Thymic anti-tumor effectors in mice cured of lymphoma by cyclophosphamide plus TNF-α therapy: Phenotypic and functional characterization up to 20 months after initial tumor inoculation

Antibody treatment of human tumor xenografts elicits active anti-tumor immunity in nude mice

“…Studies by others have shown that if immunocompetent (C57BL/6) mice transplanted with syngeneic EL4 lymphoma cells are cured of their tumor by a chemotherapy-cytokine combination -they develop life-long immunity and reject re-implanted EL4 lymphomas [15][16][17][18]. The chemotherapy-cytokine treatments included cyclophosphamide plus TNF-α [15,16] [18] and doxorubicin plus IL-2 [17].…”

“…Treatment with doxorubicin plus TNF-α, which results in prolonged survival but no cure, also gave rise to T cell-mediated immunity [19,20], including rejection of implants of doxorubicin-resistant EL4 cells [19]. This immunity was correlated with the presence of anti-EL4 CD8 + CD44 + CTLs [16][17][18]20], but no adoptive transfer experiments were reported. Interestingly, it was noted that in C57BL/6 mice that received a curative cyclophosphamide plus TNF-α combination, there was initially thymic involution followed by regrowth [15,18].…”

“…This immunity was correlated with the presence of anti-EL4 CD8 + CD44 + CTLs [16][17][18]20], but no adoptive transfer experiments were reported. Interestingly, it was noted that in C57BL/6 mice that received a curative cyclophosphamide plus TNF-α combination, there was initially thymic involution followed by regrowth [15,18]. This phenomenon may mirror the situation in nude mice where "space" for expansion of anti-tumor T cell clones is available due the paucity of T cells.…”

Protective specific immunity induced by doxorubicin plus TNF-α combination treatment of EL4 lymphoma-bearing C57BL/6 mice

“…It is anticipated, if such combinations are to be successful clinically, that a much better understanding of the host parameters that play critical roles in the overall efficacy of the therapies must be gained. Toward this end, our laboratory has been studying the widely used anti-cancer agents doxorubicin (DOX, also known as Adriamycin) and cyclophosphamide in combination with certain cytokines, e.g., IL-2 and TNF-␣, in a syngeneic mouse tumor model system, i.e., C57BL/6 mice bearing EL4 lymphoma implanted s.c. (Ehrke et al, , 1996(Ehrke et al, , 1998aKrawczyk et al, 1995;Ho et al, 1993a,b). In this model, all mice implanted with as few as 10 EL4 cells die of progressive disease, lymphoid cells from naive (i.e., without tumor) C57BL/6 mice do not respond to stimulation with EL4 cells in culture, and at no time is anti-tumorspecific cytolytic effector activity detectable in fresh cell preparations of lymphoid organs from untreated tumor-bearing animals.…”

“…Utilizing this model, effective treatment protocols have been defined which combined a single immunomodulating dose of cyclophosphamide with multiple injections of TNF-␣ (Ehrke et al, , 1998aKrawczyk et al, 1995) as well as ones which combined 2 injections of an immunomodulating dose of DOX with multiple injections of either IL-2 (Ho et al, 1993a,b) or TNF-␣ (Ehrke et al, 1998b). Because DOX plus IL-2 combination protocols, which were effective against sublines of EL4 that had been selected based on resistance to DOX, utilized a single injection of DOX 8 days after tumor implantation combined with multiple injections of low doses of IL-2 (Ho et al, 1993a;Ehrke et al, 1996), we decided to determine if effective DOX plus TNF-␣ protocols could be defined which involved (i) a single injection of DOX, (ii) doses of TNF-␣ lower than those used in the previous studies, and (iii) establishment of long-term immunity.…”