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A Belldegrun

Publications and source records attributed to A Belldegrun.

At least 19 recordsLinked to original sources
PubMed1999

Evidence for clonal outgrowth of androgen-independent prostate cancer cells from androgen-dependent tumors through a two-step process.

Prostate cancers require androgen for growth but progress to an androgen-independent stage under the selective pressure of androgen ablation therapy. Here we describe a novel human prostate cancer xenograft (LAPC-9) propagated by serial passage in male severe combined immunodeficient mice that expresses prostate-specific antigen and wild-type androgen receptor. In response to castration, LAPC-9 cells undergo growth arrest and persist in a dormant, androgen-responsive state for at least 6 months. After prolonged periods of androgen deprivation, spontaneous androgen-independent outgrowths develop. Thus, prostate cancers progress to androgen independence through two distinct stages, initially escaping dependence on androgen for survival and, subsequently, for growth. Through the use of serial dilution and fluctuation analysis, we provide evidence that the latter stage of androgen independence results from clonal expansion of androgen-independent cells that are present at a frequency of about 1 per 10(5)-10(6) androgen-dependent cells. We conclude that prostate cancers contain heterogeneous mixtures of cells that vary in their dependence on androgen for growth and survival and that treatment with antiandrogen therapy provides selective pressure and alters the relative frequency of these cells, thereby leading to outgrowths of androgen-independent cancers.

Androgens↗
PubMed1999

Sensitization of immunoresistant prostate carcinoma cell lines to Fas/Fas ligand-mediated killing by cytotoxic lymphocytes: independence of de novo protein synthesis.

BACKGROUND: We recently reported that drug-resistant prostate tumor cells (DU145, PC-3) are resistant to Fas-mediated killing by cytotoxic lymphocytes, and that this resistance can be overcome by treatment with subtoxic concentrations of chemotherapeutic drugs. Fas belongs to the tumor necrosis factor (TNF) family of receptors. Since resistance to TNF-alpha-mediated killing has been shown to be due, in part, to the presence of protective factors and that inhibitors of protein synthesis can sensitize cells to TNF-alpha killing, we hypothesized that resistance to Fas-mediated killing may be due to similar mechanisms. Since sensitization is achieved with chemotherapeutic drugs, and some chemotherapeutic drugs can also inhibit protein synthesis, we tested whether sensitization of prostate tumor cells to Fas ligand (Fas-L) occurred through inhibition of protein synthesis in a manner analogous to that of TNF-alpha. METHODS: The effect of chemotherapeutic drugs on protein synthesis in DU145 and PC-3 cells was characterized by (3)H-leucine incorporation assays. We also determined the ability of inhibitors of protein synthesis and chemotherapeutic drugs to sensitize Fas and TNF-resistant DU145 cells to killing. The ability of RNA (actinomycin-D, Act-D) and protein synthesis inhibitors (cyclohexamide (CHX), emetine) to block drug-mediated sensitization to Fas-L killing was analyzed. Sensitivity to Fas-L killing was determined by the (51)Cr-release assay using human lymphokine-activated killer cells (LAK) and tumor-infiltrating lymphocyte (TIL) effector cells and the murine Fas-L-expressing PMMI cells. RESULTS: The drugs cis-diamminedichloroplatinum (II) (CDDP), adriamycin (ADR), and etoposide (VP-16) sensitized DU145 and PC-3 cells to Fas killing. CDDP and ADR, which sensitized DU145 and PC-3 cells to Fas-L- and TNF-mediated killing, inhibited de novo protein synthesis in both cell lines, while VP-16 only inhibited protein synthesis in DU145 cells. Further, neither CHX nor emetine sensitized DU145 or PC-3 cells to Fas-L-mediated killing, despite blocking >90% de novo protein synthesis. In contrast, CDDP, VP-16, and the protein synthesis inhibitors, Act-D and CHX sensitized DU145 cells to TNF-alpha killing. Finally, pretreating cells with protein synthesis inhibitors (CHX, emetine) did not abrogate drug-mediated sensitization to Fas-mediated killing. CONCLUSIONS: These findings demonstrate that downregulation of protective factors by protein synthesis inhibition may not be the primary mechanism of drug-mediated sensitization to Fas-L killing in prostate cell lines. These findings also suggest that drug-mediated sensitization to Fas-L killing may be due to modifications of preexisting gene products that participate in Fas-L-mediated apoptosis.

