Trials with non-specifically cytotoxic LAK (lymphokine activated killer) cells have demonstrated some tumor regression and substantial toxicity. The ultimate goal of this proposal is development of a more effective, safer, specific adoptive immunotherapy regimen for sarcoma patients through improved understanding of the immunobiology of the disease and of the optimal conditions for lymphocyte mediated cytolysis.
The specific aims of this competing renewal are: 1. To further explore the nature of the HLA restriction of T cell clones cytotoxic for sarcomas. Earlier work indicates a high prevalence of the HLA-A2 haplotype and a need for concordance at this haplotype for the generation of specifically cytotoxic lymphocytes. HLA-A2 subtypes responsible for target cell recognition will be defined using isoelectric focusing. The role of concordance at other HLA loci in the generation of specifically cytotoxic T cells will be assessed to determine if the essential phenomenon is concordance or if there is a specific role for A2. 2. To continue the comparison of LAK cells and specifically cytotoxic (educated) T cells. Presence in culture of HLA-A2+ sarcoma cells precludes development of LAK-like cytotoxicity in PBLs. Future studies will assess: (a) cell surface markers using monoclonal antibodies, (b) precursors for LAK or specifically cytotoxic cells using Percoll separation of PBLs, (c) the time in culture when lymphocytes become committed to LAK or specific killing and the durability of that commitment, and (d) the role of HLA concordance in generating LAK or specific killing. 3. To conduct preclinical therapy trials using human sarcomas xenografted in nude mice. Both local (Winn test) and systemic administration of effector cells will be explored to define: (a) relative effectiveness of LAK cells, cloned specifically cytotoxic T cells, educated PBLs and tumor infiltrating lymphocytes, (b) optimal dose and schedule of administration of T cells, and (c) effects of IL-2 alone or with effector cells. It is hoped that these studies will lead to a better understanding of the biology of sarcomas and provide reagents for clinical trials.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA039286-05
Application #
3178119
Study Section
Experimental Immunology Study Section (EI)
Project Start
1984-08-01
Project End
1991-01-31
Budget Start
1989-02-01
Budget End
1990-01-31
Support Year
5
Fiscal Year
1989
Total Cost
Indirect Cost
Name
Thomas Jefferson University
Department
Type
Schools of Medicine
DUNS #
061197161
City
Philadelphia
State
PA
Country
United States
Zip Code
19107
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Slovin, S F; Lackman, R D; Mastrangelo, M J (1987) HLA-A2 in sarcomas: an immunobiologic perspective. Transplantation 43:923-5
Slovin, S F; Lackman, R D; Ferrone, S et al. (1986) Cellular immune response to human sarcomas: cytotoxic T cell clones reactive with autologous sarcomas. I. Development, phenotype, and specificity. J Immunol 137:3042-8
Hirshaut, Y; Slovin, S F (1985) Harnessing T-lymphocytes for human cancer immunotherapy. Cancer 56:1366-73