A phase I trial of cytotoxic T-lymphocyte precursor-oriented peptide vaccines for colorectal carcinoma patients

Abstract

In most protocols of peptide-based vaccination, no consideration has been paid to whether or not peptide-specific cytotoxic Tlymphocyte (CTL) precursors are pre-existent in cancer patients. Initiation of immune boosting through vaccination is better than that of immune priming to induce prompt and strong immunity. In this study, 10 human histocompatibility leukocyte antigen-A24 þ patients with advanced colorectal carcinomas were treated with up to four peptides that had been positive for pre-vaccination measurement of peptide-specific CTL precursors in the circulation (CTL precursor-oriented peptide vaccine). No severe adverse effect was observed, although local pain and fever of grade I or II were observed. Post-vaccination peripheral blood mononuclear cells (PBMCs) from five patients demonstrated an increased peptide-specific immune response to the peptides. Increased CTL response to cancer cells was detected in post-vaccination PBMCs of five patients. Antipeptide immunoglobulin G became detectable in postvaccination sera of seven patients. Three patients developed a positive delayed-type hypersensitivity response to at least one of the peptides administrated. One patient was found to have a partial response; another had a stable disease, sustained through 6 months. These results encourage further development of CTL precursor-oriented vaccine for colorectal cancer patients.

Assessment of immunological biomarkers in patients with advanced cancer treated by personalized peptide vaccination

“…We previously reported that both IgG and CTL responses were augmented in the samples after 6 th vaccination from the majority of patients who showed PR responses. 19,23,25 We also demonstrated that there were no significant differences in overall survival between patients showing both CTL and IgG responses and those showing only IgG response. 10,11 These results suggest that boosted CTL responses are involved in tumor reduction, but not necessarily involved in prolonged overall survival.…”

“…All of these peptides can induce HLA-A24-, A2-and A3-supertype-restricted and tumorspecific CTL activity in PBMCs of cancer patients. 6,[13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][42][43][44] Before the first vaccination and 7 days after every sixth vaccination, 30 ml of peripheral blood was obtained and PBMCs were isolated by means of Ficoll-Conray density gradient centrifugation. Peptide-specific CTL precursors in PBMCs were detected using the previously reported culture method.…”

“…These symptoms were manageable through routine interventions as reported previously. [13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29] The best response to the personalized peptide vaccination was assessed in 436 patients. No complete responses (CR) were observed in either group.…”

Allogeneic nonmyeloablative hematopoietic cell transplantation in metastatic colon cancer: tumor-specific T cells directed to a tumor-associated antigen are generated in vivo during GVHD

“…[45][46][47][48] Several CEA-based vaccine formulations have proven to be safe in humans and not associated with autoimmune reactions, making vaccination of healthy individuals a potential approach for increasing the frequency of CEA-specific T cells in the donor hematopoietic cell graft. 31,[49][50][51][52] As for the vaccination of engrafted patients, timing of vaccine delivery could be critical for efficacy. Data obtained at different timepoints after transplantation suggest that full donor engraftment and discontinuation of immunosuppression will likely be important requirements for success.…”

Characteristics of severe adverse events after peptide vaccination for advanced cancer patients: Analysis of 500 cases

“…The number of administered vaccinations varied widely, from 3 to 112 per patient, with the most prolonged vaccination periods being for the prostate cancer patients. Most of the safety, immune, as well as clinical responses in these studies have been previously reported (5)(6)(7)(8)(9)(10)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25). Studies are currently underway to obtain vaccination results for the treatment of pancreatic and breast cancer, as well as for the HLA-A3 supertype-positive patients.…”