Animals↗
PubMed1999

Metastatic renal cell carcinoma with concurrent inferior vena caval invasion: long-term survival after combination therapy with radical nephrectomy, vena caval thrombectomy and postoperative immunotherapy.

PURPOSE: We report our experience using aggressive multimodal therapy in a high risk group of patients with metastatic renal cell carcinoma and concurrent inferior vena caval extension. MATERIALS AND METHODS: We retrospectively reviewed the records of all patients in our kidney cancer database who had metastatic renal cell carcinoma and tumor thrombus extension into the inferior vena cava at the initial diagnosis. Patients were included in the study if they underwent radical nephrectomy and inferior venal caval thombectomy, and immunotherapy was planned for the postoperative period. Tumor size and grade, metastatic sites, level of vena caval extension, surgical complications and overall survival were obtained from the medical records. The primary end point analyzed was overall survival. RESULTS: We identified 31 cases of metastatic renal cell cancer with extensive disease and vena caval extension. Of the patients 23% had an isolated lung metastasis, and 53% had metastasis in the lung and at other sites. The remaining patients had involvement primarily at nonpulmonary metastatic sites, including lymph node in 38%, soft tissue in 13%, liver in 29% and bone in 10%. Average blood loss during nephrectomy was 3,200 cc (median 2,100) and the rate of major complications was 12%. Of the patients 80% underwent the full course of surgery and postoperative immunotherapy. At a mean followup of 18 months (34 for survivors) 26% of the patients are alive. Actuarial overall 5-year survival of the group was 17%. Tumor thrombus level did not correlate with overall survival, while immunotherapy, tumor grade and metastatic site provided significant prognostic information. In patients with an isolated pulmonary metastasis the 5-year survival rate was 43%, while in those with low grade tumors it was 52%. CONCLUSIONS: In contrast to the poor results of surgery only in patients with renal cell carcinoma and concurrent inferior venal caval invasion, reasonable 5-year survival may be achieved after combined aggressive surgery and immunotherapy. Patients in whom metastasis was limited to the lungs and those with grade 1 to 2 tumors had a better prognosis. With careful planning and experienced immunotherapists therapy may be completed in the majority of this high risk group of patients.

Adult↗
PubMed1999

Sarcomatoid renal cell carcinoma: biologic behavior, prognosis, and response to combined surgical resection and immunotherapy.

PURPOSE: Sarcomatoid variants of renal cell carcinoma (RCC) are aggressive tumors that respond poorly to immunotherapy. We report the outcomes of 31 patients with sarcomatoid RCC treated with a combination of surgical resection and immunotherapy. PATIENTS AND METHODS: Patients were identified from the database of the University of California Los Angeles Kidney Cancer Program. We retrospectively reviewed the cases of 31 consecutive patients in whom sarcomatoid RCC was diagnosed between 1990 and 1997. Clinical stage, sites of metastasis, pathologic stage, and type of immunotherapy were abstracted from the medical records. The primary end point analyzed was overall survival, and a multivariate analysis was performed to distinguish any factors conferring an improved survivorship. RESULTS: Twenty-six percent of patients were male and 74% were female, and the median age was 59 years (range, 34 to 73 years). Length of follow-up ranged from 2 to 77 months (mean, 21.4 months). Twenty-eight patients (84%) had known metastases at the time of radical nephrectomy (67% had lung metastases and 40% had bone, 21% had liver, 33% had lymphatic, and 15% had brain metastases). Twenty-five patients (81%) received immunotherapy, including low-dose interleukin (IL)-2-based therapy (five patients), tumor-infiltrating lymphocyte-based therapy plus IL-2 (nine patients), high-dose IL-2-based therapy (nine patients), dendritic cell vaccine-based therapy (one patient), and interferon alpha-based therapy alone (one patient). Two patients (6%) achieved complete responses (median duration, 46+ months) and five patients (15%) achieved partial responses (median duration, 36 months). One- and 2-year overall survival rates were 48% and 37%, respectively. Using a multivariate analysis, age, sex, and percentage of sarcomatoid tumor (< or >50%) did not significantly correlate with survival. Improved survival was found in patients receiving high-dose IL-2 therapy compared with patients treated with surgery alone or any other form of immunotherapy (P = .025). Adjusting for age, sex, and percentage of sarcomatoid tumor, the relative risk of death was 10.4 times higher in patients not receiving high-dose IL-2 therapy. Final pathologic T stage did not correlate significantly with outcome, but node-positive patients had a higher death rate per year of follow-up than did the rest of the population (1.26 v 0.76, Cox regression analysis). CONCLUSION: Surgical resection and high-dose IL-2-based immunotherapy may play a role in the treatment of sarcomatoid RCCs in select patients.

