Studies on chemically induced rat tumors. II. Partial protection against syngeneic lethal tumors by cloned syngeneic cytotoxic T lymphocytes

Abstract

In the present article we describe studies on a chemically induced sarcoma in DA rats. This tumor expresses a unique antigen which can be demonstrated by both syngeneic antibodies and cytotoxic T cells. We have established cytotoxic T-cell lines (CTLs) specific for the tumor and with high efficient killing capacity in vitro. When testing for the ability of such CTLs to inhibit tumor out-growth in vivo, we found that they had to be inoculated together with the tumor and in the presence of T-cell growth factor to provide any significant degree of protection. We thus believe not only that there is a requirement for addition of CTL-stimulating lymphokines in vivo, but also that the CTLs fail to move from one site in vivo to attack relevant tumor cells at another site. No evidence was obtained that the CTLs gradually could acquire such migratory ability in vivo.

Antigen-driven long term-cultured T cells proliferate in vivo, distribute widely, mediate specific tumor therapy, and persist long-term as functional memory T cells.

“…The demonstration that antigen-driven donor T cells could distribute widely and could be found in larger numbers in host ascites, spleen, and local-regional lymph nodes as well as in distant lymph nodes was surprising, since previous studies (30)(31)(32)(33)(34) have shown that cultured T cells traffic abnormally in vivo, localize poorly, and are unable to migrate into peripheral lymph nodes. The inability of cultured T cells to traffic and to home in other studies is presumably multifactorial, but included the major problem of being unable to proliferate in vivo (7,14,32,35), a problem seemingly circumvented by use of the culture systems described herein.…”

“…One major question concerning the use of cultured T cells in vivo to augment specific T cell immunity was whether such T cells could survive and function long term in vivo (7,14,35). Culture conditions for generating antigen-driven T cells, as described previously (13,19,20), allow for the generation in vitro of immune T cells that can rest in vitro on syngeneic filler cells (38), and therefore may represent an in vitro functional equivalent of memory T cells.…”

Studies of the invasiveness of the chemically induced mouse sarcoma FS9. I. monoclonal antibodies to a 37,000 dalton membrane glycoprotein inhibit invasion of fibroblasts in vitro

“…Quantitative estimations revealed that FS9 tumor cells bind 15 to 25 times more of the MAb than do L929 tumor cells. However, this protein in not present on normal embryonic H-2k mouse fibroblasts, DMBA-induced DA rat sarcoma P1 (Binz et al, 1983), spontaneous L.BN rat sarcoma PM (24) or El-4 mouse lymphoma cells. In addition, we found that the MAb directed against the 37 ,OOO dalton protein are cytotoxic for FS9 sarcoma cells but not for L929 tumor cells in the complement-dependent cytotoxicity assay.…”

Augmentation of the therapeutic efficacy of adoptive tumor immunotherapy by in vivo administration of slowly released recombinant interleukin 2

“…In murine therapeutic models, several reports have described that helper marker (mouse; Lyl, rat; W325) positive T cells were required for ACIT [17,18,23], whereas others have reported that Ly1-2 ÷ T cells were responsible for the tumor regression [2,11,31,39]. The first purpose of our work was to establish the systemic therapeutic model in order to clarify the subpopulation of T cells responsible for in vivo antitumor activity.…”