Postoperative active specific immunization in curatively resected colorectal cancer patients with a virus-modified autologous tumor cell vaccine

Abstract

Active specific immunotherapy was performed in a phase I study in 20 colorectal cancer patients after surgical resection of the tumor. An autologous tumor cell vaccine surface modified by Newcastle disease virus (NDV) was used, which showed the following characteristics. After mechanical and enzymatic dissociation of the tumor tissue an average of 5 x 10(7) cells/g tissue was obtained. According to trypan blue dye exclusion assay the average viability was 72%. Following irradiation (200 Gy) the inactivation of proliferative activity of the cells could be demonstrated by the absence of incorporation of 3H-labelled thymidine. The cells were, however, still metabolically active as shown by the incorporation of [3H]-uridine and a mixture of 3H-labelled amino acids. Epithelium-specific antigens (detected by mAb HEA125) were expressed on more than 75% cells of the cell suspension indicating a high amount of (epithelium-derived) tumor cells. In order to increase the immunogenicity of the tumor cells the suspended cells were infected by the nonlytic, apathogenic Ulster strain of NDV. The successful modification of tumor cells with NDV could be shown by electron microscopy. Three weeks postoperatively cells were thawed, virus-modified, and inoculated intradermally in the upper thigh. Several cell and virus concentrations were tested in each patient. As control, tumor cells without NDV, NDV alone and normal colon mucosa were used. The number of tumor cells ranged from 2 x 10(6) up to 2 x 10(7) cells and NDV concentrations from 4 to 64 hemagglutination units (HU) were tested. Sixteen patients responded with a delayed-type hypersensitivity (DTH) skin reaction to the vaccine. The best DTH reaction, measured 24 h following vaccination, was obtained using a vaccine consisting of 1 x 10(7) tumor cells and 32 HU NDV (median induration of 8 mm). Response to NDV alone was seen in 2 patients only (median induration of 3 mm); 12 patients responded to tumor cells (1 x 10(7) alone (median induration of 4 mm). Of 10 patients tested with normal colorectal mucosa, 4 responded with a median induration of 3.5 mm. DTH responses to the vaccine of 1 x 10(7) tumor cells and 32 HU NDV increased throughout the repeated vaccinations to a median induration of 9.5 mm at the end of the therapy. No severe side-effects in the course of the immunotherapy, except for mild fever in 4/20 patients, were observed. The results of our phase I study show that this type of autologous colorectal tumor cell vaccine is ready for a large clinical trial to prove its efficacy.

In situ activation of syngeneic tumour-specific cytotoxic T lymphocytes: Intra-pinna immunization followed by restimulation in the peritoneal cavity

“…In further experiments we could show that this protective effect was specific in that PEC against Eb tumour cells that express a different tumour-associated transplantation antigen did not protect against ESb cells. A detailed understanding of immune mechanisms in metastatic animal tumour models is an important prerequisite for designing new protocols of immunotherapy [14,18,30,35].…”

Active specific immunotherapy with Newcastle-diseasevirus-modified autologous tumor cells following resection of liver metastases in colorectal cancer

“…The vaccine was prepared as previously described in detail [2,13]. Briefly, fresh tumor specimens were dissociated mechanically and enzymatically by DNAse and collagenase.…”

“…We showed in an animal tumor model that the concept of active specific immunotherapy (ASI) using autologous tumor cells modified by Newcastle disease virus (NDV) is a promising strategy to treat microscopic tumor foci [4,19]. In a clinical phase I study we transferred this concept to human colorectal cancer and developed a practical and standardized vaccination protocol [2,13]. In this phase II trial we investigated whether ASI influences (a) the immune response measured by a delayed-type hypersensitivity (DTH) skin reaction to autologous tumor cells and (b) the clinical outcome of patients who underwent liver resection from metastatic colorectal cancer.…”

Active Specific Immunotherapy – A New Modality of Cancer Treatment Involving the Patient’s Own Immune System

“…Sterility and other quality controls were included [31]. Results from phase I and II studies have been reported [20,31,32], The first evaluation of clinical response to adjuvant ASI treatment with autologous tumor cell vaccines modified by NDV infection (ATV-NDV) was done in colorectal cancer patients following resection of liver métastasés [33], In this high-risk group of patients, adjuvant chemotherapy has only limited success and 70-80% relapse within 5 years from the outgrowth of micro metastasis not detectable at the time of liver resection. The objective of the study was to investigate w'hether ASI influ ences (a) the immune response to autologous tumor cells and (b) the recurrence-free and overall survival of vaccinated pati ents compared with nonvaccinated matched controls.…”