Adoptive Immunotherapy of Cancer using Activated Autologous Lymphocytes -Current Status and New Strategies-

Abstract

After the discovery of interleukin-2 (IL-2), lymphokine-activated killer (LAK) cells, tumor-infiltrating lymphocytes (TILs), and cytotoxic T lymphocytes (CTLs) sensitized with the mixed lymphocyte-tumor culture (MLTC) system have been conducted in adoptive immunotherapy (AIT) trials during past 15 years. Although the overall response rate of tumor shrinkage was marginal (9%), locoregional administration of TILs for malignant effusions was effective (77%) for a decrease or disappearance of the effusions even in terminally-ill patients, resulting in an improvement of QOL. Recent advances for molecular understanding of antigen presentation and recognition have promoted us to enhance the efficacy of AIT by using cultured dendritic cells (DCs) for generating antigen-specific CTLs in vitro. The peptide-pulsed DC-activated killer (PDAK) cells showed tumor recognition against antigen-expressing cells, and were efficiently propagated with the IL2 plus immobilized anti-CD3 antibody (IL-2/CD3) culture system. Clinical trials using PDAK cells against patients with lung metastases are now progressed, in which peptides suitable for generating CTLs were chosen in individual patients using the method designated as host-oriented peptide evaluation (HPOE) approach. Moreover, DCs were introduced with tumor-derived RNA, which was amplified with the T7 promoter system, and then were used for stimulating lymphocytes. The tumor RNA-introduced DC-activated killer (TRiDAK) cells showed tumor-specific interferon-gamma spots even in a patient in whom we failed to generate PDAK cells using DCs and peptides, suggesting that the clinical trial of AIT using TRiDAK cells is warranted for the treatment of patients with metastatic cancer. Thus, more understanding of antigen-presentation and -recognition mechanisms and immune regulation systems may promote clinical applications of AIT to establish a novel modality of cancer treatment.

Postoperative immunosuppression cascade and immunotherapy using lymphokine-activated killer cells for patients with esophageal cancer: Possible application for compensatory anti-inflammatory response syndrome

“…It has been reported that IL-2-activated peripheral blood LAK cells consist of CD4 + and CD8 cells as well as NK cells (26,27). Moreover, we have system for easily expanding LAK cells in our laboratory (13). Our preliminary clinical investigation showed that postoperative LAK cell transfer restores the decrease in helper and cytotoxic T-cell populations.…”

“…We have carried out ex vivo cell therapy for cancer treatment using activated autologous lymphocytes, including lymphokine-activated killer (LAK) cells, tumor-infiltrating lymphocytes (TILs), and tumor-sensitized lymphocytes, but tumor responses are limited with regard to quality of life in locoregional administration for malignant effusion from gastrointestinal cancers (13). Ueda et al have reported an efficacy of AIT using LAK cells for metastatic esophageal cancer (14).…”

Depletion of CD4+CD25high regulatory T cells from tumor infiltrating lymphocytes predominantly induces Th1 type immune response in vivo which inhibits tumor growth in adoptive immunotherapy

“…19,20,30 Many attempts have been made to improve the functions of adoptively transferred cells, for instance, Toh et al, activated tumor infiltrated lymphocytes in vitro by using IL-2 to optimize immunotherapy against tumor. 31 Burger et al, re-stimulated TILs with autologous irradiated tumor cells in vitro to enhance the specificity of TILs transferred into tumor-bearing mice.…”

“…[15][16][17][18] In the past decades, adoptive cell transfer (ACT) immunotherapy developed into an important therapeutic strategy against tumors. 19,20 Tumor infiltrating lymphocytes (TILs), isolated from the tumor and expanded in vitro were considered as the best candidate for ACT because of their directed interaction with tumor cells and ability to become antigen-specific lymphocytes. 21,22 However, the efficacy of adoptive transfer of TILs is limited.…”

Biological activity of cytotoxic dendritic cells cocultured with cytokine-induced killer cells and their effect on acute leukemia cells

“…Cytokine-induced killer (CIK) cells are a type of common antitumor immunocompetent cells. They exhibit strong proliferation capacity and high antitumor activity in vitro, and they are particularly effective against multidrug-resistant tumor cells (Yamaguchi et al, 2003). Previous studies have shown that when DCs are cocultured with CIK cells in vitro, they can promote the proliferation of CIK cells and enhance their cytotoxic effects against tumor cells (Marten et al, 2001b).…”