Immunotherapy of solid cancer using dendritic cells pulsed with the HLA-A24-restricted peptide of carcinoembryonic antigen

Abstract

Carcinoembryonic antigen (CEA), an oncofetal glycoprotein overexpressed in most gastrointestinal and lung cancers, is a candidate molecule for cancer immunotherapy. Recently, a CEA-derived 9-mer peptide, CEA652 (TYACFVSNL), has been identified as the epitope of cytotoxic T lymphocytes restricted with human leukocyte antigen (HLA)-A24, which is present in 60% of the Japanese population and in some Caucasians. The authors performed a clinical study of a vaccine using autologous dendritic cells (DCs) pulsed with CEA652 and adjuvant cytokines, natural human interferon alpha (nhuIFN-alpha), and natural human tumor necrosis factor alpha (nhuTNF-alpha), for the treatment of patients with CEA-expressing advanced metastatic malignancies. Ten HLA-A24 patients with advanced digestive tract or lung cancer were enrolled in the study to assess toxicity, tolerability and immune responses to the vaccine. DCs were generated from plastic adherent monocytes of granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood mononuclear cells (PBMCs) in the presence of granulocyte/macrophage colony-stimulating factor (GM-CSF) and interleukin 4 (IL-4). Generated DCs showing an immature phenotype were loaded with CEA652 and injected into patients intradermally and subcutaneously with 50% of the dose administered by each route every 2 weeks for a total of ten vaccinations. The total dose of administered DCs ranged from 2.7x10(7)cells to 1.6x10(8)cells. Adjuvant cytokines, i.e., 1x10(6) U/body of nhuIFN-alpha and nhuTNF-alpha, were administered to patients twice a week during the vaccination period. No severe toxicity directly attributable to the treatment was observed, and the vaccine was well tolerated. In the delayed-type hypersensitivity (DTH) skin test, two patients showed a positive skin response to peptide-pulsed DCs after vaccination, although none of the patients tested positive prior to vaccination. In the two patients who showed a positive skin response disease remained stable for 6 and 9 months respectively. These results suggest that active immunization using DCs pulsed with CEA652 peptide in combination with the administration of adjuvant cytokines is a safe and feasible treatment procedure.

Identification of Two Novel HLA‐A∗0201‐Restricted CTL Epitopes Derived from MAGE‐A4

“…The identification of tumor-associated antigens (TAAs) and their epitopes has boosted the development of the strategy. TAAs are composed of five major groups: cancer/testis (CT) antigens (e.g., MAGE, BAGE, GAGE, NY-ESO-1, [33–35]), mutated antigens (e.g., MUM-1, p53, and beta-catenin [36, 37]), overexpressed antigens (e.g., RCAS1, Survivin, and Her2/neu [38–40]), oncofetal antigens (e.g., Immature laminin receptor and CEA [41, 42]), and differentiation or lineage antigens (e.g., tyrosinase, Melan-A/MART-1, gp100, TRP-1, and TRP-2 [43, 44]). Because CTLs play a key role in antitumor immune responses [45] and CT antigens are expressed in many tumors but not in normal tissues except testis and placenta, the identification of CTL epitopes derived from CT antigens is very important for the studies of antitumor vaccines based on defined epitope peptides.…”

Neoantigen Identification and Dendritic Cell-Based Vaccines for Lung Cancer Immunotherapy

“…Twelve patients diagnosed with either CRC or NSCLC were enrolled in a study where they received the Flt3 ligand, a hematopoietic growth factor known to increase DCs in vivo. Following this treatment, the patients underwent peripheral blood leukapheresis [128]. Subsequently, DCs were isolated and enriched with a supplementary protein referred to as KLH, which is not only capable of monitoring the immunological responses elicited by therapy but can also be utilized for the same purpose.…”

Colorectal Cancer Immunotherapy: State of the Art and Future Directions

“… 93 , 94 These trials have provided evidence for the safety of moDC vaccines and their ability to stimulate tumor-specific T cell responses, which has been associated with improved survival. 90 However, a limitation of this approach is the availability of tumor material, which has been circumvented in other trials by pulsing moDCs with allogeneic cell line lysates 95 ; peptides (or mRNA) of tumor-associated antigens 96 – 99 and established neoantigens, 100 such as frameshifted caspase 5 101 and transforming growth factor β receptor II. These studies confirmed the feasibility and tolerability of moDC vaccines and provided evidence of T cell responses and benefit in some patients.…”