Preventative Chemotherapy? Not Quite, but Studies Are Underway in Immunoprevention

Catherine, Princess of Wales | Image credit: Wikipedia

When Catherine, Princess of Wales, told the world Friday she was undergoing “preventative chemotherapy” after surgery revealed she had cancer, experts explained the term was not quite precise.

Most likely, they said, the future queen is receiving adjuvant chemotherapy; this is given after primary treatment to kill off any remaining cancer cells, thus staving off a recurrence.

Preventing cancer’s return might seem just as important to a lay person, but the quest to keep cancer from showing up in the first place is a distinct goal of cancer researchers—and one that has seen both progress and challenges in recent years.

A recent paper published in the Journal of Immunotherapy for Cancer describes work in the emerging field of immunoprevention, which authors say the scientific community has been “slow to embrace,” despite the strides in precision medicine.

Overall, however, the review article sees the field as poised for growth, especially in the use of vaccines to prevent viral cancers or to protect high-risk individuals from heritable cancers; authors also predict greater use of cancer-antigen vaccines to target precancers.

Driving these trends, the authors say, are efforts by major US cancer research and advocacy organizations, including the National Cancer Institute (NCI), which published a National Cancer Plan that prioritized cancer prevention and is funding research in this area. The Human Tumor Atlas Network, a project of the National Institutes of Health, is organizing a precancer databank to help scientists understand what happens biologically before cancer occurs, both genetically and in the tissue microenvironment.

Sasha E. Stanton, MD, PhD | Image credit: Cancer Immunoprevention Laboratory

The review’s lead author was Sasha E. Stanton, MD, PhD, of the Cancer Immunoprevention Laboratory, Earle A. Chiles Research Institute, Providence Cancer Institute in Portland, Oregon; she was joined by several authors from NCI.

Rising cancer burden. Despite advances in treatment, “Cancer was the second most common cause of death worldwide with approximately 8.97 million deaths in 2019,” the authors wrote. “Projections by the [World Health Organization] and the American Cancer Society estimate [approximately] 18.63 million cancer deaths per year by 2060, bringing it to the leading cause of mortality.”

The need for prevention is fueled by recent reports on the rise in cancer incidence among younger adults; the connection to cancers caused by obesity accounts for some, but not all, of this trend. Cancer is also expensive—it is expected to cost the US health system $240 billion by 2030, so policy makers and employers are taking note.

A preventive approach, the authors say, would stop cancer before it starts or has time to advance. The goal is to develop novel immunoprevention and immuno-interception strategies in a multipart effort that includes current tools: vaccines, nonspecific immunomodulation, checkpoint inhibitors, and lifestyle modification. Cooperating with this effort are the American Association for Cancer Research, Cancer Research UK, and the Society for Immunotherapy of Cancer.

Vaccines against viral cancers. This has been the greatest area of progress, the authors say. Human papillomavirus and hepatitis B virus vaccines target large populations “with a safe intervention; they have good side effect profiles, and they elicit durable immune responses, even with a single vaccination.” With improvements in manufacturing and storage requirements, the authors say, these vaccines could reach even more people globally. A vaccine against Epstein-Barr virus (EBV) would be on a wish list, as EBV is linked to more than 200,000 cancers a year worldwide, of which some are extremely hard to treat.

Vaccines against nonviral cancers. This is a research-intense field; mouse models are used to identify precancerous antigens. Studies have included identifying types of serum associated with future development of breast cancer, and phase 3 trials using a therapeutic vaccine have been shown to be safe and immunogenic, but thus far have not shown efficacy. Work in vaccine development is ongoing.

The immune microenvironment. Understanding stressors and other factors in individuals with premalignant lesions who are at risk of developing full-blown cancer is a major area of study. In fact, changes to the gut microbiome are suspected as a source of the rising cancer incidence among young adults. If investigators can learn which elements can be modified, many cancers can be stopped in their tracks.

The authors illustrated work in analyzing precancerous lesions in both squamous cell carcinoma, which is associated with heavy smoking, and adenocarcinoma, a lung cancer not associated with smoking. To understand “the cellular and molecular changes that occur from normal tissue to invasive disease,” they wrote, the Human Tumor Atlas Network is performing bulk RNA sequencing of precancerous dysplastic lesions, and has even categorized them into distinct groups: proliferative, inflammatory, secretory, and normal.

Work in this area suggests great diversity in how the immune environment reacts to precancerous lesions. “Understanding the similarities and differences between different premalignant lesions and how the evolving tissue immune environment impacts the development of premalignancy and its progression to invasive disease will be essential for designing appropriate and effective interventions for immune interception and prevention,” the authors wrote.

Strategies for prevention. The authors briefly reviewed cases where existing agents may be deployed to prevent cancer development, such as trials using cell therapies in smoldering multiple myeloma. The greater challenge comes in identify patients for primary prevention. As the authors note, current research is focused on those with genetic mutations associated with higher cancer risk. Current efforts include:

• Testing of a candidate tumor antigen in patients with metastatic breast cancer that is overexpressed in 85% of cancers, which the authors said make it “a good candidate tumor antigen for a broad cancer immunoprevention strategy.”
• Progress in testing a vaccine among patients with high-risk tumors while they were in remission that allowed a version of the vaccine to move into the primary prevention setting to be tested in BRCA1/2 mutation carriers (NCT04367675).
• Two different trials are testing vaccines in carriers of Lynch syndrome; 1 trial has the option to move to a 140-patient randomized controlled trial if the first phase is successful.

The authors note that immunoprevention strategies are initially tested in patients who have advanced disease; testing in patients precancer “are a different population.” They note that the NCI PREVENT Cancer Preclinical Drug Development Program (PREVENT) can provider clinicians guidance on developing prevention trials, including the need to include advocacy groups. There is also a need for more surrogate endpoints, they wrote.

“The field of cancer immunoprevention and immune interception is still nascent and presents many exciting opportunities to address a current unmet need to prevent invasive cancer rather than to treat established cancer,” they wrote. “Work is ongoing to understand the premalignant immune environment of all tumor types and improve early detection with imaging and biomarkers to identify individuals who are candidates for immune-based prevention or interception strategies.”

Reference

Stanton SE, Castle PE, Finn OJ, et al. Advances and challenges in cancer immunoprevention and immune interception. J Immunother Cancer. 2024;12:e007815. doi:10.1136/jitc-2023-007815