Clinical protocol. Intra-Lesional rF-B7.1 versus rF-TRICOM vaccine in the treatment of metastatic cancer.
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Adult↗
Biomedical subjects
Howard L Kaufman
Publications and source records attributed to Howard L Kaufman.
Management of metastatic malignant melanoma of the bladder.
Recombinant interleukin-2 (IL-2) has demonstrated antitumor activity and durable clinical responses in patients with metastatic melanoma. Careful screening and selection of appropriate patients has improved the safety profile of IL-2 administration. Gross hematuria would ordinarily preclude the safe delivery of IL-2. We report a case of metastatic melanoma to the bladder presenting with hematuria. A complete resection was performed and subsequently allowed the administration of high-dose, bolus IL-2. The combination of resection and IL-2 therapy resulted in a partial response maintained for more than 18 months. Symptomatic bladder melanoma should be aggressively treated to allow for systemic immunotherapy, which can provide durable responses.
Antineoplastic Agents↗
Current approaches to novel therapeutics in pancreatic cancer.
Pancreatic cancer is one of the most refractory neoplasms to medical treatment. Until now there has been only modest improvement in the treatment of this disease. Standards of care for combined-modality treatment of resectable as well as locally advanced, unresectable disease have not been uniformly accepted to date because of an equivocal or conflicting data. The inception of gemcitabine introduced the new era in the management of metastatic pancreatic cancer, however, new therapeutic approaches still need to be defined. The article discusses the current knowledge of the biology of this lethal disease, its impact on treatment options, and explores novel therapeutic modalities that are likely to improve outcomes and survival for patients in the future.
Antineoplastic Agents↗
Administration of vaccinia virus to mice may cause contact or bedding sentinel mice to test positive for orthopoxvirus antibodies: case report and follow-up investigation.
Routine testing of bedding sentinels from a barrier room revealed one mouse seropositive to ectromelia virus (EV). Results of hemagglutination-inhibition testing and western blot analysis were confirmatory for orthopoxvirus antibodies. Additional seropositive animals were not identified. Interviews indicated that replication-competent vaccinia virus (VV), Western Reserve strain (VV-WR), recently had been given to mice. Although VV-WR was not expected to spread by contact or via fomites, the case evidence suggested transmission of vaccinia via soiled bedding. In a follow-up experiment, 15 index mice were inoculated with 10(7) plaque-forming units of VV by either subcutaneous or intrarectal instillation. A dedicated contact sentinel and a bedding sentinel were provided for each index mouse. All 15 index mice were positive for antibodies when tested 22 days after inoculation. One mouse, inoculated by the subcutaneous route, appeared ill and developed lesions on the proximal portion of the tail. The contact sentinel mouse housed with this index mouse was the only sentinel to seroconvert. We conclude that VV-WR can spread to contact sentinels and potentially to bedding sentinels. The ability of other VV strains to be transmitted horizontally and the susceptibility of different mouse strains to infection merit further investigation. The use of VV in animal facilities must be managed carefully since the available serologic tests do not distinguish between VV and EV, an exotic agent of major concern to laboratory animal facilities.
Animals↗
Poxviruses as vectors for cancer immunotherapy.
Despite advances in chemotherapy and surgical techniques, patients with cancer often develop local recurrence or metastatic spread. Recent advances in molecular biology, coupled with new insights in tumor immunology, have led to the design of novel antitumor vaccines. Poxviruses are a large family of DNA viruses that provide an effective and safe vector system for vaccine development. The poxvirus strategy has been successfully documented in animal models, and has been used to express both tumor-associated antigens and immune stimulatory molecules. In this review, we focus on recent advances in the use of poxvirus-based vaccines as cancer therapeutic agents.
Animals↗
Insertion of interleukin-2 (IL-2) and interleukin-12 (IL-12) genes into vaccinia virus results in effective anti-tumor responses without toxicity.
Identification of novel tumor-associated antigens (TAA) capable of eliciting T-cell responses has renewed interest in the development of anti-tumor vaccines. The insertion of genes encoding specific TAA into a vaccinia virus (rVV) is one approach to vaccination since large amounts of foreign DNA can be stably integrated into the poxvirus genome. Recent reports have documented an increased therapeutic effectiveness of poxvirus-based vaccines when additional treatment with cytokines, such as interleukin-2 (IL-2) or interleukin-12 (IL-12) were used, but the combination of these cytokines as adjuvants for a rVV encoding TAA have not been previously reported. The combination of IL-2 and IL-12 at single regimen systemic doses was toxic and sometimes fatal, manifesting largely as segmental epithelial apoptosis of the large bowel. To explore the local delivery of both cytokines to the site of vaccination, the genes encoding IL-2 and IL-12 were inserted into vaccinia virus along with a model tumor antigen gene. This construct contained five heterologous genes: LacZ (the model antigen), gpt (reporter gene), IL-2, and the two IL-12 subunit genes (p35 and p40). Treatment with this recombinant virus resulted in a reduced number of pulmonary metastases, improved survival, and minimal toxicity in a murine tumor model. The use of vaccinia virus for the insertion of other heterologous gene combinations may provide a powerful and less toxic approach for novel vaccination strategies in the treatment and prevention of cancer.
Animals↗
Combination interleukin-2 and interleukin-12 induces severe gastrointestinal toxicity and epithelial cell apoptosis in mice.
