Phase Ib evaluation of a self-adjuvanted protamine formulated mRNA-based active cancer immunotherapy, BI1361849 (CV9202), combined with local radiation treatment in patients with stage IV non-small cell lung cancer

Abstract

BackgroundPreclinical studies demonstrate synergism between cancer immunotherapy and local radiation, enhancing anti-tumor effects and promoting immune responses. BI1361849 (CV9202) is an active cancer immunotherapeutic comprising protamine-formulated, sequence-optimized mRNA encoding six non-small cell lung cancer (NSCLC)-associated antigens (NY-ESO-1, MAGE-C1, MAGE-C2, survivin, 5T4, and MUC-1), intended to induce targeted immune responses.MethodsWe describe a phase Ib clinical trial evaluating treatment with BI1361849 combined with local radiation in 26 stage IV NSCLC patients with partial response (PR)/stable disease (SD) after standard first-line therapy. Patients were stratified into three strata (1: non-squamous NSCLC, no epidermal growth factor receptor (EGFR) mutation, PR/SD after ≥4 cycles of platinum- and pemetrexed-based treatment [n = 16]; 2: squamous NSCLC, PR/SD after ≥4 cycles of platinum-based and non-platinum compound treatment [n = 8]; 3: non-squamous NSCLC, EGFR mutation, PR/SD after ≥3 and ≤ 6 months EGFR-tyrosine kinase inhibitor (TKI) treatment [n = 2]). Patients received intradermal BI1361849, local radiation (4 × 5 Gy), then BI1361849 until disease progression. Strata 1 and 3 also had maintenance pemetrexed or continued EGFR-TKI therapy, respectively. The primary endpoint was evaluation of safety; secondary objectives included assessment of clinical efficacy (every 6 weeks during treatment) and of immune response (on Days 1 [baseline], 19 and 61).ResultsStudy treatment was well tolerated; injection site reactions and flu-like symptoms were the most common BI1361849-related adverse events. Three patients had grade 3 BI1361849-related adverse events (fatigue, pyrexia); there was one grade 3 radiation-related event (dysphagia). In comparison to baseline, immunomonitoring revealed increased BI1361849 antigen-specific immune responses in the majority of patients (84%), whereby antigen-specific antibody levels were increased in 80% and functional T cells in 40% of patients, and involvement of multiple antigen specificities was evident in 52% of patients. One patient had a partial response in combination with pemetrexed maintenance, and 46.2% achieved stable disease as best overall response. Best overall response was SD in 57.7% for target lesions.ConclusionThe results support further investigation of mRNA-based immunotherapy in NSCLC including combinations with immune checkpoint inhibitors.Trial registrationClinicalTrials.gov identifier: NCT01915524.Electronic supplementary materialThe online version of this article (10.1186/s40425-019-0520-5) contains supplementary material, which is available to authorized users.

mRNA Vaccine Era—Mechanisms, Drug Platform and Clinical Prospection

“…In recent years, protamine-formulated mRNA delivery system has been widely used in clinical trials, and gained pretty good clinical treatment effects, such as rabies, non-small cell lung cancer, etc. [ 90 , 91 , 92 ]. The RNActive ® vaccine platform, which use the protamine-mRNA only to activate immune responses, is a prevailing technique to resolve this problem [ 54 ].…”

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“…Regarding in vivo delivery, CV9201 and CV9202 (NCT00923312 and NCT01915524), based on CureVac's RNActive ® technology, have been applied intradermally for the treatment of non-small cell lung carcinoma (NSCLC). CV9202, containing a sequence-optimized mRNA encoding six NSCLC-associated antigens (NY-ESO-1, MAGE-C1, MAGE-C, Survivin, 5T4, and MUC-1), was well tolerated, and antigen-specific immune responses were detected [189]. Different types of prostate cancers have been addressed by intradermal administration of RNActive ® vaccines (NCT01817738, NCT02140138, NCT00831467).…”

RNA Drugs and RNA Targets for Small Molecules: Principles, Progress, and Challenges

“…This concept was first demonstrated by the findings on efficient expression of target proteins in mouse tissues in vivo after the administration of in vitro-transcribed (IVT) mRNAs, which was reported in 1990 (Wolff et al, 1990). After extensive preclinical studies, many IVT mRNA therapeutics have already entered clinical trials (Heiser et al, 2002;Weide et al, 2009;Rittig et al, 2011;Allard et al, 2012;Van Gulck et al, 2012;Maus et al, 2013;Wilgenhof et al, 2013;Bahl et al, 2017;Leal et al, 2018;de Jong et al, 2019;Papachristofilou et al, 2019). Different from plasmid DNA or virus-based gene therapy, mRNA drugs are translated into target proteins by the cellular machinery without interference with the genome (Fig.…”