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E M Hersh

Publications and source records attributed to E M Hersh.

At least 19 recordsLinked to original sources
PubMed2001

Transduction of human dendritic cells with a recombinant modified vaccinia Ankara virus encoding MUC1 and IL-2.

The epithelial mucin MUC1 is considered an opportune target antigen for cancer immunotherapy, as it is over-expressed and exhibits aberrant glycosylation in malignant cells. Because dendritic cells (DC) are powerful initiators of immune responses, efforts have focused on tumor antigen-bearing DC as potent cancer vaccines. In this study we have characterized the transduction of monocyte-derived DC with a highly attenuated vaccinia virus vector [modified vaccinia Ankara (MVA)] encoding human MUC1 and the immunostimulatory cytokine IL-2. Analysis of transduced DC cultures generated from a number of donors revealed MUC1 expression in the range of 27-54% of the cells and a co-regulated secretion of bioactive IL-2. As shown by FACS analysis with MUCI-specific antibodies, the MVA-MUC1/IL-2-transduced DC predominantly expressed the fully processed glycoform of MUC1, typical of that displayed by normal epithelia. Over a 3-day period after transduction, transgene expression declined concurrent with an increase in MVA-induced cytopathic effects. The transduced DC stimulated allogeneic lymphocyte proliferation, indicating that DC immunostimulatory function is not impaired by vector transduction. In the presence of IL-2, MVA-transduced DC were able to enhance autologous lymphocyte proliferation. Also, vector expression was analyzed in DC cultures treated with TNF-alpha, a known DC maturation factor. As indicated by the up-regulation of several DC maturation markers, neither virus infection nor transgene expression influenced the maturation capacity of the cells. The MVA-MUC1/IL-2 vector effectively transduced both immature and TNF-alpha-matured DC. Overall, our results are encouraging for the clinical application of MVA-MUC1/IL-2-transduced DC.

Antigen Presentation↗
PubMed2001

A phase I and pharmacodynamic evaluation of polyethylene glycol-conjugated L-asparaginase in patients with advanced solid tumors.

PURPOSE: To evaluate the in vitro activity of polyethylene glycol-conjugated L-asparaginase (PEG-Lasparaginase) against fresh human tumor specimens, using the human tumor clonogenic assay (HTCA), and to perform a phase I dose-escalation clinical trial of PEG-L-asparaginase. The goal of the clinical study was to determine the toxicity and optimum biologic dose of PEG-L-asparaginase based on depletion of serum L-asparagine in patients with advanced solid tumors. METHODS: A modified method for determination of serum L-asparagine is described. PEG-L-asparaginase was administered by intramuscular injection every 2 weeks to 28 patients with various types of advanced solid tumor malignancies. At least 3 patients were evaluated at each dose level: 250 IU/m2, 500 IU/m2, 1,000 IU/m2, 1,500 IU/m2, 2,000 IU/m2. RESULTS: The in vitro HTCA studies suggested good antitumor activity against malignant melanoma and multiple myeloma. Serum L-asparagine was most consistently and profoundly depleted (up to 4 weeks) in patients treated with 2,000 IU/m2. Patients receiving this dose level also showed more frequent grade 1, grade 2, and occasional grade 3 toxicities of fatigue/weakness, nausea/vomiting, and anorexia/ weight loss. Three patients developed hypersensitivity reactions, but these were not dose related. Two patients developed deep vein thromboses. We saw no episodes of clinical pancreatitis, but there were minor fluctuations of serum amylase and lipase. We saw no partial or complete responses in patients treated in this study, including 11 patients with malignant melanoma. CONCLUSIONS: We conclude that PEG-L-asparaginase is generally well tolerated in patients with advanced solid tumors, and a dosage of 2,000 IU/m2 by intramuscular injection every 2 weeks results in significant depletion of serum L-asparagine.

Adult↗
PubMed2001

Preclinical antitumor activity of the azonafide series of anthracene-based DNA intercalators.

