Abstract:In this study we have analyzed the in vitro cell-mediated cytotoxicity of immune peritoneal exudate cells (PEC), elicited in syngeneic mice against the MCA-induced, TSTA-bearing BALB/c fibrosarcoma CA-2, GI-17 and C-3. The 4 h 51Cr-release assay showed the immune PEC effectors to be specifically cytotoxic to fibrosarcoma used for the immunization, but not to other syngeneic MCA-induced tumors or normal fibroblasts. Cold target inhibition experiments on CA-2 cells confirmed the specificity of the reaction. When… Show more
“…Tumor Rejection . BALB/c mice were challenged subcutaneously in the left inguinal region with 10' cells of the poorly immunogenic syngeneic tumor CE-2 (31) . Starting 4 h after tumor challenge, mice received in the peritumoral area 10 daily subcutaneous injections of 0 .4 ml HBSS alone, or containing IL-1p, the 163-171 peptide of IL-1(3, or the 166-174 peptide of hCS .…”
The synthetic nonapeptide VQGEESNDK, corresponding to the fragment 163-171 of human IL-1 beta, showed in vivo immunomodulatory capacities qualitatively and quantitatively comparable to those of the mature human IL-1 beta protein. In fact, both IL-1 beta and the 163-171 fragment stimulated the immune response of normal mice and restored immune reactivities of immunocompromised animals. In addition, the synthetic IL-1 peptide was as efficient as the entire protein in inducing tumor rejection and radioprotection. On the other hand, the 163-171 fragment did not cause any of several inflammation-associated metabolic changes inducible by the whole IL-1 beta molecule in vivo: hypoferremia, hypoglycemia, hyperinsulinemia, increase in circulating corticosterone, SAA and fibrinogen, decrease in hepatic drug-metabolizing enzymes. Furthermore, at variance with IL-1 beta, the 163-171 peptide did not show the toxic effects causing shock and death in adrenalectomized mice. Thus, these results confirm our previous in vitro observations that functional domains are identifiable within the multipotent cytokine IL-1 beta, and demonstrate the biological relevance of this finding in a variety of in vivo systems. The identification of a selectively active fragment of a cytokine may thus represent a significant step towards a better directed and more rational immunotherapeutic approach.
“…Tumor Rejection . BALB/c mice were challenged subcutaneously in the left inguinal region with 10' cells of the poorly immunogenic syngeneic tumor CE-2 (31) . Starting 4 h after tumor challenge, mice received in the peritumoral area 10 daily subcutaneous injections of 0 .4 ml HBSS alone, or containing IL-1p, the 163-171 peptide of IL-1(3, or the 166-174 peptide of hCS .…”
The synthetic nonapeptide VQGEESNDK, corresponding to the fragment 163-171 of human IL-1 beta, showed in vivo immunomodulatory capacities qualitatively and quantitatively comparable to those of the mature human IL-1 beta protein. In fact, both IL-1 beta and the 163-171 fragment stimulated the immune response of normal mice and restored immune reactivities of immunocompromised animals. In addition, the synthetic IL-1 peptide was as efficient as the entire protein in inducing tumor rejection and radioprotection. On the other hand, the 163-171 fragment did not cause any of several inflammation-associated metabolic changes inducible by the whole IL-1 beta molecule in vivo: hypoferremia, hypoglycemia, hyperinsulinemia, increase in circulating corticosterone, SAA and fibrinogen, decrease in hepatic drug-metabolizing enzymes. Furthermore, at variance with IL-1 beta, the 163-171 peptide did not show the toxic effects causing shock and death in adrenalectomized mice. Thus, these results confirm our previous in vitro observations that functional domains are identifiable within the multipotent cytokine IL-1 beta, and demonstrate the biological relevance of this finding in a variety of in vivo systems. The identification of a selectively active fragment of a cytokine may thus represent a significant step towards a better directed and more rational immunotherapeutic approach.
“…CE-2 is a methylcholanthrene-induced sarcoma of BALB/c mice raised by Dr. G. Parmiani (Carbone et al, 1983). Its earlier transplant generations were preserved by slow freezing and storage at -80°C.…”
Ten international units (IU) of recombinant (r) or natural (n) murine interferon (MuIFN)-gamma were used for the in vivo immunotherapy of a chemically induced fibrosarcoma (CE-2) of BALB/c mice. In vitro, doses of r-IFN-gamma below 100 units have a marginal antiproliferative effect on CE-2 cells and do not induce expression of H-2d class-II antigens, whereas they do increase that of class-I antigens. In vivo, 10 daily injections of 10 IU of r- or n-MuIFN-gamma at the challenge site provide significant protection against increasing doses of CE-2 tumor cells. This protection was enhanced when non-reactive T-lymphocytes from CE-2 tumor-bearing mice were admixed at a 10:1 ratio with the CE-2 tumor cells. Combined lymphocyte and r-MuIFN-gamma treatment also inhibited the growth of already established tumors when it was started before these reached a mean diameter of 5 mm. Tumor inhibition depends upon activation of the host immune system. The antitumor activity of r-MuIFN-gamma and T-lymphocytes was null when mice were first irradiated with 450 rads. Moreover, host leukocytes massively infiltrated the area of tumor growth and the small r-MuIFN-gamma doses injected daily activated various host immunoreactivity mechanisms.
“…against human or animal sarcoma targets did indeed demonstrate an ex vivo lysis of the tumor cells, although this did not translate into an in vivo TLS in either animals or humans treated with this therapy [34,35]. None of the other responding patients in the ACIT study employing ALT and CY developed a TLS .…”
Adoptively transferred immune cells in combination with chemotherapeutic agents form the basis for adoptive chemoimmunotherapy (ACIT) of neoplastic disease. Autolymphocytes (ALT-cells) are ex vivo activated peripheral blood lymphocytes (PBL) from tumor-bearing hosts (TBH) that consist primarily of tumor-specific CD45RO+ (memory) T-cells. These ALT-cells combined with cimetidine (CIM) as autolymphocyte therapy (ALT), have previously been demonstrated to be a safe and active form of outpatient adoptive immunotherapy (AIT) in human TBH with metastatic renal cell cancer (RCC). We have previously described an effective ACIT protocol using ALT and cyclophosphamide (CY) for patients with relapsed and refractory non-RCC solid tumors. We now report a case of a patient with a metastatic gastric leiomyosarcoma to the liver, who developed a clinical picture consistent with a tumor-lysis syndrome (TLS), following salvage therapy for his tumor with ACIT using ALT and CY. TLS is a well-known complication resulting from the treatment of rapidly proliferating hematopoietic tumors such as Burkitt's lymphoma and acute lymphocytic leukemia. TLS has also been rarely described in chronic lymphocytic leukemia, as well as certain solid tumors such as breast cancer, small cell lung cancer, and medulloblastoma. However, there have been no previous reports of TLS occurring either secondary to immunotherapy or in sarcomas. The nature of these unusual findings is discussed.
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