to work decades ago—long before clinical evidence that the immune system can be targeted to fight cancer—to develop a vaccine capable of stimulating the immune system to eradicate cancer.
The conventional wisdom then was that the immune system is built to protect individuals against external dangers (i.e., infections), but not cancer as an internal danger, he continues. It does so by using the immune system’s two “armies”—innate immunity, which is the first line of defense and is not sophisticated but deters the danger until the more sophisticated and effective adaptive immunity kicks in. Adaptive immunity is responsible for long-lasting protection conferred by vaccines against infectious agents, such as COVID and flu.
The latest study provides striking evidence that the exact same immune mechanisms are at work for cancer, Shirwan says. The SA-4-1BBL immune checkpoint stimulator not only works against lung cancer, but multiple other cancers including cervical cancer (Cancer Research, DOI: 10.1158/0008-5472.CAN-18-2401). This, he believes, is “grounds for cancer immunoprevention.”
With nonviral cancers, about 80% of all cancers, the causal agent is unknown, but the immune system nonetheless has the capacity to fight off the invasion. “This is only the tip of the iceberg,” says Shirwan, who believes the approach could be used to prevent specific cancers in high-risk individuals.
“All we are trying to do is make the immune system see the evil side of the cancer cells,” says Yolcu. This is expected to overcome the trickery of cancer cells that has weakened the effectiveness of immune checkpoint blockade therapy.
Among the candidate groups of patients for clinical trials would be cigarette smokers and individuals who are genetically predisposed to cancer, including those diagnosed with Lynch syndrome who are at heightened risk of many types of cancer. As suggested by the latest study, SA-4-1BBL might also serve as a therapy for early-stage disease when patients have better odds of success and treatment costs are significantly lower than cases where the cancer has progressed.
The proposed immunopreventive strategy with a single agent against cancer is a “provocative idea” that won’t easily win over advocates without a compelling case being made for its further study and evidence for preventing cancer in high-risk individuals who can be identified with existing imaging technologies and genetic testing, says Shirwan. In the case of lung cancer, the National Cancer Institute (NCI) has criteria by which high-risk individuals can be identified based on variables that include smoking status and environmental exposures such as radiation and asbestos.
“The NCI is strongly standing behind this concept of cancer immunoprevention and interception,” he notes. “This is an important validation, and funding from the NCI will be instrumental to the development and translation of our technology to the clinic.” Shirwan and his colleagues would also like to evaluate the utility of SA-4-1BBL in controlling the recurrence of cancer, which for certain types of breast cancer can be as high as 40 to 50 percent.
The novel molecule has been patented in the U.S., Japan, and the European Union for cancer immunotherapy, Shirwan says. A patent on its application in preventing cancer is pending in the U.S. and European Union.
Shirwan and Yolcu agree that a future that includes preventive treatments for cancer will require ongoing public support of federal dollars being funneled into the discovery process. Yolcu notes this is unlikely to happen unless more young people consider going into research so science can continue giving hope to people who are suffering.