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

Abstract

Immunization of C57BL/6 mice with MMC-treated syngeneic lymphoma cells, MBL-2, caused the generation of antitumor effector cells in vivo and the immunized mice permanently rejected viable MBL-2 lymphoma cells. Both plastic nonadherent T cells and plastic adherent M phi obtained from MBL-2 immunized mouse peritoneal exudate cells revealed strong cytotoxic activity against MBL-2 lymphoma cells, whereas immune spleen cells were not highly active against MBL-2 lymphoma cells in vitro. However, systemic adoptive transfer of immune spleen cells into the MBL-2-bearing mice by i.v. infusion in conjunction with i.p. cyclophosphamide (100 mg/kg) treatment cured the mice of tumor. This therapeutic efficacy of immune spleen cells was reflected by the number of transferred effector cells and over 5 X 10(7) immune spleen cells were required to cure the mice completely. The cells mediating in vivo rejection of MBL-2 lymphoma cells were Thy 1.2+ T cells. This ACIT was specific against MBL-2 lymphoma cells and had no effect on the growth of other syngeneic tumors, B16 melanoma or BMC6A fibrosarcoma. In vivo administration of recombinant interleukin 2 (r-IL2) combined with ACIT greatly modulated the cure rate of tumor-bearing mice. In addition, we found that slowly released r-IL 2 administratered from an ALZET miniosmotic pump was more effective in augmenting the therapeutic efficacy of immune spleen cells in ACIT than a single injection of the same total dose of r-IL 2.

Augmented induction of antitumor cells in vivo by cyclophosphamide fails to benefit antitumor resistance of the host

“…Cytotoxic activity associated with spleen cells from animals undergoing regression of an autochthonous or a syngeneic tumor as well as those immunized with syngeneic tumors is often not detectable, or very low if detected [4,6,8,9,14,15,20]. Nevertheless substantial cytotoxic activities are often developed at the site of the regressing tumor or of tumor immunization [4,8,14,20].…”

Critical role of the Th1/Tc1 circuit for the generation of tumor‐specific CTL during tumor eradication in vivo by Th1‐cell therapy

“…Thus, the Th1/Tc1 circuit appeared to be crucial for the induction of CTL with killing activity, which is beneficial for tumor eradication. We also demonstrated that cyclophosphamide (CY) treatment, which has been used for combined immunotherapy, 26) augmented the therapeutic effect of Th1-cell therapy, indicating that adoptive chemoimmunotherapy represents a new strategy for tumor cell therapy.…”

Mechanism of Enhanced Hematopoietic Response by Soluble β‐Glucan SCG in Cyclophosphamide‐Treated Mice

“…These cytokines play important roles in the rejection of tumors and protection against microbial infection. CY treatment, which has been used for combined immunotherapy (29), augments the therapeutic effect of Th1-cell therapy (4). SCG induced the splenocytes in CY-treated mice to produce IFN-γ and IL-12p70, on which Th1 polarization has been shown to depend.…”