The azonafides are a series of anthracene-based DNA intercalators which inhibit tumor cell growth in vitro at low nanomolar concentrations and are not affected by the multidrug resistance phenomenon (MDR). Prior studies have described antitumor efficacy in murine tumor models including L-1210 and P-388 leukemias, and B-16 melanoma. The current results extend these cell line observations to human tumors tested in the NCI panel of 56 cell lines, in freshly isolated tumors tested in colony-forming assays in soft agar and in several animal models. In the NCI panel, the overall mean 50% cell kill (LC50) for the unsubstituted azonafide, AMP-1, was 10(-5.53) M, with some selectivity noted in melanomas (10(-6.22) M). The mean LC50 for the 6-ethoxy substituted analog, AMP-53, was 10(-5.53) M, with some selectivity found in non-small cell lung cancer (10(-5.91)) and renal cell carcinoma (10(-5.84)). In freshly isolated human tumors tested in soft agar, there was marked activity (mean IC50 in microg/ml) for AMP-53 in four cell types: breast cancer (0.09), lung cancer (0.06), renal cell carcinomas (0.06) and multiple myeloma (0.03). These effects were superior to doxorubicin and to several other azonafides, including AMP-1, AMP-104 and the 6-hydroxyethoxy derivative, AMP-115. Compound AMP-1 was shown to be superior to amonafide in the mammary 16C breast cancer model in B6CF31 mice, but it had little activity in Colon-38 nor in M5076 ovarian sarcomas in vivo. Nine azonafides were evaluated in the Lewis lung cancer model in C57/bl mice, but only AMP-53 demonstrated significant efficacy with a treated/control x 100% (T/C) value of 30%. Because AMP-53 demonstrated the greatest breadth of activity, it was then evaluated in several human tumor cell lines growing in mice with severe combined immunodeficiency disease (SCID). Only three tumors were sensitive (T/C<42%), including HL-60 leukemia (T/C=39%), MCF-7 breast cancer (T/C=39%) and A549 non-small cell lung cancer (T/C=37%). Overall, these results demonstrate that the 6-ethoxy substituted azonafide, AMP-53, has consistent (in vitro and in vivo) experimental antitumor activity in human breast and lung cancer, and could be considered for clinical testing in patients with MDR tumors.

Adenine↗
PubMed2001

Phase II study of direct intralesional gene transfer of allovectin-7, an HLA-B7/beta2-microglobulin DNA-liposome complex, in patients with metastatic melanoma.

Cutaneous melanoma is one of the most rapidly increasing cancers in the United States. Because of the lack of effective treatment options and toxicities of most chemotherapeutic and radiation regimes, immunotherapies such as vaccination therapy represent an attractive approach for patients with advanced melanoma. The purpose of this study was to evaluate the response rate, time to progression, and survival of patients with metastatic melanoma treated by direct intratumoral injection with Allovectin-7 (a plasmid DNA encoding the genes HLA-B7 and beta2-microglobulin complexed with a cationic lipid mixture, DMRIE/DOPE. Fifty-two patients with metastatic melanoma were enrolled in this Phase II study. Therapy consisted of six intratumoral injections of 10 microg of Allovectin-7 over a 9-week period. Treatment was well tolerated. Treatment-related adverse events were mild to moderate, the most frequent of which were ecchymosis, pruritus (and/or discomfort at the injection site), and pneumothoraces. Regression of the injected lesion was observed in 18% of patients, including one complete response, three partial responses, and five minor responses. An overall response rate of 4% (two partial responses) was documented, and nine patients (18%) maintained stable disease for at least 11 weeks. Six patients remained alive 25.1 to 39.4 months from their first injection, including two patients with local (injected tumor) responses and one patient with an overall disease partial response. This study demonstrates that intratumoral administration of Allovectin-7 in metastatic melanoma is safe and can produce both responses in injected lesions and in overall disease. Clinical trials optimizing patient selection and combining Allovectin-7 with other modalities of therapy are currently ongoing in an effort to improve response rates.

Adult↗
PubMed2000

Cationic lipid gene transfer of an IL-2 transgene leads to activation of natural killer cells in a SCID mouse human tumor xenograft.

Natural killer (NK) cells play an important role in combating infectious and malignant diseases and interleukin-2 (IL-2) has been shown to promote proliferation and activation of NK cells in vitro and in vivo. Here we investigate the effects of local cationic lipid-mediated IL-2 gene transfer on intratumoral accumulation and activation of NK cells in a SCID mouse tumor model. UM449 human melanoma tumors in SCID mice received intratumoral injections of DMRIE/DOPE admixed with VR1103, a DNA plasmid encoding the gene for human IL-2. Dissagregated tumor cells were tested for IL-2 secretion and were characterized using antibodies to asGM1, MAC-1, and F4/80 antigens. Granzyme A, a proteolytic serine esterase, was also measured in tumor cell lysates. IL-2 secretion from tumors injected with VR1103:DMRIE/DOPE peaked at 48 h after injection and fell to baseline levels on day 8. Intratumoral granzyme A activity was significantly increased in tumors injected with IL-2 plasmid:DMRIE/DOPE complexes, but not by an irrelevant plasmid DNA:DMRIE/DOPE control. Importantly, the growth of UM449 tumors was slowed in VR1103:DMRIE/DOPE-injected tumors. These results indicate that local cationic lipid-mediated gene transfer of IL-2 induces activation of intratumoral NK cells and slows tumor growth.

