Transfection of the gene for B7-1 but not B7-2 can induce immunity to murine malignant mesothelioma

Abstract

Transfection of the genes encoding the co-stimulatory molecules B7-1 and B7-2 has enhanced the development of immunity to a variety of experimental tumors, although most of these were inherently immunogenic. We have determined the effect of expression of these genes on the induction of immunity to 2 non-immunogenic murine malignant mesothelioma (MM) cell lines (AC29 and AB1). We had previously shown that B7-1 transfection into AC29 delayed but did not prevent tumor development by certain of the transfectant clones. Here we demonstrate that over-expression of B7-1 can inhibit tumor development by certain AB1-B7-1 clones, that inhibition of transfectant growth is dependent on CD4 1 and CD8 1 T cells and that mice that reject some of these transfectant clones are capable of rejecting subsequent inocula of the parental cell line, AB1. The transfectant clones can generate tumor-specific cytotoxic T cells. By contrast, expression of B7-2 in several clones derived from either AB1 or AC29 had no significant effect on the development of tumors in vivo. Our data are consistent with data from other systems that show differences in the effect of modification by B7-1 or B7-2 on the modulation of anti-tumor immune responses. They demonstrate that such modifications can induce protective immunity against an MM cell line but confirm the intra-and inter-tumoral heterogeneity in the effect of genetic modification on the induction of immunity. Our observations are relevant to human MM because these cell lines have been derived from asbestos-induced tumors and share many properties with human cell lines of the same histological type. Int.

The immune anti-tumor effects of GM-CSF and B7-1 gene transfection are enhanced by surgical debulking of tumor

“…7,10,11,21 As control transfectants, tumor cells were transfected with the phb -Apr-neo vector alone and maintained as described above.…”

“…3,4 More recent treatment strategies for solid tumors such as MM, particularly gene therapy and immunotherapy, have shown some promise in both human 5,6 and murine studies. Several cytokines, including IL -2, 7,8 GM -CSF, 9 B7 -1, 10,11 IL -12, 12 IFN -, 13,14 and IFN - 15 have demonstrated significant antitumor effects. However, the delivery of these cytokines has been problematic, which has limited the use of these cytokines in clinical practice, hence the need for gene therapy approaches that aim to improve cytokine delivery.…”

Antitumor activity of the intratumoral injection of fowlpox vectors expressing a triad of costimulatory molecules and granulocyte/macrophage colony stimulating factor in mesothelioma

“…31 Furthermore, transduction of B7-1 but not of B7-2 was effective in previous studies of mesothelioma. 13 This study examined the ability of a fowlpox vector encoding the TRICOM construct, which encodes for costimulatory molecules B7-1, ICAM-1, and LFA-3, to stimulate anti-mesothelioma immunity. Tumor cells modified to express high levels of these costimulatory molecules can activate T cells to a greater extent than tumor cells transduced with any one or two of these molecules.…”

“…12 Expressing the costimulatory molecule, B7-1 (CD80), in a nonimmunogenic mesothelioma tumor enhances the generation of tumorspecific CTL with consequent inhibition of tumor development. 13,14 More recently, combinations of 3 costimulatory molecules, B7-1, ICAM-1 (CD54) and LFA-3 (CD58), have been shown to activate T cells to a far greater extent than the combination of 1 or 2 costimulatory molecules. This triad of costimulatory molecules, also known as TRICOM, has been encoded in recombinant pox viral vectors and has been shown to significantly enhance antitumor immune responses in mouse colon cancer and lymphoma models.…”

Expression of B7.1 (CD80) in a renal cell carcinoma line allows expansion of tumor-associated cytotoxic T lymphocytes in the presence of an alloresponse

“…Earlier studies in animals revealed that tumor cells modified to express B7.1 costimulatory molecules had enhanced immunogenicity and were capable of inducing immune responses in naive animals that could protect against challenge with unmodified tumor cells. [11][12][13][14][15][16][17] Introduction of B7.1 into several human tumor lines also improved their immunogenicity in vitro and in some cases led to activation of specific CTL. [18][19][20][21][22][23][24][25] …”