癌症疫苗：转化科学综述

IMPORTANCE: Advances in tumor immunology and vaccine technology are reshaping cancer vaccine development after decades of limited clinical success. More than 2000 immunogenic tumor proteins or antigens have been identified, the types of immune responses required for tumor eradication have been defined, and safe and effective vaccine delivery technologies have been developed. This progress has renewed clinical investigation of cancer vaccines for multiple types of cancer.

OBSERVATIONS: Vaccines, such as those against human papillomavirus and hepatitis B, are composed of (1) an antigen target, (2) an adjuvant to activate the immune system, and (3) a vaccine delivery vehicle. Antigens can be derived from tumor mutations termed neoantigens, or cancer-associated nonmutated proteins, which are normal human proteins that are abnormally expressed in cancer. The tumor can also act as an antigen source, such as when immunization occurs with whole tumor cells or by directly injecting an immunogenic substance into the tumor to elicit an adaptive immune response. T and B lymphocytes, cells of the adaptive immune system, are stimulated by cancer vaccines and can provide a highly specific and durable immune response directed against cancer. Vaccines that elicit adaptive immunity are approved for cancer treatment. Sipuleucel-T, a vaccine against the antigen prostatic acid phosphatase, reduced all-cause mortality compared with placebo in men with metastatic castrate-resistant prostate cancer (32% vs 23%; hazard ratio, 0.78 [95% CI, 0.61-0.98]; P = .03). Compared with granulocyte-macrophage colony-stimulating factor, a systemic immune stimulant, talimogene laherparepvec increased rates of a 6-month or longer complete or partial response, defined as the disappearance of all treated disease and at least a 50% decrease in the sum of the products of perpendicular diameters of the measurable lesion with no new lesions, respectively, when injected into advanced melanoma lesions (16.3% [95% CI, 12.1%-20.5%] vs 2.1% [95% CI, 0%-4.5%]; odds ratio, 8.9; P < .001). Most cancer vaccines have mild adverse effects, such as fatigue, fever, and injection site reactions. Combining cancer vaccines with chemotherapy or immunotherapy can increase the magnitude of the immune response and potentially result in greater reduction in cancer size. Combining the personalized mutation-based messenger RNA (mRNA) vaccine (mRNA-4157) with the immune checkpoint inhibitor pembrolizumab for resected high-risk stage IIIB to IV cutaneous melanoma improved relapse-free survival compared with pembrolizumab alone (76.6% vs 60%; hazard ratio, 0.56 [95% CI, 0.31-1.02]; P = .05). Cancer vaccines are undergoing evaluation in clinical trials to prevent cancer recurrence and for primary cancer prevention.

CONCLUSIONS AND RELEVANCE: Cancer vaccines can treat several types of malignant neoplasms, including melanoma, prostate cancer, and bladder cancer. Adverse effects associated with cancer vaccines are generally mild and of short duration, promoting eventual integration of vaccination into treatment regimens with chemotherapy and immunotherapy. Cancer vaccines are increasingly undergoing evaluation for primary prevention.