Retroviral Vectors for Use in Human Gene Therapy for Cancer, Gaucher Disease, and Arthritis (original) (raw)
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Cancer Gene Therapy, 1999
The transfer of genes encoding cytokines into tumor cells has emerged as a new strategy to increase in vivo host reactivity to a variety of tumors. Because gene transfer into tumor cells cannot be easily applied in the clinical setting, we have developed an experimental model of gene transfer into fibroblasts and examined the capacity of these engineered cells to elicit an antitumor immune response. Interleukin-12 (IL-12) is a heterodimeric cytokine with pleiotropic activities presenting strong antitumor and antimetastatic effects in murine models. A bicistronic retroviral vector was constructed that contained the cDNAs encoding both chains (p40 and p35) of murine IL-12 separated by an internal ribosomal entry site sequence. Syngeneic cutaneous fibroblasts obtained from newborn mice and transduced to secrete either IL-12 or IL-2 were injected subcutaneously with B16F0 or B16F1 melanoma cells. The time of tumor occurrence and overall survival of mice were significantly prolonged when B16F1 cells were coinjected with cytokine-producing fibroblasts compared with B16F1 alone or B16F1 together with unmanipulated fibroblasts. Systemic effects were seen in the mice injected with either IL-2-or IL-12-secreting fibroblasts, with the highest proliferation capability and interferon-␥ production observed in vitro from splenocytes from recipients of IL-2-secreting fibroblasts. Injection of IL-2-secreting fibroblasts or coinjection of IL-2-and IL-12-producing fibroblasts resulted in a significant increase of survival in the B16F0 model; in some cases, complete disease eradication was observed. These results suggest that cutaneous fibroblasts represent a target of choice for gene transfer and would be useful in the treatment of minimal residual disease in humans.
Journal of Gastroenterology and Hepatology, 1996
Continuing advances in molecular biology have provided tools for a promising approach to the treatment of cancer. Among the various strategies of gene therapy for cancer, many are aimed at killing tumour cells indirectly by the induction or reinforcement of a host immune response by gene transduction of various cytokines, major histocompatibility complex or immune accessory molecules. In the present study, we selected the tumour necrosis factor-a, interleukin-2 and interleukin-3 genes as potential cytokine genes to induce antitumour effects. We constructed retroviral vectors carrying these cytokine genes under the control of the murine albumin enhancer and promoter and retrovirally transduced these genes into hepatoma and non-hepatoma cell lines. Strong expression of the cytokine genes was induced in transduced hepatoma cells, while no evident expression was detected in transduced non-hepatoma cells. These results demonstrate the hepatoma-specific expression of cytokine genes and imply the feasibility of in vivo gene transfer into hepatomas without affecting any other tissues. Furthermore, these cytokine genes were expressed much more intensively when they were derived from the albumin enhancer and promoter than when derived from the simian virus 40 early region promoter. These results indicate that transcriptional regulatory sequences specific for the target tissues could be preferable to viral promoters for the gene therapy of cancer.
Immunotherapy. I: Cytokine gene transfer strategies
Cancer metastasis reviews
The cytokine approach to gene therapy of cancer stems from early studies of direct, repeated injection of recombinant cytokines at the tumor site, and extension of the bystander effect that enables a few cytokine gene transduced cells in a tumor to bring about its total destruction. This effect can be extended through the immune system, since cytokine-activated regression of a small mass of tumor cells can afford systemic protection. Transduced cells used as a vaccine provide a local concentration of both cytokine and tumor antigens. Cytokines sustain antigen uptake and presentation by increasing the immunogenic potential of the environment through the recruitment of antigen presenting cells and leukocytes, and activation of a cascade of events which amplify and tone up the efficacy of a vaccine. The promises and difficulties of this approach are discussed by considering what is still missing from experimental studies and what can best be done as soon as possible in animals and huma...
Murine Models of Cancer Cytokine Gene Therapy Using Interleukin-12
Annals of the New York Academy of Sciences, 1996
INTRODUCTION: RATIONALE FOR IL-12 GENE THERAPY Cytokines mediate all aspects of immune response including the activation of endothelial tissue, the recruitment of immune effectors, the uptake and processing/ presentation of antigen, and the regulation of immune effectors. Cytokine gene a This work was supported by a Career Development Award (1994) of the American Society of Clinical Oncology for H.T. and lPOl CA68067-01
Human Gene Therapy, 1998
The antitumoral activity of recombinant canarypox virus vectors (ALVAC) expressing murine interleukin 12 (IL-12) was evaluated in the syngeneic, nonimmunogenic murine mammary adenocarcinoma model (TS/A). Seven-day preestablished subcutaneous tumors (5-to 6-mm mean diameters) were injected on days 7,10,14, 17, 21, and 24 with the vector ALVAC-IL12 at 2.5 X 10^ TCID50 (50% tissue culture infective dose). Total tumor regression occurred in 40 to 50% of the treated mice. Furthermore, 100% of the cured mice were protected against a contralateral subsequent challenge with the TS/A parental cells on day 28. The ALVAC-IL12 treatment is not effective in nude mice, suggesting the critical role of T cells. CD4 and CDS T cells infiltrated the tumors treated with ALVAC-IL12 in the BALB/c model. Furthermore, in vivo depletion of CD4+ T cells totally abrogated the induction of the long-term antitumoral immune response by ALVAC-IL12. Interestingly, some tumor growth inhibition was also observed with ALVAC-/3Gal treatment and a vaccinal effect was found in 33% of the treated animals, suggesting an adjuvant effect of the vector itself. Other ALVAC vectors expressing murine cytokines (IL-2, GM-CSF, IFN-y) were evaluated in the same model. Major antitumoral activity was observed with ALVAC-GM-CSF. However, a combination of ALVAC-GM-CSF and AL-VAC-IL12 had no synergistic effect. These results suggest that in vivo gene transfer with canarypox virus expressing IL-12 may provide an effective and safe strategy for the treatment of human cancers. OVERVIEW SUMMARY preestablished tumors and led to a long-term antitumoral immune response. Other ALVAC constructs expressing IL-In the present study, we evaluated the antitumoral effect of 2, GM-CSF, or IFN-y were evaluated in the same model. direct in vivo gene therapy, using a canarypox virus re-Antitumoral activity was also observed with ALVAC-GMcombinant vector expressing IL-12 (ALVAC-IL12), in a CSF. These results support the feasibility of in vivo gene poorly immunogenic tumor model. In humans, the recom-therapy with ALVAC-IL12 for the treatment ofhuman canbinant ALVAC vectors expressing foreign viral proteins cer. have already been shown to be safe and efficient for vaccination. Their ability to induce cytotoxic T lymphocyte (CTL) priming has led to interest in their use for cancer im
Gene therapy approaches against cancer usingin vivoandex vivogene transfer of interleukin-12
Immunotherapy, 2016
IL-12 is an immunostimulatory cytokine with strong antitumor properties. Systemic administration of IL-12 in cancer patients led to severe toxic effects, prompting the development of gene therapy vectors able to express this cytokine locally in tumors. Both nonviral and viral vectors have demonstrated a high antitumor efficacy in preclinical tumor models. Some of these vectors, including DNA electroporation, adenovirus and ex vivo transduced dendritic cells, were tested in patients, showing low toxicity and moderate antitumor efficacy. IL-12 activity can be potentiated by molecules with immunostimulatory, antiangiogenic or cytotoxic activity. These combination therapies are of clinical interest because they could lower the threshold for IL-12 efficacy, increasing the therapeutic potential of gene therapy and preventing the toxicity mediated by this cytokine.