Abstract
Lung cancer is one of the most commonly diagnosed cancer and despite therapeutic advances, mortality remains high. The long period of clinical latency associated with lung cancer provides an ideal window of opportunity to administer vaccines to at-risk individuals that can prevent tumor progression and initiate long-term anti-tumor immune surveillance. Here we describe a personalized vaccination regime that could be applied for both therapeutic and prophylactic prevention of lung cancer, based on the derivation of lung cancer cells from induced pluripotent stem cells. Stem cells from healthy mice were modified to express Cre-dependent KRASG12D and Trp53R172H prior to differentiation to lung progenitor cells. Subsequent viral delivery of Cre caused activation of exogenous driver mutations, resulting in transformation and development of lung cancer cells. iPSC-derived lung cancer cells were highly antigenically related to lung cancer cells induced in LSL-KRASG12D/+; Trp53R172H/+ transgenic mice and were antigenically unrelated to original pluripotent stem cells or pancreatic cancer cells derived using the same technological platform. For vaccination, induced lung cancer cells were infected with oncolytic Adenovirus or Vaccinia virus, to act as vaccine adjuvants, prior to delivery of vaccines sequentially to a murine inducible transgenic model of lung cancer. Application of this Virus-Infected, Reprogrammed Somatic cell-derived Tumor cell (VIReST) regime primed tumor-specific T cell responses that significantly prolonged survival in both subcutaneous post-vaccine challenge models and induced transgenic models of lung cancer, demonstrating that stem cell-derived prophylactic vaccines may be a feasible intervention for treatment or prevention of lung cancer development in at-risk individuals.
Highlights
Lung cancer remains one of the most fatal malignant tumors
Markers of induced pluripotent stem cells (iPSCs), endoderm, anterior foregut endoderm (AFE), and lung progenitors (LP) were detected by immunofluorescence (Figure 1C) and RT-qPCR (Figure S1A). iPSC-derived LP cells were infected with non-replicating Adenovirus serotype 5 (Ad5) vector expressing Cre (AdCre) to induce mutant KRASG12D and p53R172H expression and transformation to lung cancer cells (KP-LC) (Figure 1D)
Genotyping confirmed the presence of mutant KRAS in the KRASG12D/+; LSL-Trp53R172H/+ (KP)-LC cell line and KPL 160302S and KPL160424S cell lines [lung adenocarcinoma cell lines derived from the lung cancer KP transgenic mouse model [21]], but not in LP cells that were not infected with AdCre
Summary
Lung cancer remains one of the most fatal malignant tumors. The 2018 GLOBOCAN report suggested that lung cancer is the most commonly diagnosed cancer (11.6% of total cases) and the leading cause of cancer death (18.4% of total cancer deaths) [1] and despite advances in therapeutic approaches, the 5 year survival rate is 16% for the majority of patients whose tumor is not diagnosed at an early, localized stage [2].Recent immunotherapeutic approaches for the treatment of lung cancer have investigated therapeutic vaccination as a method of controlling disease progression. Vaccination strategies are a promising therapeutic option as they can provoke an anergic immune system to activation against one or more tumor cell antigens, resulting in a long-term immune response against the tumor. The majority of these approaches have their basis in targeting specific tumor associated antigens (TAAs) such as epidermal growth factor receptor (EGFR), overexpressed in over half of lung cancer cases, which has been targeted using Cimavax-EGF, an immunogenic recombinant protein vaccine or Mucin-1 (MUC1), over-expressed in nonsmall cell lung cancer using Simuvax, a liposomally delivered MUCI peptide. Immunosuppressive cells are rare at this stage [7]
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