IL-2 gene was introduced through retroviral vectors into the highly malignant and poorly immunogenic 3LL-D122 clone. Both high and low D122-IL-2 secretors showed elimination of tumorigenicity in syngeneic immune-competent mice; however, in nude mice only the high IL-2 secretor showed reduced tumorigenicity as compared with parental D122 cells. Also, following intravenous inoculation, only the high IL-2 secretor showed reduced generation of metastases, whereas the low IL-2 secretors were as highly metastatic as parental cells. These results seem to indicate that low levels of IL-2 secreted by tumor cells are sufficient to activate T cells, while higher levels are needed in order to activate non-T-cell effectors. D122-IL-2 secretors induced high levels of anti-tumor CTL, while their sensitivity to the lytic activity of these CTL was similar to the sensitivity of D122 cells, thus indicating that the elevation of immunogenicity of IL-2 secretors was essentially due to the secreted IL-2. In accordance with CTL induction, pre-immunization with IL-2 secretors protected mice against subsequent challenge of parental cells. Moreover, immunization in an "immunotherapy protocol" i.e., vaccination of mice carrying an established tumor of parental D122 cells with inactivated D122-IL2 infectants, almost completely eliminated the generation of lung metastases by D122 cells, thus providing a rationale for the use of IL-2 gene transferred tumor cells as a modality for treatment of metastasis.
Purpose: Cryotherapy of localized prostate, renal, and hepatic primary tumors and metastases is considered a minimally invasive treatment demonstrating a low complication rate in comparison with conventional surgery. The main drawback of cryotherapy is that it has no systemic effect on distant metastases. We investigated whether intratumoral injections of dendritic cells following cryotherapy of local tumors (cryoimmunotherapy) provides an improved approach to cancer treatment, combining local tumor destruction and systemic anticancer immunity. Experimental Designs: The 3LL murine Lewis lung carcinoma clone D122 and the ovalbumintransfected B16 melanoma clone MO5 served as models for spontaneous metastasis. The antimetastatic effect of cryoimmunotherapy was assessed in the lung carcinoma model by monitoring mouse survival, lung weight, and induction of tumor-specific CTLs. The mechanism of cryoimmunotherapy was elucidated in the melanoma model using adoptive transfer of T cell receptor transgenic OT-I CTLs into the tumor-bearing mice, and analysis of Th1/Th2 responses by intracellular cytokine staining in CD4 and CD8 cells. Results: Cryoimmunotherapy caused robust and tumor-specific CTL responses, increased Th1 responses, significantly prolonged survival and dramatically reduced lung metastasis. Although intratumor administration of dendritic cells alone increased the proliferation rate of CD8 cells, only cryoimmunotherapy resulted in the generation of effector memory cells. Furthermore, cryoimmunotherapy protected mice that had survived primary MO5 tumors from rechallenge with parental tumors. Conclusions: These results present cryoimmunotherapy as a novel approach for systemic treatment of cancer. We envisage that cryotherapy of tumors combined with subsequent in situ immunotherapy by autologous unmodified immature dendritic cells can be applied in practice.Minimally invasive therapies are an alternative approach to surgical intervention in the treatment of malignant diseases. Cryoablation, i.e., tissue destruction by repeated deep freezing and thawing, is under the larger category of thermal therapy and, during the past decade, it has become an acceptable clinical tool for the management of dermatologic tumors, hepatocellular carcinoma, renal and prostate tumors, and hepatic colorectal metastases (1, 2). Compared with surgical excision, the main advantages are the potential for less invasiveness resulting in reduced mortality and morbidity, and the ability to perform ablative procedures on outpatients, which decreases the treatment cost. In the case of hepatic colorectal metastases, the use of cryosurgery improves the percentages of resectability (2). A comparative study on domestic pigs showed that the cryoablation of renal parenchyma is beneficial over other necrosis-inducing ablations such as microwave thermoablation, radiofrequency energy, and chemoablation by ethanol, hypertonic saline, and acetic acid gels, in terms of reproducibility, consistency in size and shape, and the ability to monitor b...
Specific immunotherapy of prostate cancer may be an alternative or be complementary to other approaches for treatment of recurrent or metastasized disease. This study aims at identifying and characterizing prostate cancerassociated peptides capable of eliciting specific CTL responses in vivo. Evaluation of peptide-induced CTL activity in vitro was done following immunization of HLA-A2 transgenic (HHD) mice. An in vivo tumor rejection was tested by adoptive transfer of HHD immune lymphocytes to nude mice bearing human tumors. To confirm the existence of peptide-specific CTL precursors in human, lymphocytes from healthy and prostate cancer individuals were stimulated in vitro in the presence of these peptides and CTL activities were assayed. Two novel immunogenic peptides derived from overexpressed prostate antigens, prostatic acid phosphatase (PAP) and sixtransmembrane epithelial antigen of prostate (STEAP), were identified; these peptides were designated PAP-3 and STEAP-3. Peptide-specific CTLs lysed HLA-A2.1 + LNCaP cells and inhibited tumor growth on adoptive immunotherapy. Furthermore, peptide-primed human lymphocytes derived from healthy and prostate cancer individuals lysed peptide-pulsed T2 cells and HLA-A2.1 + LNCaP cells. Based on the results presented herein, PAP-3 and STEAP-3 are naturally processed CTL epitopes possessing anti-prostate cancer reactivity in vivo and therefore may constitute vaccine candidates to be investigated in clinical trials. (Cancer Res 2005; 65(14): 6435-42)
A stromal protein, designated restrictin-P, that specifically kills plasma-like cells was purified to homogeneity and shown to be identical with activin A. The specificity to plasma-like cells stemmed from the ability of restrictin-P/activin A to competitively antagonize the proliferation-inducing effects of interleukin (IL) 6 and IL-11. Restrictin-P further interfered with the IL-6-induced secretion of acute phase proteins by HepG2 human hepatoma cells and with the IL-6-mediated differentiation of M1 myeloblasts. A competition binding assay indicated that restrictin-P did not interfere with the binding of IL-6 to its receptor on plasma-like cells, suggesting that it may act by intervening in the signal transduction pathway of the growth factor. Indeed, concomitant addition of restrictin-P and IL-6 to cytokinedeprived B9 hybridoma cells was followed by sustained overexpression of junB gene until cell death occurred, while IL-6 alone caused a transient increase only. This altered response to IL-6 stimulation was accompanied by a moderate increase in STAT protein activation. Thus, in this study, we identified the plasmacytoma growth inhibitor, restrictin-P, as being activin A of stromal origin. It is shown that activin A is an antagonist of IL-6-induced functions and that it modifies the IL-6 signaling pattern.
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