Long-term survival of patients with stage III colon cancer treated with VRP-CEA(6D), an alphavirus vector that increases the CD8+ effector memory T cell to Treg ratio

Abstract

BackgroundThere remains a significant need to eliminate the risk of recurrence of resected cancers. Cancer vaccines are well tolerated and activate tumor-specific immune effectors and lead to long-term survival in some patients. We hypothesized that vaccination with alphaviral replicon particles encoding tumor associated antigens would generate clinically significant antitumor immunity to enable prolonged overall survival (OS) in patients with both metastatic and resected cancer.MethodsOS was monitored for patients with stage IV cancer treated in a phase I study of virus-like replicon particle (VRP)-carcinoembryonic antigen (CEA), an alphaviral replicon particle encoding a modified CEA. An expansion cohort of patients (n=12) with resected stage III colorectal cancer who had completed their standard postoperative adjuvant chemotherapy was administered VRP-CEA every 3 weeks for a total of 4 immunizations. OS and relapse-free survival (RFS) were determined, as well as preimmunization and postimmunization cellular and humoral immunity.ResultsAmong the patients with stage IV cancer, median follow-up was 10.9 years and 5-year survival was 17%, (95% CI 6% to 33%). Among the patients with stage III cancer, the 5-year RFS was 75%, (95%CI 40% to 91%); no deaths were observed. At a median follow-up of 5.8 years (range: 3.9–7.0 years) all patients were still alive. All patients demonstrated CEA-specific humoral immunity. Patients with stage III cancer had an increase in CD8 +TEM (in 10/12) and decrease in FOXP3 +Tregs (in 10/12) following vaccination. Further, CEA-specific, IFNγ-producing CD8+granzyme B+TCM cells were increased.ConclusionsVRP-CEA induces antigen-specific effector T cells while decreasing Tregs, suggesting favorable immune modulation. Long-term survivors were identified in both cohorts, suggesting the OS may be prolonged.

Identification of Gene-Set Signature in Early-Stage Hepatocellular Carcinoma and Relevant Immune Characteristics

“…Considering the changes in the TME between non-tumor and HCC (87,88), our Cluster C1 signature has shown a predictive advantage in distinguishing the specific eHCC immune cell (CD8 Tem and CTLs) infiltration level from non-tumor samples. In this respect, in line with previous studies (89)(90)(91)(92), these two immune cells (CD8 Tem and CTLs) markedly elucidated the immune characteristics of HCC initiation and progress, which has also shown benefit in improving patient prognosis in both eHCC and aHCC. Therefore, we infer that the effect of Cluster C1 signature on the eHCC patients is probably related to the remodeling of specific immune cells in the TME.…”

Perspectives on Immunotherapy of Metastatic Colorectal Cancer

“…CD8+T EM increased and FOXP3 + Tregs decreased in 83% patients (10/12) after vaccination treatment. The results suggested that VRP-CEA may prolong the OS in stage III CRC patients (76,80). A Randomized Clinical Trial reported that PFS and OS of mCRC patients in the modified vaccinia Ankara-5T4 (MVA-5T4) treatment group was significantly prolonged, compared with those in the no treatment group (5.6 months vs 2.4 months,P <.001; 20.0 vs 10.3 months; HR, 0.32; 95% CI, 0.14-0.74; P = .008).In addition, baseline anti-5T4 responses was doubled in 16 of 35 mCRC patients treated with MVA-5T4 (81).…”

The Role of the Tumor Microenvironment and Treatment Strategies in Colorectal Cancer

“…The 5-year RFS rate was 75% (95% CI 40-91%), and no deaths were observed during the period. After vaccination, levels of CD8 + TEMs increased (10/12), Foxp3 + Tregs decreased (10/12), and specific CEA and IFN-γ produced by CD8 + granzyme B + TCM cells increased ( 287 ).…”