Wang and Hume explained why a preventive cancer vaccine is easier to test in people at high risk of the disease
Wang and Hume explained why a preventive cancer vaccine is easier to test in people at high risk of the disease
On 20 July, Linette Wang and Samuel Hume explained why cancer prevention is difficult to test before the disease develops. With age, the range of T-cells carrying different receptors narrows, while future cancer cases are too rare among young, healthy people for a short trial to detect an effect.
A peptide vaccine introduces the immune system to a fragment of a mutated protein. A precancerous cell displays the same fragment on its surface together with an MHC molecule, a protein that presents the target to T-cells. A T-cell recognizes this pair. In the AGE1 essay, Wang and Hume write that a vaccine requires T-cells capable of recognizing the selected target.
The thymus is an organ behind the breastbone where immature T-cells acquire their receptors. It produces fewer new cells with age. In adults, the pool of naive T-cells, meaning cells that have not yet encountered their target, is maintained mainly through the division of existing clones. Cell division preserves the number of cells, while the thymus generates new receptor variants. Wang and Hume reason that a vaccine response may be harder to produce if the required clones are rare or functionally impaired.
“Immunology says that vaccination should happen early, while the T-cell repertoire is still broad. The economics of clinical trials demands the opposite,” write Linette Wang and Samuel Hume.
In a 2023 observational study, researchers compared 1 146 adults who had undergone thymus removal with the same number of patients who had similar operations but retained their thymus. Over five years, cancer was diagnosed in 7,4% of people after thymectomy and 3,7% of those in the matched group. A separate laboratory subgroup, comprising 22 patients after thymectomy and 19 controls, had fewer markers of newly formed T-cells. This was a retrospective comparison, and differences in the reasons for surgery may also have affected risk.
In a phase I study published on 16 July, 20 people with an inherited predisposition to pancreatic cancer and an abnormality visible on imaging received mKRAS-VAX, a peptide vaccine targeting mutations in the KRAS gene. A T-cell response to mutant KRAS developed in 18 of 20 participants, and the vaccine-induced clones persisted for up to two years. The phase I study measured safety and immune response.
An inherited predisposition combined with a pancreatic abnormality makes future cancer cases more likely than they are in the general population. This would allow a longer controlled study to compare cancer incidence between vaccinated participants and controls. Among people at average risk, most participants will not receive such a diagnosis for years, regardless of vaccination. A trial would therefore require an enormous sample and prolonged follow-up.
The authors identify an early measure of efficacy as one possible way to accelerate testing. Circulating tumor DNA consists of fragments of tumor DNA found in the blood. After treatment, it can help track residual disease and the risk of recurrence. Prevention requires a measure that reliably predicts a reduction in cancer incidence in a controlled study. No such measure has yet been validated.