Animals↗
PubMed2000

Studies of direct intratumoral gene transfer using cationic lipid-complexed plasmid DNA.

Cationic lipid-mediated gene transfer is a safe and effective means of delivering potent immunomodulatory cytokines directly into tumors. This approach avoids undesirable side effects, including systemic toxicities. To investigate key factors affecting intratumoral (i.t.) gene transfer, cationic lipid-DNA complexes were injected into subcutaneous human melanoma tumors in severe combined immunodeficient mice. Animals received i.t. injections of VR1103, a DNA plasmid encoding the gene for human interleukin-2 (IL-2), either alone or complexed with the cationic lipid N-(1-(2,3-dimyristyloxypropyl)-N,N-dimethyl-(2-hydroxyethyl) ammonium bromide/dioleoyl phosphatidylethanolamine (DMRIE/DOPE). Tumors were subcultured and supernatants were tested for IL-2 secretion by enzyme-linked immunosorbent assay. IL-2 secretion was consistently higher when lipid:DNA (L:D) complexes were formulated at high L:D ratios (wt/wt), and IL-2 transgene expression increased in a DNA dose-dependent manner. A comparison of naked plasmid and lipid-complexed DNA revealed that lipid complexes were more effective for i.t. gene transfer. Using an enhanced green fluorescent protein reporter plasmid and flow cytometry, i.t. transfection efficiency was 1.74% (+/- 1.08%). Tumor injection technique, including injection volume and location, had a limited impact on i.t. gene transfer. These results indicate that the formulation and dosage of cationic L:D complexes, but not injection technique, play a key role in determining the level of i.t. transgene expression.

Animals↗
PubMed2000

Loss of B7.2 (CD86) and intracellular adhesion molecule 1 (CD54) expression is associated with decreased tumor-infiltrating T lymphocytes in diffuse B-cell large-cell lymphoma.

Tumor-infiltrating CD8+ T-lymphocytes (T-TILs) are thought to be relevant to immunosurveillance of several tumor types including B-cell non-Hodgkin's lymphoma. B- and T-lymphocyte interactions via cellular adhesion molecules (CAMs), recognition molecules (HLAs), and costimulatory molecules (CSMs) are necessary for optimal antigen-specific T-cell activation to occur and may be important in generating effective host T-TIL responses. We previously found that low T-TIL response (CD8+ T cells < 6%) correlates with statistically shorter relapse-free survival in patients with diffuse large-cell lymphoma (DLCL). We now extend our observations in 71 DLCL patients by analyzing malignant B-cell expression of the following molecules important in T-cell activation: (a) recognition molecules [MHC I (MAS and MCA) and MHC II (HLA-DR, -DP, -DQ)]; (b) CAMs [leukocyte function antigen 1 (CD11a and CD18) and intracellular adhesion molecule 1 (CD54)]; and (c) CSMs [B7.1 (CD80) and B7.2 (CD86)]. Eighteen patients (25%) had low a T-TIL response, and 53 patients (75%) had a high T-TIL response. Overall, expression of the MHC class H molecules HLA-DR and HLA-DQ was most conserved. The loss of B7.2 (P = 0.04), intracellular adhesion molecule 1 (P = 0.0004), MAS (P = 0.02), and HLA-DR (P = 0.0004) expression was significantly associated with decreased T-TIL response. In 100% of patients with low T-TIL responses, at least one HLA, CAM, or CSM was undetectable on the malignant B cells by immunohistochemical staining (mean number of molecules lost = 2.67). In contrast, 49% of patients with high T-TIL responses had no losses in HLA, CAM, or CSM expression (mean number of molecules lost = 0.89). The mean number of absent molecules (HLA, CAM, or CSM) was significantly associated with T-TIL response (P = 0.0001). We conclude that loss of HLA, CAM, or CSM expression on malignant B cells is associated with a poor host T-cell immune response. In addition, because patients with low T-TIL response had lost expression of multiple cellular adhesion, recognition, and costimulatory molecules, our results suggest that a combination of immunorestorative therapies may be required to generate effective antitumor T-cell responses in B-cell DLCL.