Adult↗
PubMed1999

Presentation of renal tumor antigens by human dendritic cells activates tumor-infiltrating lymphocytes against autologous tumor: implications for live kidney cancer vaccines.

The clinical impact of dendritic cells (DCs) in the treatment of human cancer depends on their unique role as the most potent antigen-presenting cells that are capable of priming an antitumor T-cell response. Here, we demonstrate that functional DCs can be generated from peripheral blood of patients with metastatic renal cell carcinoma (RCC) by culture of monocytes/macrophages (CD14+) in autologous serum containing medium (RPMI) in the presence of granulocyte macrophage colony-stimulating factor and interleukin (IL) 4. For testing the capability of RCC-antigen uptake and processing, we loaded these DCs with autologous tumor lysate (TuLy) using liposomes, after which cytometric analysis of the DCs revealed a markedly increased expression of HLA class I antigen and a persistent high expression of class II. The immunogenicity of DC-TuLy was further tested in cultures of renal tumor infiltrating lymphocytes (TILs) cultured in low-dose IL-2 (20 Biologic Response Modifier Program units/ml). A synergistic effect of DC-TuLy and IL-2 in stimulating a T cell-dependent immune response was demonstrated by: (a) the increase of growth expansion of TILs (9.4-14.3-fold; day 21); (b) the up-regulation of the CD3+ CD56- TcR+ (both CD4+ and CD8+) cell population; (c) the augmentation of T cell-restricted autologous tumor lysis; and (d) the enhancement of IFN-gamma, tumor necrosis factor-alpha, granulocyte macrophage colony-stimulating factor, and IL-6 mRNA expression by TILs. Taken together, these data implicate that DC-TuLy can activate immunosuppressed TIL via an induction of enhanced antitumor CTL responses associated with production of Thl cells. This indicates a potential role of DC-TuLy vaccines for induction of active immunity in patients with advanced RCC.

Antigen Presentation↗
PubMed1999

Comparison of helical computerized tomography, positron emission tomography and monoclonal antibody scans for evaluation of lymph node metastases in patients with prostate specific antigen relapse after treatment for localized prostate cancer.

PURPOSE: We compare the detection of metastatic disease by helical computerized tomography (CT), positron emission tomography (PET) with F-18 fluorodeoxyglucose and monoclonal antibody scan with 111indium capromab pendetide in patients with an elevated prostate specific antigen (PSA) after treatment for localized prostate cancer. MATERIALS AND METHODS: A total of 45 patients with an elevated PSA (median 3.8 ng./ml.) were studied following definitive local therapy with radical prostatectomy in 33, radiation therapy in 9 and cryosurgery in 3. CT of the abdomen and pelvis, and whole body PET were performed in all patients, of whom 21 also underwent monoclonal antibody scan. Lymph nodes 1 cm. in diameter or greater on CT were considered abnormal and were sampled by fine needle aspiration in 12 patients. RESULTS: PET and CT were positive for distant disease in 50% of 22 patients with PSA greater than 4, and in 4 and 17%, respectively, of 23 with PSA less than 4 ng./ml. The detection rate for metastatic disease was similar for CT and PET, and higher overall than that for monoclonal antibody scan. Monoclonal antibody scan was true positive in only 1 of 6 patients, while PET was true positive in 6 of 9 with CT guided fine needle aspiration proved metastases. CONCLUSIONS: CT and PET each detected evidence of metastatic disease in 50% of all patients with a high PSA or PSA velocity (greater than 4 ng./ml. or greater than 0.2 ng./ml. per month, respectively). Both techniques are limited for detecting metastatic disease in patients with a low PSA or PSA velocity. Our data suggest that monoclonal antibody scan has a lower detection rate than CT or PET.

Aged↗
PubMed1998

The University of California, Los Angeles/Jennifer Jones Simon Foundation symposium on prostate cancer and epithelial cell biology: bringing together basic scientists and clinicians in the fight against advanced prostate cancer.

