Treatment and Prevention of Lung Cancer Using a Virus-Infected Reprogrammed Somatic Cell-Derived Tumor Cell Vaccination (VIReST) Regime

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 KRAS G12D and Trp53 R172H 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-KRAS G12D/+ ; Trp53 R172H/+ 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.

Development of the T-ALLiPSC-based Therapeutic Cancer Vaccines for T-cell Acute Lymphoblastic Leukemia

“…Joseph et al used the irradiated autologous iPSCs to produce iPSC vaccines inhibiting the recurrence of a variety of tumors and reducing the burden of metastatic tumors [12]. Tailoring iPSCs by introducing other driver mutations as a vaccine can prevent the initiation and progression of pancreatic cancer [24] and lung cancer [25]. Although the irradiated iPSC-based vaccines are effective at inducing immunity against multiple cancer types in mice, it is still fraught with risks such as tumorigenicity[26] and immunogenicity [27] which need to be overcome [28].…”

Development of the T-ALLiPSC-based Therapeutic Cancer Vaccines for T-cell acute Lymphoblastic Leukemia

“…Tailoring iPSCs by introducing other driver mutations as a vaccine can prevent the initiation and progression of pancreatic cancer (Lu et al 2020) and lung cancer (Zhang et al 2020). Although the irradiated iPSC-based vaccines are effective at inducing immunity against multiple cancer types in mice, it is still fraught with risks such as tumorigenicity (Lee et al 2013) and immunogenicity (de Almeida et al 2014) which need to be overcome (Yaddanapudi et al 2018).…”

Oncolytic Vaccinia Virus in Lung Cancer Vaccines

“…The therapeutic cancer vaccines for NSCLC have been investigated, and they provided positive results in murine tumor models and in phase I and II clinical trials, but achieved insignificant benefits in phase III clinical trials. There are several factors responsible for the failure of cancer vaccines for NSCLC, including the advanced stage of the disease, the choice of antigens or adjuvants, tumor-induced immunosuppression in the tumor microenvironment, or immunosenescence [15,17]. It is likely that the immune response induced by cancer vaccines is not strong enough to trigger therapeutic anti-tumor effects.…”

“…Recombinant VVs created by engineering the VV to express TAAs and/or immune stimulatory molecules have been demonstrated to break immune tolerance, overcome immune inhibitory pathways, and induce strong anti-tumor immune responses. Since immunosuppressive TME is a big challenge to current immunotherapies in NSCLC patients, VV-based therapeutic vaccines are expected to improve anti-cancer therapeutic effects and clinical outcomes [17,69].…”

“…However, no positive data has been reported in the late phase clinical trials over the last decade [12][13][14]. The failure of therapeutic cancer vaccines in NSCLC is attributed to the suboptimal vaccine design including inappropriate antigen targeting, inadequate patient selection (stage of disease) [15], ineffective adjuvants [16], tumor-induced immunosuppression, or immunosenescence [17]. These challenges drive a critical need for novel research in tumor immunology and vaccine development to design effective vaccine regimens for treatment of NSCLC.…”