An MVA-based Vaccine Targeting the Oncofetal Antigen 5T4 in Patients Undergoing Surgical Resection of Colorectal Cancer Liver Metastases

Abstract

We investigated the use of a therapeutic vaccine, TroVax in patients undergoing surgical resection of colorectal cancer liver metastases. Systemic immunity generated by vaccination before and after resection of metastases was measured in addition to assessing safety and analyzing the function and phenotype of tumor-associated lymphocytes. Twenty patients were scheduled to receive 2 TroVax vaccinations at 2-week intervals preoperatively and 2 postoperatively; if immune responses were detected, 2 further vaccinations were offered. Blood was taken at trial entry and 2 weeks after each vaccination; tumor biopsies were collected at surgery. 5T4-specific cellular responses were assessed by lymphocyte proliferation and enzyme-linked immunosorbent spot, with antibody responses by enzyme-linked immunosorbent assay. Immunohistochemistry characterized the phenotype of tumor-infiltrating lymphocytes. Seventeen of 19 colorectal cancer patients showed 5T4 expression in the liver metastases or surrounding stroma and 18 mounted a 5T4-specific cellular and/or humoral response. In patients who received at least 4 vaccinations and potentially curative surgery (n=15), those with above median 5T4-specific proliferative responses or T-cell infiltration into the resected tumor showed significantly longer survival compared with those with below median responses. Seven of 8 patients who had preexisting proliferative responses to 5T4 were longer-term survivors; these patients showed significantly higher proliferative responses after vaccination than those who subsequently died. These data suggest that the magnitude of 5T4 proliferative responses and the density of CD3 cells in colorectal cancer liver metastases are associated with longer survival. These observations warrant more studies to identify the precise underlying mechanisms.

Vaccination of Metastatic Renal Cancer Patients with MVA-5T4: A Randomized, Double-Blind, Placebo-Controlled Phase III Study

“…Results from phase I and II clinical studies of MVA-5T4 in renal, colorectal, and prostate cancer patients were encouraging and showed that immune responses were induced in almost all treated patients, and associations between 5T4-specific cellular or humoral responses and clinical benefit were reported in seven of nine studies (8)(9)(10)(11)(12)(13)(14)(15)(16). In particular, studies in RCC and colorectal cancer patients have detected an association between 5T4-specific (but not MVA) antibody responses and enhanced survival (9,12,16).…”

“…These studies showed MVA-5T4 to be well tolerated and able to induce 5T4-specific immune responses in most patients. Furthermore, associations between 5T4-specific cellular or humoral responses and clinical benefit were reported in seven of the nine studies (8)(9)(10)(11)(12)(13)(14)(15)(16).…”

Modulation of Lymphocyte Regulation for Cancer Therapy: A Phase II Trial of Tremelimumab in Advanced Gastric and Esophageal Adenocarcinoma

“…The possible induction of antitumor-specific lymphocytes by CTLA4 blockade requires further investigation in man, but may suggest a rationale for combining anti-CTLA4 blockade with one of the antigen-targeted therapies currently in clinical development, such as CEA or 5T4 vaccination (27,40), 5T4 superantigen (41), or CEA-targeted cytotoxic T cells. CTLA4 blockade has previously been administered to melanoma and ovarian cancer patients who had received vaccination with antitumor immunity being shown (42).…”

“…To explore changes in in vitro responses to relevant TAAs, overlapping 5T4 32-mer peptides (18 patients, 24 cycles) and purified CEA (13 patients, 15 cycles) were used in a thymidine incorporation proliferation assay (26). All time points for each patient were investigated in the same assay: cryopreserved PBMCs were thawed and 1.5 × 10 5 viable cells per well were cultured in Iscove's modified Dulbecco's medium with 10% AB serum, with six pools of four overlapping 5T4 peptides (defined as A-X) spanning the whole sequence of human 5T4 (10 μg/mL of each peptide); media controls with and without the appropriate concentration of dimethyl sulfoxide were used to prepare peptide stocks (27,28). In parallel assays, PBMCs were cultured with purified CEA (Calbiochem) at 100, 200, and, if sufficient cells are present, 300 ng/mL.…”

“…A pretreatment response was defined by a mean SI of ≥2. A posttreatment response was defined as a mean SI of ≥2, with a doubling of pretreatment response (27). Patients with new posttreatment responses were considered responders.…”