Prostate cancer is the most common solid tumor in American men and is the second most common cause of cancer deaths. Although surgery and radiation therapy are effective for the treatment of organ-confined cancer, there is no effective treatment that is currently available for patients who have metastatic disease. Antiandrogen therapy is only palliative, and chemotherapy has largely been ineffective. However, recent advances in the understanding of the molecular biology of prostate cancer have lead to the development of new treatment strategies for metastatic cancer, including gene-based therapies, immunotherapies, and antiangiogenesis-based therapy. In association with the Jonsson Comprehensive Cancer Center and the University of California, Los Angeles Department of Urology, the Jennifer Jones Simon Foundation assembled 30 of the world's experts in prostate cancer research to review the most recent advances in the study of prostate cancer, with the hope that the resulting discussions would facilitate the rapid translation of new discoveries from the laboratory bench to the clinic.

Antineoplastic Agents↗
PubMed1998

Highly efficient and consistent gene transfer into dendritic cells utilizing a combination of ultraviolet-irradiated adenovirus and poly(L-lysine) conjugates.

Dendritic cells (DCs) are capable of presenting tumor-associated antigens and subsequently play an essential role in T-cell activation. The aim of this study was to develop an efficient method for gene transfer into DCs. These genetically transduced DCs can then be used as potent inducers of specific cell-mediated immune response. When compared with physical methods for gene transfer (lipofection and calcium phosphate precipitation), adenovirus (AdV) vectors proved to be highly efficient for gene transfer into DCs. To overcome concomitant AdV gene expression and potential immunogenicity, AdVs were irradiated with UV. The UV dose was optimized to block AdV transcription without altering AdV receptor binding and endocytosis capacity. We subsequently used a polycationic amino acid compound, poly(L-lysine), to conjugate the irradiated AdVs to transgenes. The resulting complexes were found to mediate a highly efficient transfer of transgenes into DCs, without concomitant expression of AdV gene products. Low titers of irradiated AdVs were sufficient for a consistent gene transfer into DCs. This is the first study to demonstrate efficient, consistent, and practical gene transfer using an UV approach to irradiated AdV-poly(L-lysine) conjugates and should be useful for the development of DC-based tumor vaccine therapies.

Adenoviridae↗
PubMed1998

Positron emission tomography in urological oncology.

PURPOSE: We provide scientists and clinicians with an introduction to the basic principles and methods of positron emission tomography (PET) and summarize the recent research and clinical applications of PET in the urological field. Specifically, we introduce PET so that the reader can understand and objectively review current and future articles that involve this imaging technology. MATERIALS AND METHODS: The recent applications of PET in urology in the published literature were searched and reviewed. RESULTS: In prostate carcinoma preliminary studies using radiotracer 18-fluoro-2-deoxyglucose (FDG) demonstrated that PET cannot reliably differentiate between primary prostate cancer and benign prostatic hyperplasia, and that PET is not as sensitive as bone scintigraphy for the detection of osseous metastases. However, PET may have a role in the detection of lymph node metastases in patients with prostate specific antigen relapse after primary local therapy. In renal cell carcinoma recent studies have shown the ability of FDG PET to detect primary and metastatic lesions and to monitor response to therapy. In the staging of testicular cancer FDG PET has been used to differentiate viable carcinoma from benign teratomas and/or fibrotic or necrotic changes. CONCLUSIONS: Current developments in PET technology that accurately stage the extent of tumor before surgery as well as monitor effectiveness or ineffectiveness of new or current therapies may make PET a valuable tool in research and in the management of urological diseases.

Humans↗
PubMed1998

Oral bropirimine immunotherapy of bladder carcinoma in situ after prior intravesical bacille Calmette-Guérin.

