Phase Ib study evaluating a self-adjuvanted mRNA cancer vaccine (RNActive®) combined with local radiation as consolidation and maintenance treatment for patients with stage IV non-small cell lung cancer

Abstract

BackgroundAdvanced non-small cell lung cancer (NSCLC) represents a significant unmet medical need. Despite advances with targeted therapies in a small subset of patients, fewer than 20% of patients survive for more than two years after diagnosis. Cancer vaccines are a promising therapeutic approach that offers the potential for durable responses through the engagement of the patient’s own immune system. CV9202 is a self-adjuvanting mRNA vaccine that targets six antigens commonly expressed in NSCLC (NY-ESO-1, MAGEC1, MAGEC2, 5 T4, survivin, and MUC1).Methods/DesignThe trial will assess the safety and tolerability of CV9202 vaccination combined with local radiation designed to enhance immune responses and will include patients with stage IV NSCLC and a response or stable disease after first-line chemotherapy or therapy with an EGFR tyrosine kinase inhibitor. Three histological and molecular subtypes of NSCLC will be investigated (squamous and non-squamous cell with/without EGFR mutations). All patients will receive two initial vaccinations with CV9202 prior to local radiotherapy (5 GY per day for four successive days) followed by further vaccinations until disease progression. The primary endpoint of the study is the number of patients experiencing Grade >3 treatment-related adverse events. Pharmacodynamic analyses include the assessment of immune responses to the antigens encoded by CV9202 and others not included in the panel (antigen spreading) and standard efficacy assessments.DiscussionRNActive self-adjuvanted mRNA vaccines offer the potential for simultaneously inducing immune responses to a wide panel of antigens commonly expressed in tumors. This trial will assess the feasibility of this approach in combination with local radiotherapy in NSCLC patients.Trial registrationClinicaltrials.gov: NCT01915524/EudraCT No.: 2012-004230-41

Current state in the development of candidate therapeutic HPV vaccines

“…DNA-launched KUN replicons encoding HPV16-E7 antigen were capable of generating E7-specific T cell responses and antitumor effects in preclinical models [62]. Despite the promising results demonstrated by RNA replicon vaccines in the preclinical model and the ongoing clinical trials testing the efficacy of RNA vaccines in treating other types of cancer such as lung cancer [63], RNA vaccines targeting HPV antigens and HPV related diseases have not yet progressed to be tested in clinical settings.…”

Immune modulation in advanced radiotherapies: Targeting out-of-field effects

“…A range of vaccine types have been used in combination with radiotherapy and examples of the human studies are listed in Table 3 [92][93][94][95][96][97][98]. At present vaccine therapy with radiotherapy is confined to early phase studies across a range of tumour types including lung cancer [98]. Furthermore, the optimal radiotherapy dose and scheduling of vaccine delivery around radiotherapy will likely depend on the vaccine and tumour type and this will require further clinical investigation [97].…”

“…The rationale behind this combination is that the immune response mediated by radiotherapy may enhance the efficacy of the vaccine or vice versa. A range of vaccine types have been used in combination with radiotherapy and examples of the human studies are listed in Table 3 [92][93][94][95][96][97][98]. At present vaccine therapy with radiotherapy is confined to early phase studies across a range of tumour types including lung cancer [98].…”

Afatinib-Based Combination Regimens for the Treatment of Solid Tumors: Rationale, Emerging Strategies and Recent Progress

“…As another approach, a clinical development program is planned that will assess the combination of afatinib with a self-adjuvanted mRNA vaccine (CV9202) in patients with NSCLC. CV9202 targets six antigens commonly expressed in NSCLC [101].…”