Antigens, CD↗
PubMed1999

Novel antitumor 2-cyanoaziridine-1-carboxamides.

A set of 20 2-cyanoaziridine-1-carboxamides was synthesized from 2-cyanoaziridine and appropriate isocyanates. These compounds were active against a variety of solid and hematological tumor cells in culture, including strains resistant to doxorubicin and mitoxantrone. Their potencies in these assays correlated with the lipophilicity of substituents. The N-phenyl derivative was more potent and equally effective to imexon, a cyclized 2-cyanoaziridine-1-carboxamide of clinical interest, against cloned fresh human tumors.

Antineoplastic Agents↗
PubMed1999

Topical DMSO treatment for pegylated liposomal doxorubicin-induced palmar-plantar erythrodysesthesia.

PURPOSE: Chemotherapeutic regimens that utilize fluorouracil, cytarabine, and doxorubicin have been shown to cause a dermatologic syndrome known as hand-foot syndrome, or palmar-plantar erythrodysesthesia syndrome (PPES). Pegylated liposomal doxorubicin has proven effective in the treatment of AIDS-related Kaposi's sarcoma, ovarian cancer refractory to platinum and paclitaxel therapies, and metastatic breast cancer. In a study of the treatment of refractory epithelial cell ovarian cancers with lipozomal doxorubicin utilizing intravenous doses of 50 mg/m(2) every 3 weeks, grade 3 PPES was observed in 29% of patients (10/35) and required dose reductions and/or dose delay after a median of three therapy cycles. METHODS: Current methods to prevent pegylated liposomal doxorubicin-induced PPES include dose reduction, lengthening of the drug administration interval and ultimately, drug withdrawal. Topical 99% dimethylsulfoxide (DMSO) also has shown strong activity in treating tissue extravasation reactions during intravenous administration of doxorubicin. RESULTS: Two patients undergoing chemotherapy with pegylated liposomal doxorubicin, 50 mg/m(2) every 4 weeks, developed grade 3 PPE after three cycles. Their PPES resolved over a period of 1 to 3 weeks while receiving topical 99% DMSO four times daily for 14 days. CONCLUSIONS: While these results are promising, patients must be treated in a prospective study of this topical DMSO formulation to definitively document its therapeutic efficacy.

Administration, Topical↗
PubMed1999

Phase II trial of biochemotherapy with interferon alpha, dacarbazine, cisplatin and tamoxifen in metastatic melanoma: a Southwest Oncology Group trial.

The therapeutic benefit of adding interferon alpha (IFNalpha) to established single-agent and combination chemotherapy regimens for the treatment of metastatic melanoma has not been proven. We designed the present study to estimate the response rate of IFNalpha, dacarbazine, cisplatin and tamoxifen in patients who had not been treated with systemic therapy for advanced disease. Using a schedule similar to that which had previously been shown to favor IFNalpha plus dacarbazine over dacarbazine alone, we treated patients with an "induction" regimen of IFNalpha, 15 mU m(-2) day(-1) intravenously 5 days/week for 3 weeks. Following induction, schedules of IFNalpha, 5 mU m(-2) day(-1) subcutaneously three times a week, and tamoxifen, 10 mg orally twice a day, were begun. Dacarbazine, 250 mg m(-2) day(-1) and cisplatin 33 mg m(-2) day(-1) for 3 consecutive days were repeated every 4 weeks, and subcutaneous IFNalpha and oral tamoxifen were continued until the discontinuation of chemotherapy. We treated 25 patients (18 men and 7 women, median age 52 years) and observed only 1 objective response (response rate 4%, 95% confidence interval 0.1%-20%). The toxicities of the regimen consisted of moderate myelosuppression and constitutional side-effects. On the basis of the low antitumor activity of this regimen, we do not recommend it for further study or for use as standard therapy of metastatic melanoma.

Adolescent↗
PubMed1999

Immunotherapy of advanced malignancy by direct gene transfer of an interleukin-2 DNA/DMRIE/DOPE lipid complex: phase I/II experience.

