A Safety and Feasibility Study of an Allogeneic Colon Cancer Cell Vaccine Administered with a Granulocyte–Macrophage Colony Stimulating Factor–Producing Bystander Cell Line in Patients with Metastatic Colorectal Cancer

Abstract

Background Despite recent advances in earlier detection and improvements in chemotherapy, the 5-year survival rate of patients with metastatic colorectal carcinoma remains poor. Immunotherapy is a potentially effective therapeutic approach to the treatment of colorectal carcinoma. Preclinical studies have supported the antitumor activity of immunization with a granulocyte–macrophage colony-stimulating factor (GM-CSF) producing murine colon tumor cell vaccine. Methods A novel colorectal cancer vaccine composed of irradiated, allogeneic human colon cancer cells and GM-CSF-producing bystander cells was developed and tested in combination with a single intravenous low dose of cyclophosphamide in a phase 1 study of patients with metastatic colorectal cancer. Results A total of nine patients were enrolled onto and treated in this study. Six patients had a history of colorectal adenocarcinoma hepatic metastases and underwent curative metastasectomy, while three other patients had unresectable stage IV disease. This study demonstrates the safety and feasibility of this vaccine administered in patients with metastatic colorectal cancer. At last follow-up, the six patients who underwent curative metastasectomy survived longer than 36 months, and four of these six patients were without disease recurrence. Immunologic correlate results suggest that the GM-CSF-producing colon cancer vaccine enhances the production of anti-MUC1 antibodies. Conclusions This vaccine is feasible and safe. Future investigation of the efficacy and antitumor immunity of this vaccine is warranted.

A phase 2 study of GVAX colon vaccine with cyclophosphamide and pembrolizumab in patients with mismatch repair proficient advanced colorectal cancer

“…The GVAX colon vaccine is an allogeneic, whole‐cell, granulocyte‐macrophage colony‐stimulating factor (GM‐CSF)‐secreting cellular immunotherapy that induces T‐cell immunity against a broad range of colon cancer‐associated antigens. It consists of two CRC cell lines (SW837, SW620), and a bystander cell line transfected with a plasmid vector encoding human GM‐CSF as a vaccine adjuvant . Preclinical and clinical studies from our group and others have shown that GM‐CSF‐secreting allogeneic vaccines can increase tumor infiltrating CD8 + T effector cells, but these cells produce interferon gamma, leading to upregulation of the PD‐1/ programmed death‐ligand 1 (PD‐L1) pathway .…”

“…It consists of two CRC cell lines (SW837, SW620), and a bystander cell line transfected with a plasmid vector encoding human GM-CSF as a vaccine adjuvant. 5 Preclinical and clinical studies from our group and others have shown that GM-CSF-secreting allogeneic vaccines can increase tumor infiltrating CD8 + T effector cells, but these cells produce interferon gamma, leading to upregulation of the PD-1/ programmed death-ligand 1 (PD-L1) pathway. 6,7 In a prior study utilizing a similar vaccine approach in pancreatic cancer, neoadjuvant treatment with pancreatic GVAX induced high levels of PD-L1 expression on the epithelial tumor cells and led to the formation of novel vaccine-induced, immunologically active, tertiary lymphoid aggregates; these are organized lymph node-like structures that are not observed in tumor tissue resected from unvaccinated patients.…”

An effective cytokine adjuvant vaccine induces autologous T-cell response against colon cancer in an animal model

“…It is shown that a sustained level of GM-CSF and IL-2 at the vaccination site is important for the activation of anti-tumor immune response [ 13 ], as GM-CSF acts to recruit DCs to present antigen, and IL-2 strengthens the T-cell response. Consistently, we showed that, if given sufficient amount in the colorectal cancer model, the vaccine may release GM-CSF and IL-2 in a good timing and effectively elicited an autologous T cells response, which achieved high efficacy in preventing from the tumor formation.…”

“…GM-CSF is an important growth and differentiation factor for dendritic cells, which are potent antigen-presenting cells that can take up cellular proteins as tumor antigens [ 13 ]. For an effective antitumor response, preclinical studies suggested that GM-CSF secretion occur at the site of vaccination and high levels of the cytokine must be sustained for several days [ 14 , 15 ].…”

The emerging role of immunotherapy in colorectal cancer

“…While the trials have not been shown to have any significant impact on overall survival, the vaccine has been shown to augment antitumor immunity in melanoma (10) and lung cancer (11). In a phase I study, nine patients with metastatic CRC were treated with a CRC vaccine composed of irradiated, allogeneic human colon cancer cells and GM-CSF-producing bystander cells in combination with a single dose of cyclophosphamide in order to deplete regulatory T (Treg) cells (12). GM-CSF acts as an important differentiation factor for dendritic cells thereby improving their capacity to present tumor antigens.…”