Turning tumor cells in situ into T-helper cell-stimulating, MHC class II tumor epitope-presenters: immuno-curing and immuno-consolidation.
Immunological control or cure of tumors depends on initiating a robust T helper cell response to MHC class II epitopes of tumor-associated antigens. T helper cells regulate the potency of cytotoxic T lymphocyte and antibody responses. We have developed a novel approach to stimulate T helper cells by converting tumor cells into MHC class II molecule-positive, antigen presenting cells. Furthermore, using antisense methods, we suppress expression of the Ii protein, that normally blocks the antigenic peptide binding site of MHC class II molecules during synthesis in the endoplasmic reticulum. In such gene-engineered tumor cells, the MHC class II molecules pick up antigenic peptides, which have been transported into the endoplasmic reticulum for binding to MHC class I molecules. All nucleated cells create such "surveys of self" to detect viral or malignant transformation. Our method extends that survey of self to MHC class II endogenous tumor-associated antigens. Simultaneous presentation of tumor antigens by both MHC class I and II generates a robust and long-lasting antitumor immune response. Injecting murine tumors with genes, which induce MHC class II molecules and suppress Ii protein, cures a significant number of animals with renal and prostate tumors. We have developed analogous human gene vectors that are suitable for most patients and cancers, because they are monomorphic and active in all HLA-DR alleles. We review our findings, and analyze remaining issues for preclinical study and the design of clinical trials.
Hillman
Gilda G
GG
Department of Radiation Oncology, Barbara Ann Karmanos Cancer Institute at Wayne State University School of Medicine, 4100 John R., Detroit, MI 48201, USA.
Kallinteris
Nikoletta L
NL
Lu
Xueqing
X
Wang
Yu
Y
Wright
Jennifer L
JL
Li
Yu
Y
Wu
Shuzhen
S
Forman
Jeffrey D
JD
Gulfo
Joseph V
JV
Humphreys
Robert E
RE
Xu
Minzhen
M
D000818:Animals; D002986:Clinical Trials as Topic; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D000949:Histocompatibility Antigens Class II / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007111:Immunity, Cellular / Q000502:physiology; D007167:Immunotherapy / Q000379:methods*; D008213:Lymphocyte Activation; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D009369:Neoplasms / Q000276:immunology / Q000628:therapy*; D018570:Risk Assessment; D012680:Sensitivity and Specificity; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology* / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000276:immunology
D016207:Cytokines; D000949:Histocompatibility Antigens Class II