OBJECTIVES: Bropirimine is an oral immunomodulator that has demonstrated anticancer activity in transitional cell carcinoma in situ (CIS) in both the bladder and upper urinary tract. Activity also has been documented in patients after prior therapy with bacille Calmette-Guérin (BCG). To more accurately estimate bropirimine's efficacy in BCG-resistant bladder CIS, a Phase II trial was performed. A separate analysis was performed in additional patients intolerant of BCG toxicity. METHODS: Patients received bropirimine 3.0 g/day by mouth for 3 consecutive days, weekly, for up to 1 year. Bladder biopsies and cytologic examination were performed quarterly. Complete response (CR) required negative biopsy and cytology results. RESULTS: Twenty-one of 86 patients entered were not evaluable. CR was seen in 21 (32%; 95th percentile confidence interval [CI], 21% to 44%) of 65 evaluable patients, including 14 (30%, CI 17% to 43%) of 47 BCG-resistant, and 7 (39%, CI 16% to 61%) of 18 BCG-intolerant patients. Overall, by intent-to-treat analysis, CR was thus seen in 21 (24%) of 86 subjects. Most BCG-resistant patients were failures to BCG without relapse, and had received 12 to 36 (median 12) BCG treatments; intolerant patients had received 4 to 11 treatments (median 6). Response duration ranged from 65 to 810 days, with median not yet reached (but greater than 12 months). Thirteen (15%) of 86 stopped bropirimine due to toxicity. Progression to invasive or metastatic disease during or immediately after therapy was documented in only 4 patients (6%), all nonresponders. CONCLUSIONS: Bropirimine may be an alternative to cystectomy for some patients with bladder CIS who have failed or have not tolerated BCG. Further evaluation to improve responses and durability is warranted.

Adjuvants, Immunologic↗
PubMed1998

Adenovirus-mediated interleukin-2 production by tumors induces growth of cytotoxic tumor-infiltrating lymphocytes against human renal cell carcinoma.

Combination therapy with interleukin-2 (IL-2) and tumor-infiltrating lymphocytes (TILs) demonstrates significant clinical activity in patients with metastatic renal cell carcinoma (RCC). To investigate whether local delivery of IL-2 via gene transfer is capable of improving the potency and efficacy of in vitro propagated TILs as compared with standard growth conditions [400 BRMP U (BU)/ml], a replication-deficient adenovirus expressing the human IL-2 gene under control of the cytomegalovirus (CMV) promoter (Ad-IL-2) has been constructed in our laboratory. RCC-TIL cultures were initiated by directly infecting RCC tumor suspension with Ad-IL-2 at a multiplicity of infection of 10:1. Subsequently the TIL cultures were restimulated with nonirradiated autologous RCC infected with Ad-IL-2 (RCC-Ad-IL-2) every 10 days (TIL/tumor = 50:1). Cell growth, phenotype, cytotoxicity, and cytokine messenger RNA (mRNA) expression were analyzed and compared with TIL growth stimulated with exogenous IL-2 (400 BU/ml). All five TILs tested responded to RCC-Ad-IL-2 activation, and a completed clearance of tumor cells was observed in cultures within 7-10 days. Lysis of nonirradiated RCC-Ad-IL-2 cells by TILs also was observed in cultures 3-5 days after restimulation. The IL-2 concentration in cell culture supernatants was maintained between 10 BU and 35 BU/ml (2 and 7 ng/ml), respectively. When compared with exogenous IL-2, RCC-Ad-IL-2 induced less growth expansion of TILs whereas a reduced CD56+ (23 +/- 14% vs. 44 +/- 13%; p < 0.05) but increased CD3+CD4+ cell population (32 +/- 11% vs. 15 +/- 6%; p < 0.05) with enhanced T cell-receptor use (59 +/- 10% vs. 42 +/- 7%; p < 0.005) was determined. An augmented human leukocyte antigen (HLA)-restricted and tumor-specific cytotoxicity was detected in RCC-Ad-IL-2-expanded TILs (day 35, 15.3 +/- 4.2 LU vs. 4.6 +/- 1.8 LU; p < 0.005). These properties were mediated by the CD8+ and CD4+ T-cell populations, as demonstrated by antibody-blocking assays. A unique cytokine profile also was detected in RCC-Ad-IL-2-induced TILs, which demonstrated an upregulation of both GM-CSF and IL-6 mRNA as compared with TILs expanded in the presence of exogenous IL-2. These data suggest that RCC-Ad-IL-2 is a potent immune stimulant that can be used in vitro as an immunogen to propagate cytotoxic RCC-TILs for adoptive immunotherapy or potentially in vivo by direct injection as a live tumor vaccine.

Adenoviridae↗
PubMed1997

Immunosensitization of prostate carcinoma cell lines for lymphocytes (CTL, TIL, LAK)-mediated apoptosis via the Fas-Fas-ligand pathway of cytotoxicity.

