IMMUNITY BY EPISOMETRANSFER TO LUNG TUMORS

  • Podack, Eckhard R, (PI)

Project: Research project

Description

The long range objective of this program is the induction of an effective,
cellular immune response to tumors in cancer patients. To achieve this
goal, the two phases of the immune system, initiation of a response and its
amplification, will be modulated by gene transfer to tumor cells and to
specific effector T cells. In the first stage, non immunogenic tumors are
rendered immunogenic by the transfection of lymphokine cDNA to explanted
tumor cells. Complementary DNAs for I12 and I14 will be used initially.
Based on our previous results in preclinical experiments (murine Lewis lung
carcinoma), reimplantation of lymphokine producing cells is expected to
result in a tumor specific, cellular response in patients. This prediction
will be tested in clinical trials of patients suffering from Small Cell
Lung Carcinoma (SCLC) and from Melanoma. An episomal plasmid vector system
pBMG-Neo allowing high level and stable expression of the gene products
will be used for gene transfer in all trials. The induced tumor specific immune response will be evaluated by the
clinical response of the patient and by a novel in vivo assay measuring the
clearance of subcutaneously administered, radiolabeled and transfected
tumor cells. In addition, the frequency of tumor specific effector cells
will be determined that can be cultured from the peripheral blood of
patients. Cultured tumor specific effector cells will be engineered by gene transfer
and used for amplification of the initial cellular response. This stage of
gene transfer is aimed at enhancing the effectiveness of T-cells upon
reimplantation. The lack of a complete response after lymphokine gene
transfer to tumor bearing mice may be due to the downregulation
(suppression) of the initially activated effector cells, once they
encounter large numbers of non-lymphokine producing (natural) tumor cells.
It will be tested whether uncoupling of effector T-cells from normal
regulatory controls will improve their efficiency in tumor rejection.
These studies will first be carried out in our preclinical Lewis lung cell
carcinoma murine model. Cultured tumor specific T-cells will be transfected in order to achieve
dysregulated expression of genes known to influence T-cell proliferation
(I12 receptor, I12 and I14), T-cell survival (bcl2) and effector function
(perforin). The cotransfected HSV thymidine kinase will serve as safety
device against uncontrolled T-cell growth.
StatusFinished
Effective start/end date9/30/929/29/97

Funding

  • National Institutes of Health
  • National Institutes of Health: $829,364.00
  • National Institutes of Health
  • National Institutes of Health: $785,432.00

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Immunity
Lung
Neoplasms
T-Lymphocytes
Lymphokines
Complementary DNA
Genes
Gene Expression
Perforin
Thymidine Kinase
Replantation
Cellular Immunity
Transfection
Immune System
Melanoma
Cell Survival
Plasmids
Down-Regulation
Cell Proliferation
Clinical Trials

ASJC

  • Medicine(all)