Phase I/II study of immunotherapy with T-cell peptide epitopes in patients with stage IV melanoma

Abstract

Previous studies in small groups of patients suggested that immunization of melanoma patients with peptide epitopes recognized by T cells could induce regression of melanoma. This approach was tested in 36 patients with stage IV melanoma. The (MHC class I-restricted) peptides were from gp100, MART-1, tyrosinase, and MAGE-3. The gp100 and MART-1 peptides had been modified to increase their immunogenicity. In half the patients (groups 3 and 4) the peptides were given in the adjuvant Montanide-ISA-720, and half the patients in both groups were given GM-CSF s.c. for 4 days following each injection. Treatment was well tolerated except for two severe erythematous responses to Montanide-ISA-720 and marked inflammatory responses at sites of GM-CSF administration in three patients. There were no objective clinical responses but stabilization of disease for periods from 3 to 12 months were seen in seven patients. Five of these were patients given the peptides in Montanide-ISA-720. Delayed-type hypersensitivity (DTH) skin test responses were also seen mainly in the patients given the peptides in Montanide-ISA-720. GM-CSF did not increase DTH responses in patients in the latter group but may have increased DTH responses in those not given peptides in Montanide-ISA-720. Inflammatory responses around s.c. metastases or regional lymph nodes were observed in two patients. These results suggest that the peptides are more effective when given in the adjuvant Montanide-ISA-720. Nevertheless, results from this study, together with those from a number of comparable studies, indicate that peptide vaccines are currently of minimal benefit to patients and support the need for ongoing development of new strategies in treatment of this disease.

MHC Class I–Presented Tumor Antigens Identified in Ovarian Cancer by Immunoproteomic Analysis Are Targets for T-Cell Responses against Breast and Ovarian Cancer

“…We used GM-CSF at 100 mg per injection and believe the GM-CSF was likely immunostimulatory at this dose. Regarding our use of a weekly schedule (with a 1-week break in the middle), the best immunization schedule is unclear with some studies by using weekly or biweekly followed by monthly (28)(29)(30)(31)(32)(33)(34)(35)(36)(37).…”

“…Numerous clinical trials testing tumor associated peptides have used adjuvants based on bacterial cell wall products [Incomplete Freund's adjuvant (IFA) or Montanide ISA-51] or with immuneactivating agents such as GM-CSF (35)(36)(37)(38)(39)(40)(41)(42)(43). There is controversy as to whether GM-CSF improves immune responses or activates suppressive responses (44,45).…”

Autologous Melanoma Vaccine Induces Antitumor and Self-Reactive Immune Responses That Affect Patient Survival and Depend on MHC Class II Expression on Vaccine Cells

“…Objective tumor response to autologous melanoma vaccines is low and is seen only sporadically in patients with small tumor burden, mostly restricted to the skin or lung (2,3). Other complex vaccines, including allogeneic melanoma cells and genetically modified autologous cells also yield a modest response rate (4,5). In the adjuvant setting, autologous melanoma vaccines have not been compared with other treatments or with observation alone in randomized controlled studies.…”

Phase I Trial of a CD8+T-Cell Peptide Epitope-Based Vaccine for Infectious Mononucleosis

“…The vaccine comprised the HLA B*0801-restricted CD8 ϩ T-cell epitope FLRGRAYGL (FLR) from the latent antigen EBNA3 (9, 10) and tetanus toxoid (TT) as a source of CD4 ϩ T-cell help formulated in the water-in-oil adjuvant, Montanide ISA 720. This adjuvant has been successfully used to induce peptide-epitope-specific CD8 ϩ T-cell responses in mice (20,48) and has been used in several human vaccine trials (23,36,46,62).…”