Several reports suggest that immunotherapy mediated by cytotoxic lymphocytes is beneficial in the destruction of drug-resistant tumor cells. Cytotoxic T lymphocytes kill target cells by two main mechanisms, namely by the perforin pathway and by the Fas-ligand (Fas-L) pathway. The role of the Fas-L pathway in tumor cell killing is not clear because many Fas(+)-expressing tumor cells are resistant to the Fas-L agonist cytotoxic anti-Fas antibody. The human prostate tumor cell lines (PC-3, DU145, and LnCAP) express Fas on the cell surface but are resistant to killing by anti-Fas antibody. This study examined the sensitivity of prostate tumor cells to Fas-L-mediated cytotoxicity and sensitization of the tumor cells by drugs to Fas-L-mediated killing. All three prostate tumor cell lines are resistant to Fas-L killing as determined by the use of the murine CTL hybridoma PMMI that kills only through the Fas-L pathway. However, the addition of subtoxic concentrations of CDDP or VP-16 significantly sensitized the PC-3 and DU145, but not LnCAP, tumor cells to Fas-L killing and apoptosis by PMMI. The sensitization of tumor cells by drugs was inhibited by neutralizing anti-Fas antibody. These findings demonstrate that immunoresistant Fas(+)-expressing DU145 and PC-3 prostate tumor cells can be sensitized by drugs to Fas-L killing. We then examined the role of Fas-L killing by TIL and LAK cells. All three prostate tumor cell lines were sensitive to killing by TIL and LAK and cell killing was primarily mediated through the Ca(2+)-dependent perforin pathway because it was blocked by the addition of EGTA/MgCl2. Sensitization by CDDP or VP-16 did not significantly augment killing of untreated tumor cells by TIL or LAK cells. However, in the presence of EGTA/MgCl2, the addition of CDDP or VP-16 significantly augmented killing of PC-3 and DU145, but not LnCAP, by TIL and LAK, and killing was blocked by neutralizing anti-Fas antibody. These findings demonstrate that both TIL and LAK exhibit a Fas-L-mediated killing pathway that is revealed once the perforin pathway is blocked by the Ca2+ chelator EGTA/MgCl2. Altogether, these findings show that drug-resistant, Fas(+)-expressing PC-3 and DU145 prostate tumor cells can be sensitized by CDDP and VP-16 to killing by Fas-L-bearing CTL, TIL, and LAK cells. Sensitization of tumor cells by drugs may augment the efficacy of immunotherapy in the eradication of tumor cells that are resistant to Fas-L-mediated killing.

Animals↗
PubMed1997

The in vitro effects of interleukin-12 upon tumor-infiltrating lymphocytes derived from renal cell carcinoma.

Clinical trials utilising interleukin (IL)-2 with tumor-infiltrating lymphocytes (TIL) have demonstrated efficacy in the treatment of metastatic renal cell carcinoma (RCC). Several cytokines, as well as growth factors have demonstrated modulatory effects upon the biological properties of TIL from RCC, suggesting a potentially important role for cytokines other than IL-2 in the development of active and tumor-specific TIL. IL-12 was recently characterized as a natural-killer-cell-stimulatory factor or cytotoxic-T-cell-maturation factor. These properties of IL-12 prompted us to investigate the impact of this cytokine upon the activation of TIL from human RCC. In an attempt to enhance the in vitro growth and activity of renal TIL, we have grown eight renal TIL cultures in varying concentrations of IL-2 (8, 40, 80, 400 U/ml) and IL-12 (200 U/ml). In addition, IL-12 (200 U/ml) was added to TIL cultures pre-activated with IL-2 (400 U/ml). Growth, cell expansion, and the ability of TIL to release certain cytokines upon tumor stimulation were determined. Proliferation assays, phenotypic analysis, and cytotoxicity assays were performed at an early and a late culture stage. IL-12, alone and when added to suboptimal concentrations of IL-2, failed to induce TIL growth. While the addition of IL-12 to optimal doses of IL-2 suppressed TIL culture expansion, sequential culture exposure first to IL-2 and then to IL-2+IL-12 increased the number of cells expressing CD3+/CD56+ and these cultures demonstrated enhanced in vitro lysis of autologous tumor. IL-12 clearly demonstrated a sequence-dependent impact of the biological behaviour of TIL from RCC. The optimal use of IL-12 in the in vitro expansion of renal TIL may result in cells with an enhanced specific anti-tumor effect.

