The main objective of this proposal is to understand the mechanism by which a widely used anticancer drug, melphalan (L- PAM) shifts the balance from immunosuppression to potent antitumor immunity when administered to mice at an advanced stage to tumor growth. We know already that the immunomodulatory activity of a low dose of this alkylating agent consists, in some plasmacytoma tumor models, not only of elimination of suppressor cell activity, but also of induction of appearance of immunopotentiating activity in T-cells that coexpress the Lyt 2 and the L3T4 antigens even when these cells reside in secondary lymphoid organs. Experiments will be performed to determine to role of the thymus in the appearance of T cells with such an unusual phenotype (i.e., expressing simultaneously the Lyt 2 and the L3T4 antigens) in the spleens of adult tumor bearing mice shortly after the low dose chemotherapy since (a) greater than or equal to 80% of the lymphocytes within the thymus coexpress both markers, and (b) the low dose L-PAM therapy renders thymocytes from MOPC-315 tumor bearing mice (but not from normal mice) capable of bringing about the generation of enhanced antitumor cytotoxicity when added to the immunization culture of normal spleen cells and the """"""""autochthanous"""""""" tumor. In addition, we will elucidate the effect of the low dose chemotherapy on the cellular composition of the tumor bearer thymus. As part of this study, we will determine the Lyt 2 and L3T4 phenotype of the immunologically """"""""active"""""""" cell in the thymus of L-PAM treated MOPC-315 tumor bearers as well as elucidate the mechanism by which the low dose L-PAM renders thymoctyes from MOPC-315 tumor bearers immunologically """"""""active"""""""". In addition, we will determine the mechanism by which these """"""""active"""""""" thymocytes bring about the generation of enhanced lytic activity. Emphasis will be placed on extending our observations to other tumor models. For these purpose, we will employ selected plasmacytomas that differ in their immunogenicity. Thus, the results obtained from these experiments will also provide information as to the correlation between tumor cell immunogenicity and the subsequent ability of low dose L-PAM therapy to induce the appearance of """"""""active"""""""" cells in the thymus of tumor bearing mice. Finally, we will determine the importance of the thymus to the curative effectiveness of low dose L-PAM therapy for MOPC-315 or MOPC-104E tumor bearers since the therapeutic effectiveness of this therapeutic protocol depends, in the MOPC-315 and MOPC- 104E tumor systems, on the ability of T-cell-dependent antitumor immunity to eradicate a large tumor load.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA035761-05
Application #
3173341
Study Section
Experimental Therapeutics Subcommittee 2 (ET)
Project Start
1984-06-01
Project End
1991-05-31
Budget Start
1988-06-01
Budget End
1989-05-31
Support Year
5
Fiscal Year
1988
Total Cost
Indirect Cost
Name
University of Illinois at Chicago
Department
Type
Overall Medical
DUNS #
121911077
City
Chicago
State
IL
Country
United States
Zip Code
60612
Ben-Efraim, S (1999) One hundred years of cancer immunotherapy: a critical appraisal. Tumour Biol 20:1-24
Ben-Efraim, S (1996) Cancer immunotherapy: hopes and pitfalls: a review. Anticancer Res 16:3235-40
Rubin, M; Mokyr, M B (1993) Characterization of the exogenous interleukin-2 requirements for the generation of enhanced antitumor cytotoxicity by thymocytes from low-dose melphalan-treated MOPC-315 tumor bearers. Cancer Immunol Immunother 36:37-44
Bartik, M M; Baumgartel-Scofield, B A; Mokyr, M B (1991) Enhanced expansion of the thymic CD8+ cell subset as a potential mechanism for the generation of enhanced antitumor cytotoxicity by thymocytes from low-dose melphalan-treated MOPC-315 tumor bearers. Cancer Immunol Immunother 34:79-89
Bartik, M M; Ahn, M C; Baumgartel, B A et al. (1990) Presence of an enlarged pool of MOPC-315-specific cytotoxic T lymphocyte precursors in the thymuses of mice that eradicated a large MOPC-315 tumor as a consequence of low-dose melphalan therapy. Cancer Immunol Immunother 32:143-53
Mokyr, M B; Barker, E; Weiskirch, L M et al. (1989) Importance of Lyt 2+ T-cells in the curative effectiveness of a low dose of melphalan for mice bearing a large MOPC-315 tumor. Cancer Res 49:4597-606
Barker, E; Wise, J A; Dray, S et al. (1989) Lysis of antigenically unrelated tumor cells mediated by Lyt 2+ splenic T-cells from melphalan-cured MOPC-315 tumor bearers. Cancer Res 49:5007-15
Wise, J A; Mokyr, M B; Dray, S (1989) Enhancement of the effectiveness of Lyt-2+ T-cells for adoptive chemoimmunotherapy by short-term exposure of tumor-bearer spleen cells to polyethylene glycol and/or melphalan. Cancer Res 49:3613-9
Mokyr, M B; Bartik, M M; Ahn, M C (1989) Interleukin 2 requirement for the in vitro generation of antitumor cytotoxicity by thymocytes from melphalan-cured MOPC-315 tumor bearers. Cancer Res 49:870-6
Dray, S; Mokyr, M B (1989) Cyclophosphamide and melphalan as immunopotentiating agents in cancer therapy. Med Oncol Tumor Pharmacother 6:77-85

Showing the most recent 10 out of 19 publications