PURPOSE: We have completed a phase I study, followed by three phase I/II studies, in patients with metastatic melanoma, renal cell carcinoma (RCC), and sarcoma in order to evaluate the safety, toxicity, and antitumor activity of Leuvectin (Vical Inc, San Diego, CA), a gene transfer product containing a plasmid encoding human interleukin (IL)-2 formulated with the cationic lipid 1, 2-dimyristyloxypropyl-3-dimethyl-hydroxyethyl ammonium bromide/dioleyl-phosphatidyl-ethanolamine (DMRIE/DOPE) and administered intratumorally. PATIENTS AND METHODS: Twenty-four patients were treated in the phase I study. Leuvectin doses were 10 microg, 30 microg, or 300 microg weekly for 6 weeks. In three subsequent phase I/II studies, a total of 52 patients (18 with melanoma, 17 with RCC, and 17 with sarcoma) were treated with further escalating doses of Leuvectin: 300 microg twice a week for 3 weeks, 750 microg weekly for 6 weeks, and 1,500 microg weekly for 6 weeks. RESULTS: There were no drug-related grade 4 toxicities and only one grade 3 toxicity, but the majority of patients experienced mild constitutional symptoms after treatment. In the phase I/II studies, 45 patients were assessable for response (14 with RCC, 16 with melanoma, and 15 with sarcoma). Two patients with RCC and one with melanoma have achieved partial responses lasting from 16 to 19 months and continuing. In addition, two RCC, three melanoma, and six sarcoma patients had stable disease lasting from 3 to 18 months and continuing. The plasmid was detected by polymerase chain reaction assay in the posttreatment samples of 29 of 46 evaluated patients. Immunohistochemistry studies on serial biopsy specimens showed increased IL-2 expression and CD8(+) infiltration after treatment in the tumor samples of several patients (12 and 16, respectively). CONCLUSION: Direct intratumoral injection of Leuvectin is a safe and possibly effective immunotherapeutic approach in the treatment of certain tumor types.

Adult↗
PubMed1999

Cationic lipid-mediated gene transfer: current concepts.

Infectious disease, heart disease, cancer, autoimmunity, genetic defects and even traumatic injury may someday be treated with gene therapy and gene transfer strategies. The potential impact of this new technology on human disease has produced optimism and expectation for scientists and lay people alike. As more effort is directed at harvesting the potential of this technology it has become clear that the success or failure of gene therapy will hinge on our ability to manipulate and control the process of gene transfer in somatic cells. Today, somatic gene transfer is accomplished using either viral or non-viral gene transfer methods. The benefits and limitations of each system are aggressively being investigated to determine which characteristics are most compatible with safe and reliable gene transfer. Gene transfer with cationic lipid/plasmid DNA complexes (cationic lipoplexes) has become a popular means of delivering therapeutic genes and is being tested in preclinical and clinical trials. Cationic lipoplexes are easy and inexpensive to produce, they are composed of non-toxic and non-immunogenic precursor, and they have the potential of delivering large polynucleotides into somatic cells. Additionally, these reagents are easily manipulated in the laboratory to incorporate novel biological functions or to produce new formulations that can be screened for in vivo gene transfer activity. The last few years has seen many advances in our understanding of molecular and biological factors that influence cationic lipid-mediated gene transfer. In this review we discuss recent developments in the field of cationic lipid-mediated gene transfer with emphasis on in vivo application where possible. We will consider new discoveries concerning the molecular and cellular events that control the uptake, transit and expression of lipoplexes in somatic cells. Recent biodistribution and pharmacokinetic studies and current concepts regarding the toxicity and immunogenicity of cationic lipoplexes will also be discussed. We also survey some of the many preclinical and clinical trials using cationic lipid-mediated gene transfer, with emphasis on cancer applications.

Animals↗
PubMed1997

Human tumor models in the severe combined immune deficient (scid) mouse.