Interleukin 2 (IL-2) and interleukin 12 (IL-12) have potent anti-tumour activity as single agent therapy against several different murine and human tumours. Combining these cytokines may result in improved therapeutic effectiveness, however, the toxicity associated with simultaneous administration is prohibitive. This study was designed to determine the specific histopathologic changes associated with combination therapy. Mice were treated with 5 days of interleukin-2, interleukin-12, or both using standard doses and schedules. Histologic specimens were prepared from all internal organs on a daily basis to identify specific pathologic abnormalities. Treatment with interleukin-2, interleukin-12, or both resulted in pathologic insult to the liver and gastrointestinal tract. Mild lymphoplasmacytic infiltrates were seen in the liver. The most significant pathology was seen in the large bowel and consisted of apoptosis of colonic epithelial cells. While recovery of injured gastrointestinal mucosa occurred in mice treated with interleukin-2 or interleukin-12 alone, combination therapy resulted in death before recovery was possible. Combination interleukin-2 and interleukin-12 therapy results in irreversible injury of the colon as manifested by increased epithelial cell apoptosis and death in mice. Understanding the pathologic changes associated with combination cytokine therapy may lead to strategies that prevent toxicity while maintaining therapeutic effects.
Animals↗
Immunotherapy for pancreatic cancer: current concepts.
Despite advances in chemotherapy and surgical technique, patients with pancreatic cancer often succumb to local recurrence or metastatic spread. The need for new therapeutic strategies for this disease coupled with a better understanding of basic immunology have led to the development of novel anti-tumor vaccines. This review focuses on the historical development of tumor vaccines emphasizing the identification of potential pancreatic tumor antigens. The role of both B-cell and T-cell responses in tumor rejection will be reviewed. Methods for antigen presentation, including peptides, recombinant viral and bacterial vectors, dendritic cells, and whole cell approaches will be discussed. The use of immune adjuvants and improved methods of vaccine delivery will also be explored. The full potential for the immunotherapy of pancreatic cancer awaits the results of early phase clinical trials. The development of pancreatic cancer vaccines represents a useful paradigm for the translation of basic research into the clinical arena.
Adenocarcinoma↗
Chemokines and cancer.
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Cell Differentiation↗
Prostate-specific antigen vaccines for prostate cancer.
Prostate cancer is the most common malignant tumour in men and there are few treatment options available once the tumour becomes refractory to hormonal manipulation. Prostate-specific antigen (PSA) is a secretory glycoprotein that is commonly expressed by prostatic epithelial cells and is found in elevated levels in the serum of men with prostate cancer. The identification of T cell specific epitopes within the coding sequence of PSA has led to the development of various vaccine strategies that target PSA in an attempt to treat established prostate cancer. These strategies have included human leukocyte antigen-restricted PSA peptides, dendritic cells pulsed with PSA, recombinant viruses expressing PSA and combinations of different vectors. In addition to PSA, several other antigens have been described that may be useful for targeting prostate tumours by vaccines. Animal studies have established the feasibility and safety for many of these agents and clinical trials are now in progress to evaluate the immunological and clinical responses of PSA vaccines. Further research in manipulating anti-PSA immunity with cytokines, costimulatory molecules and other immune modulating agents will likely improve the therapeutic effectiveness of PSA vaccines. Clinical trials designed to evaluate the effects of vaccination in different stages of disease and through different routes of administration need to be performed to define the optimal schedule for PSA vaccines in patients with prostate cancer, or for those at high risk of developing the disease.
Animals↗
CEA-based vaccines.
Carcinoembryonic antigen (CEA), the first tumor-associated antigen to be described, was cloned in 1987 and is expressed on nearly 50% of all human tumors. The identification of T-cell specific epitopes within the coding region of the CEA protein has led to the development of various vaccine strategies that target CEA and CEA-expressing tumors. These vaccines have shown evidence of therapeutic effectiveness in animal models and are being evaluated in early phase clinical trials. Although trials are not designed to elucidate clinical responses, they have provided important information about the ability of individual vaccines to induce CEA-specific immune responses through the use of newer in vitro monitoring assays. Continued clinical testing in patients with less advanced disease and the administration of vaccines in combination with other standard therapy will help define the role of CEA-based vaccines in the treatment and prevention of human cancer.
Animals↗
Treatment of pediatric ocular melanoma with high-dose interleukin-2 and thalidomide.
Uveal melanoma is the most common primary ocular malignancy, although it is rare in children, and patients presenting with metastatic disease have a median survival of only 2 to 5 months. The tumor is generally unresponsive to systemic chemotherapy, but immunotherapy may be effective in selected patients. This report describes an 8-year-old girl with metastatic uveal melanoma treated with high-dose, bolus interleukin-2 (IL-2) and the antiangiogenic agent thalidomide. She tolerated treatment well and initially responded with stable disease in the liver and pancreas for 23 months. New pulmonary metastases developed and she was re-treated with high-dose IL-2, resulting in regression of her liver lesions and stable pulmonary disease for more than 18 months. These results suggest that IL-2 at high doses, and in combination with thalidomide, may be useful for uveal melanoma with tolerable side effects in children. Further study of this combination in children with immune-responsive tumors is warranted.
Angiogenesis Inhibitors↗