CD3 Complex↗
PubMed1997

Progression of metastatic human prostate cancer to androgen independence in immunodeficient SCID mice.

Prostate cancer mortality results from metastasis to bone and hormone-independent tumor growth. Models to study these progressive changes are lacking. Here we describe the propagation of advanced human prostate cancer by direct transfer of surgical samples from patients into immune-deficient male SCID mice. Explants from six of eight patients formed prostate tumors and two showed unique cytogenetic, biologic and molecular features that were retained through six or more passages. One grew in an androgen-independent fashion, whereas the second formed tumors that regressed following castration then regrew. Micrometastatic disease was detected in the hematopoietic tissues of half of the recipient mice. Thus selected specimens of advanced human prostate cancer can be propagated in SCID mice in a manner that recapitulates the clinical transition from androgen-sensitive to androgen-independent growth, accompanied by micrometastasis.

Androgens↗
PubMed1997

Treatment of metastatic renal cell carcinoma with nephrectomy, interleukin-2 and cytokine-primed or CD8(+) selected tumor infiltrating lymphocytes from primary tumor.

PURPOSE: Metastatic renal cell carcinoma is a disease with a mean survival of 6 to 10 months. Interleukin-2 (IL-2), the only approved therapy for metastatic renal cell carcinoma, is associated with a 14% response rate and durable remissions in some patients with high performance status. We performed a series of trials of IL-2 plus tumor infiltrating lymphocyte cell therapy and report the clinical results from 62 patients enrolled in these trials. MATERIALS AND METHODS: Patients were eligible if they had metastatic renal cell carcinoma with the primary tumor in place and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were treated with cytokines before nephrectomy and preparation of cytokine primed tumor infiltrating lymphocytes or CD8(+) tumor infiltrating lymphocytes were isolated for infusion into patients. Of 62 patients enrolled 55 were treated with tumor infiltrating lymphocytes and IL-2, and were evaluable for toxicity, response and survival. RESULTS: There were no postoperative mortalities. Of the patients 7 (11%) could not undergo systemic therapy. No unexpected IL-2 related toxicities or significant toxicities related to cell infusion were noted. Overall 5 patients (9.1%) achieved a complete response and 14 (25.5%) achieved a partial response. The responses were durable with a median duration of 14 months (range 0.8+ to 64+). The actuarial survival was 65% at 1 year and 43% at 2 years from the time of nephrectomy, with an overall median survival for all patients of 22 months (range 2 to 70+). The median survival for the responding patients has not yet been reached (range 2 to 63+). CONCLUSIONS: These results demonstrate that immunotherapy with radical nephrectomy, tumor infiltrating lymphocytes, and IL-2 provides substantial clinical benefit in the majority of patients. Component cellular therapy with enriched cell fractions allows the administration of a more standardized cell product. The present results with nephrectomy, tumor infiltrating lymphocytes and IL-2 are encouraging, and a randomized clinical trial of nephrectomy, CD8(+) tumor infiltrating lymphocytes, plus IL-2 versus nephrectomy and IL-2 alone is currently in progress.

Adult↗
PubMed1997

Sensitization of renal carcinoma to radiation using alpha interferon (IFNA) gene transfection.

The rationale for this study was that local delivery of interferon-alpha (IFN-alpha) by gene transfection may be of value during radiotherapy. To investigate the feasibility of this approach, cells of the human renal carcinoma cell line R11 were transfected with the IFNA gene and evaluated for radiation responses in vitro by clonogenic assays. R11 cells expressing IFN-alpha after gene transfection were more sensitive to radiation than R11 control cells (SF2 = 0.33 and 0.51, respectively). In addition to increasing radiosensitivity, IFNA gene transfection slowed cellular growth and reduced the plating efficiency in clonogenic assays. The addition of exogenous rhIFN-alpha to cells at different times relative to irradiation showed that its presence during the postirradiation period was critical for radiosensitization, but repair of sublethal damage did not seem to be affected. No apoptosis of R11 cells was found 1-5 days after exposure to 2-25 Gy with or without IFN-alpha. Extensive formation of multinuclear giant cells was present beginning 2 days after irradiation; however, IFN-alpha did not cause any major alterations in the yield of radiation-induced giant cells. These studies suggest that gene transfection might be an effective means of delivering IFN-alpha for clinical use in radiotherapy of cancer.

Carcinoma, Renal Cell↗