PURPOSE: To test a number of established human tumor cell lines and early passage breast cancer (UACC2150) and melanoma cells (UACC1273) for growth in the scid mouse and the tumors' response to conventional chemotherapeutic drugs. METHODS: Established melanoma (A375, C81-61), colon (SW480), lung (A549), lymphomoblastoid leukemia (LCL-B), promyelocytic leukemia (HL60), prostate (PC-3, DU145), and breast (MCF7) cell lines were injected at subcutaneous (s.c.), intraperitoneal (i.p.), or mammary fat pad (MFP) sites. Tumor volume growth curves and survival curves were established for the various tumor cell lines. Carmustine (BCNU), cisplatin (CDDP), cyclophosphamide (CPA), doxorubicin, dacarbazine (DTIC), tamoxifen and vincristine were injected s.c. or i.p.. The chemotherapeutic drug effects on tumor volumes and survival were determined. RESULTS: Tumor growth occurred with each cell type. After i.p. injection, 90% mortality occurred within 26 to 60 days except for the early passage melanoma cell line UACC1273 with which mortality occurred within approximately 90 days. In the MCF7 breast model, treatment with tamoxifen (P < 0.001) and CPA (P < 0.0001) resulted in significant tumor growth delay compared with control groups. BCNU and CDDP resulted in significant tumor growth delays relative to control in SW480 colon cancer (P < 0.0014) and A375 melanoma (P < 0.0001) models, respectively. CPA and doxorubicin improved survival in the HL60 leukemia model (P = 0.0018). CONCLUSIONS: These scid mouse human tumor models appear to reflect the clinical situation in that clinically active chemotherapeutic drugs are similarly active in the scid mouse models. Therefore, the scid mouse models may be useful for testing new chemotherapeutic agents against various human cancer types.

Animals↗
PubMed1997

Phase I study of direct gene transfer of an allogeneic histocompatibility antigen, HLA-B7, in patients with metastatic melanoma.

PURPOSE: To determine the safety, toxicity, and efficacy of direct intratumoral injection of an allogeneic major histocompatibility complex (MHC) class I gene, HLA-B7, in a cationic lipid vector (Allovectin-7; Vical Inc, San Diego, CA) in patients with metastatic melanoma. PATIENTS AND METHODS: Seventeen HLA-B7-negative patients were treated with intralesional injection of Allovectin-7. Twelve patients received a single intralesional injection containing 10 micrograms (four patients), 50 micrograms (five patients), or 250 micrograms (three patients) of plasmid DNA. Five patients received two or three injections of 10 micrograms DNA to a single tumor site at 2-week intervals. Tumor biopsies pretherapy and 2 and 4 weeks after gene injection were obtained to determine expression of the plasmid by polymerase chain reaction (PCR), reverse transcriptase (RT)-PCR, flow cytometry, and immunohistochemistry. RESULTS: Toxicities were related to technical aspects of the injections or biopsies. These included pain, hemorrhage, pneumothorax, and hypotension. Two patients were hospitalized overnight for observation. Seven patients (50%) had tumor responses insofar as the injected nodule decreased > or = 25% by radiologic or physical examination. One patient with a single site of disease achieved a complete remission. Ninety-three percent of the patients' post-gene therapy biopsies contained HLA-B7 plasmid DNA, mRNA, or protein. CONCLUSION: Intratumoral injection of the allogeneic histocompatibility gene, HLA-B7, in a lipid vector can be performed safely at plasmid DNA doses < or = 250 micrograms. The safety profile and biologic activity of this therapy warrants further studies to define the mechanism of action, predictors of response, and antitumor efficacy of this approach.

Adult↗
PubMed1997

Advances in the biological therapy and gene therapy of malignant disease.

Biological and gene therapy of cancer have become important components of clinical cancer research. Advances in this area are based on evidence for the presence of tumor antigens, antitumor immune responses, evasion of host control by tumors, and the recognition of host defense failure in cancer patients. These mechanisms are being corrected or exploited in the development of biological and gene therapy. Over the last decade, 9 biological therapies have received Food and Drug Administration approval, and another 12 appear promising and will likely be approved in the next few years. Our approach to gene therapy has been to allogenize tumors by the direct intratumoral injection of HLA-B7/beta2-microglobulin genes as plasmid DNA in a cationic lipid into patients with malignant melanoma. In four Phase I studies, we found a 36% response by the local injected tumor and a 19% systemic antitumor response. In other cancers, gene transfer, expression, and an intratumoral T-cell response were seen, but no clinical response was seen. A variety of follow-up studies with HLA-B7 and other genes are planned. Evasion of host control is now a major target of gene therapy. Strategies to overcome this include up-regulation of MHC and introduction of cell adhesion molecules into tumor cells, suppression of transforming growth factor and interleukin 10 production by tumor cells, and blockade of the fas ligand-fas interaction between tumor cells and attacking lymphocytes. With these approaches, it seems likely that gene therapy may become the fifth major modality of cancer treatment in the next decade.

BCG Vaccine↗