Viral based vaccine TG4010 induces broadening of specific immune response and improves outcome in advanced NSCLC

Abstract

Background: Advanced non-small cell lung cancer patients receiving TG4010, a therapeutic viral vaccine encoding human Mucin 1 and interleukin-2 in addition to standard chemotherapy, displayed longer overall survival in comparison to that of patients treated with standard chemotherapy alone. Our study intended to establish the association between overall survival and vaccine-induced T cell responses against tumor associated antigens (TAA) targeted by the vaccine.

Method: The TIME trial was a placebo-controlled, randomized phase II study aimed at assessing efficacy of TG4010 with chemotherapy in NSCLC. 78 patients from the TIME study carrying the HLA-A02*01 haplotype were analyzed using combinatorial encoding of MHC multimers to detect low frequencies of cellular immune responses to TG4010 and other unrelated TAA.

Results: We report that improvement of survival under TG4010 treatment correlated with development of T cell responses against MUC1. Interestingly, responses against MUC1 were associated with broadening of CD8 responses against non-targeted TAA, thus demonstrating induction of epitope spreading.

Conclusion: Our results support the causality of specific T-cell response in improved survival in NSCLC. Additionally, vaccine induced epitope spreading to other TAA participates to the enrichment of the diversity of the anti-tumor response. Hence, TG4010 appears as a useful therapeutic option to maximize response rate and clinical benefit in association with other targeted immuno-modulators.

Trial registration: Registered on ClinicalTrials.gov under identifier NCT01383148 on June 23rd, 2011.

Keywords: Cancer vaccine; Lung cancer; T cell response; Tumor associated antigen; Viral vaccine.

Conflict of interest statement

Ethics approval and consent to participate

Samples used in the research reported herein were obtained from patients enrolled in the TIME study. The study was approved in each country by the appropriate regulatory bodies and independent ethics committees or institutional review boards (see the Additional file 3: Ethics committee list for a complete listing of bodies having approved the study). Patients provided written informed consent before entering the screening process. The study was done under the oversight of an independent data monitoring committee in accordance with the principles of the Declaration of Helsinki and the Good Clinical Practice guidelines of the International Conference on Harmonization. This trial is registered with Consent for publication

Not applicable.

Competing interests

All authors were employed by Transgene, the manufacturer of TG4010 and sponsor of the TIME study at the time of analysis.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1

Kaplan-Meier plot of survival in HLA-A02*01 patients enrolled in the TIME study in the TG4010 (n = 47; red line) and placebo arms (n = 31; black line). Median survival of patients is 15.5 months in the TG4010 arm and 10.9 months in the placebo arm (HR = 0.58) (*: p < 0.05, Log-Rank test)

Fig. 2

a. Plots of individual responses against 3 known MVA HLA-A02*01-restricted epitopes in the Placebo (n = 31) and TG4010 (n = 47) arms expressed as percentage of positive CD8+ T cells before and after treatment. The percentage of patients with an analytically significant amplification of the response during the treatment course is indicated as a squared figure in each graph. b. Same as in A for 3 known MUC-1 HLA-A02*01-restricted epitopes. c. Representative dot plot example of combinatorial encoded MHC multimer staining for one patient from the TG4010 arm for HLA-A02*01-restricted epitopes of MVA KVDDTFYYV. The x and y axis of dot plots are exponential and fluorescence is given in arbitrary units. Left dot plot displays all CD8+ events; right dot plots are restricted to the two-color positive events. d. Same as in C for HLA-A02*01-restricted epitope of MUC1 VLVCVLVAL. (n.s.: not significant, *: p < 0.05, Mann-Withney U test)

Fig. 3

a. Kaplan-Meier plot of survival in patients classified per their response to MUC1 in the TG4010 arm. Patients with no MUC1-specific response (black line, No Resp. Median OS: 11 months, n = 6), patients who had a baseline MUC1-specific response without change upon treatment (blue line, Bsl resp., Median OS: 13 months, n = 24) and patient acquiring a MUC1 response during treatment (red line, Acq Resp Median OS: 32.1 months, n = 16). (*p < 0.05, ns: not significant, Log rank test). b. Kaplan-Meier plot of survival in patients in the TG4010 arm classified per the diversity of response to the MUC1 antigen of TG4010. Patients with no or only one MUC1 epitope specific response (black line, LDMUC1, Median OS: 9.7 months, n = 16). Patients with responses directed against 2 or 3 MUC1 epitopes (red line, HDMUC1, Median OS: 23.5 months, n = 31). (*: p < 0.05, Log rank test). c. Same as in A for patients of the placebo arm. Patients with no MUC1-specific response (black line, No Resp. Median OS: 7.5 months, n = 5), patients who had a baseline MUC1-specific response without change upon treatment (blue line, Bsl resp., Median OS: 14.1 months, n = 15) and patient acquiring a MUC1 response during treatment (red line, Acq Resp Median OS: 15.5 months, n = 11). (ns: not significant, Log rank test). d: Kaplan-Meier plot of survival in patients in the TG4010 arm stratified on the intensity of response against known cytomegalovirus HLA-A02*01-restricted epitope. Patients were stratified based on the response intensity and allocated to the “high” subgroup (blue line, Median OS: 10.4 months, n = 22) when above median or “low” group (green line, Median OS: 12.2 months, n = 25) when below median. (ns: not significant, Log rank test)

Fig. 4

Plots of individual responses against 15 tumor associated antigens (TAA) in the Placebo (n = 31) and TG4010 (n = 47) arms expressed as percentage of positive epitope-specific CD8+ T cells before and after treatment. The percentage of patients with onset of a response or an analytically significant amplification of a preexisting response during the treatment course is indicated as a squared figure in each graph. (changes for each individual epitopes were not significant unless otherwise stated, *: p < 0.05, non parametric Mann-Whitney test)

Fig. 5

Spreading of immune response to other TAA. a. Number of TAA-specific responses in the TG4010 arm with patient classified per the diversity of MUC1-specific response (LDMUC1 (n = 16) vs HDMUC1 (n = 31)). Dots are representative of individual patients; the horizontal bar represents the average number of response b. Same as in A for patients of the placebo arm (LDMUC1 (n = 9) vs HDMUC1 (n = 22)). c Number of TAA-specific responses in the TG4010 arm with patients classified per the acquisition or not of MUC1-specific responses during treatment (Subjects with unchanged baseline MUC1 response without change upon treatment (n = 28) vs. Subjects with acquisition of a de novo response (n = 16)). d: Same as in C for patients of the placebo arm (Subjects with unchanged baseline MUC1 response without change upon treatment (n = 20) vs. Subjects with acquisition of a de novo response (n = 11)). (*: p < 0.05, **: p < 0.01, ns: not significant, non parametric Mann-Whitney test)