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

Background: Preclinical 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.

Methods: We 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).

Results: Study 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.

Conclusion: The results support further investigation of mRNA-based immunotherapy in NSCLC including combinations with immune checkpoint inhibitors.

Trial registration: ClinicalTrials.gov identifier: NCT01915524 .

Keywords: BI1361849; CV9202; Clinical trial; Hypofractionated radiotherapy; Immunomonitoring; Non-small cell lung cancer; mRNA active cancer immunotherapy.

Conflict of interest statement

Ethics approval and consent to participate

This study was approved by local ethics committees. The names and reference numbers are provided in Additional file 11: Table S7.

All patients provided written informed consent before receiving any study-related procedures.

Consent for publication

Not applicable

Competing interests

AP declares non-financial support from CureVac during the conduct of the study. MS declares personal fees from Boehringer Ingelheim, BMS, MSD, Lilly, Pfizer, Astra Zeneca, Roche, Celgen, and Novartis and non-financial support from Boehringer Ingelheim, BMS, and Novartis outside the submitted work. MP declares personal fees from Astra Zeneca, BMS, Boehringer Ingelheim, Merck, Novartis, Pfizer, and Roche outside the submitted work. FG declares grants and personal fees from Astra Zeneca, Boehringer Ingelheim, Pfizer, Lilly, BMS, MSD, Novartis, Celgene, and Roche and personal fees from Ariad, Takeda, and Chugai outside the submitted work. AZ declares study fees from CureVac during the conduct of the study and research funding from BeyondSprings, Secarna, and Roche outside the submitted work. UK, MFM, BS, CS, AM, TS, FD and UG-V are employees of CureVac. AS, MMH, HSH and SDK were employees of CureVac during the conduct of this study. K-JK was a consultant to CureVac until 2015 and was an employee at CureVac until 2012. K-JK, MFM and UG-V jointly hold patent WO/2015/024666. MF, CW, RC, WH, GP, TW, JA, HB, and MG have no conflicts of interest to declare.

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Figures

Fig. 1

a Study design. b Patient disposition

Fig. 2

Frequencies of patients with an at least two-fold increase in antigen-specific immune responses following BI1361849 immunotherapy combined with local radiation treatment. Values displayed above the bars indicate the percentages and actual number of patients with increase in immune responses. a Summary graph showing frequencies of patients with antigen-specific T cells, antibodies or both exhibiting an at least two-fold increase compared to baseline against one or more antigens encoded by BI1361849 (any post-vaccine time point). CD4 = antigen-specific CD4+ T cells, CD8 = antigen-specific CD8+ T cells. b Frequencies of patients with an at least a two-fold increase in immune responses compared to baseline to each of the antigens encoded by BI1361849 shown as percentage of all evaluable patients; any post-vaccine time point. c Frequencies of patients with antigen-specific T cells, antibodies or both showing at least a two-fold increase compared to baseline against multiple antigens encoded by BI1361849 shown as percentage of all evaluable patients; at any post-vaccine time point

Fig. 3

a Vaccine antigen-specific CD4+ and CD8+ T cells detected by ICS at baseline (n = 7 patients for panel CD4, n = 11 patients for panel CD8, n = 16 patients for panel CD4 and/or CD8), and days 19 (n = 13 patients for panel CD4, n = 15 patients for panel CD8, n = 23 patients for panel CD4 and/or CD8) and 61 (n = 7 patients for panel CD4, n = 7 patients for panel CD8, n = 10 patients for panel CD4 and/or CD8) following BI1361849 immunotherapy combined with local radiation treatment. Vaccine antigen-specific T cell responses were determined and are shown as percentages of all possible responses. The denominator for calculating the percentage was defined as the maximum of all possible at least two-fold increases over background (unstimulated cells). Example: 4 functions (IFN-γ, TNF-α, IL-2, CD107a) * 2 T cell subsets (CD4+ or CD8+ T cells) * 6 BI1361849 antigens * 25 patients = 1200 possible responses. The numbers in the key show fold-increases over the background control. b & c Magnitude of T cell responses as measured by b ICS or c IFN-γ ELISpot of patients with an at least two-fold increase in antigen-specific immune responses following BI1361849 treatment. Values are shown as the percentage of positive cells gated on both CD4+ or CD8+ populations for ICS. ELISpot results are plotted as number of spots per 1 million PBMCs after background subtraction (PBMCs that received only cell culture medium). Legends indicate patient ID, antigen, measured cytokine (only for ICS) and time point

Fig. 4

Efficacy outcomes following BI1361849 immunotherapy combined with local radiation treatment. a Change in target lesion sum of longest diameters (SLD) from baseline. b Survival, progression-free survival, and response kinetics of individual patients (post hoc swimmer plot)