Epidermal growth factor receptor derived peptide vaccination to prevent lung adenocarcinoma formation: An in vivo study in a murine model of EGFR mutant lung cancer

Abstract

The ability to prevent disease is the holy grail of medicine. For decades, efforts have been made to extend the successes seen with vaccination against infectious diseases to cancer. In some instances, preventive vaccination against viruses (prototypically HPV) has successfully prevented tumorigenesis and will make a major impact on public health in the decades to come. However, the majority of cancers that arise are a result of genetic mutation within the host, or non-viral environmental exposures. We present compelling evidence that vaccination against an overexpressed self-tumor oncoprotein has the potential to prevent tumor development. Vaccination against the Epidermal Growth Factor Receptor (EGFR) using a multipeptide vaccine in a preventive setting decreased EGFR-driven lung carcinogenesis by 76.4% in a mouse model of EGFR-driven lung cancer. We also demonstrate that anti-EGFR vaccination primes the development of a robust immune response in vivo. This study provides proof of concept for the first time that targeting tumor drivers in a preventive setting in lung cancer using peptide vaccination can inhibit tumorigenesis and may provide useful clinical insights into the development of strategies to vaccinate against EGFR in populations that where EGFR-mutant disease is highly prevalent.

Cancer immunoprevention

“…The same group has tested in mouse models the ability of vaccines based on non-mutated tumor antigens to prevent cancer. They showed that a multi-antigen vaccine that included Neu, IGFBP2 and IGF-IR could prevent breast cancer development in two different transgenic mouse models even in mice that already had premalignant lesions [31]. This report also showed that a multi-antigen vaccine was more effective than a single antigen vaccine, and that the vaccine could be combined with some chemopreventative agents resulting in increased efficacy of both.…”

Current modalities in cancer immunotherapy: Immunomodulatory antibodies, CARs and vaccines

“…In another study researchers found that a multi-partite vaccine targeting three antigens on pre-invasive breast disease (Neu, IGFBP2, IGF-IR) could prevent breast cancer in a spontaneous mouse tumor model in which mice were treated after developing premalignant lesions (Disis et al, 2013). Other pre-clinical studies in mice with premalignant lesions have shown that common oncogene mutations that appear early and drive cancer formation could perhaps also be targeted by vaccines in animals including H-ras in carcinogen-induced tumors and EGFR in a lung cancer model (Ebben, Lubet, Gad, Disis, & You, 2016; Nasti et al, 2015). These common oncogenes in addition to others such as K-ras and p53 have been tested in therapeutic vaccines with limited efficacy but warrant further investigation as prophylactic vaccines (Carbone et al, 2005).…”

“…Pre-clinical studies in mice engineered to develop spontaneous tumors show that such lesions either do not develop in vaccinated mice or do not progress to cancer (P. L. Beatty, Narayanan, Gariepy, Ranganathan, & Finn, 2010; Ebben et al, 2016). The increasing focus on early detection of cancer, including pre-malignant lesions, as well as identifying genetic and behavioral risk factors for cancer, can define candidate patient populations for prophylactic vaccination.…”

Transforming Cancer Prevention through Precision Medicine and Immune-oncology

“…Although more complex and recent than the development of vaccines against foreign pathogen-associated targets (e.g., hepatitis B), vaccines against the less-immunogenic genetic drivers and other tumor antigens are showing promise in preclinical prevention models (e.g., KRAS in pancreas models; activating EGFR mutations in lung adenocarcinoma [64, 65]) and have now entered early phase clinical trials (e.g., HER2, MUC1). This focus is very timely, as evidenced by a major new initiative by Cancer Research UK, which recently issued a £20M Grand Challenge that includes a charge to develop vaccines to prevent non-viral cancers (66).…”