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Biomedical subjects

Howard L Kaufman

Publications and source records attributed to Howard L Kaufman.

At least 37 records · Page 2Linked to original sources
PubMed2004

Local delivery of recombinant vaccinia virus expressing secondary lymphoid chemokine (SLC) results in a CD4 T-cell dependent antitumor response.

Secondary lymphoid chemokine (SLC) attracts mature dendritic cells (DCs) and naïve T cells. Co-localization of these cells within local tumor environments may enhance the induction of tumor-specific T cells. However, the presence of danger signals or other DC maturation signals are required to optimize T-cell priming. We hypothesized that expression of SLC in vaccinia virus would provide local chemokine delivery and adjuvant factors. A recombinant vaccinia virus expressing murine SLC (rVmSLC) was constructed and characterized. SLC expression was confirmed by Western blot analysis and functional activity was determined by in vitro chemotaxis assay. Supernatants from rVmSLC-infected cells attracted CD4 T cells, and also induced the migration of CD8 T cells and DCs. Although poxviruses are known to express several chemokine-binding proteins, systemic injection of rVmSLC was well tolerated in mice up to a dose of 1 x 10(7) pfu and did not significantly alter vaccinia-specific T-cell immunity. Local injection of rVmSLC into established tumors derived from the murine colon cancer line, CT26, resulted in enhanced infiltration of CD4 T cells, which correlated with inhibition of tumor growth. The central role of CD4 T cells was further demonstrated by loss of anti-tumor activity in CD4 T-cell depleted mice. Intratumoral delivery of SLC using a poxviral vaccine extends the use of SLC in anti-tumor therapies and may present an effective alternative for improving the immunotherapy of cancer alone or in combination with other anti-tumor agents for clinical therapy.

Animals↗
PubMed2004

Phase II randomized study of vaccine treatment of advanced prostate cancer (E7897): a trial of the Eastern Cooperative Oncology Group.

PURPOSE: A phase II clinical trial was conducted to evaluate the feasibility and tolerability of a prime/boost vaccine strategy using vaccinia virus and fowlpox virus expressing human prostate-specific antigen (PSA) in patients with biochemical progression after local therapy for prostate cancer. The induction of PSA-specific immunity was also evaluated. PATIENTS AND METHODS: A randomized clinical trial was conducted by the Eastern Cooperative Oncology group and 64 eligible patients were randomly assigned to receive four vaccinations with fowlpox-PSA (rF-PSA), three rF-PSA vaccines followed by one vaccinia-PSA (rV-PSA) vaccine, or one rV-PSA vaccine followed by three rF-PSA vaccines. The major end point was PSA response at 6 months, and immune monitoring included measurements of anti-PSA and anti-vaccinia antibody titers and PSA-specific T-cell responses. RESULTS: The prime/boost schedule was well tolerated with few adverse events. Of the eligible patients, 45.3% of men remained free of PSA progression at 19.1 months and 78.1% demonstrated clinical progression-free survival. There was a trend favoring the treatment group that received a priming dose of rV-PSA. Although no significant increases in anti-PSA antibody titers were detected, 46% of patients demonstrated an increase in PSA-reactive T-cells. CONCLUSION: Therapy with poxviruses expressing PSA and delivered in a prime/boost regimen was feasible and associated with minimal toxicity in the cooperative group setting. A significant proportion of men remained free of PSA and clinical progression after 19 months follow-up, and nearly half demonstrated an increase in PSA-specific T-cell responses. Phase III studies are needed to define the role of vaccination in men with prostate cancer or those who are at risk for the disease.

Aged↗
PubMed2004

Immune properties of recombinant vaccinia virus encoding CD154 (CD40L) are determined by expression of virally encoded CD40L and the presence of CD40L protein in viral particles.

Expression of costimulatory molecules by recombinant poxviruses is a promising strategy for enhancing therapeutic vaccines. CD40-CD40L interactions are critical for conditioning dendritic cells (DC) and priming T- and B-cell immunity. We constructed a vaccinia virus expressing murine CD40L (rV-CD40L) and studied its immunomodulatory properties in vitro. Direct DC infection with control vaccinia or psoralen/UV-inactivated rV-CD40L stimulated high levels of interleukin 12 (IL-12) release. However, replication-competent rV-CD40L did not stimulate IL-12 under similar conditions. We observed a high level of CD40L protein on purified viral particles and demonstrated that induction of IL-12 by nonreplicating rV-CD40L was blocked by anti-CD40 antibodies suggesting that functional CD40L on viral particles contributed to alterations in IL-12 synthesis. Since cross-presentation of tumor-associated antigens by DC is augmented by viral infection of tumor cells, we infected MC38 murine colon carcinoma cells with rV-CD40L. Infected cells stimulated IL-12 secretion by DC and proliferation of B cells and DX5(+) (NK/NKT) cells through direct CD40-CD40L interaction. A subpopulation of NKT cells expressing CD40 (NK1.1(+), CD3(lo)) appeared to be a major effector population responding to MC38/rV-CD40L. These results highlight the complex immune regulatory effects of rV-CD40L defined by the cumulative effects of CD40L expression, presence of CD40L protein in viral particles, and the replication potential of the virus.

Animals↗
PubMed2004

Immune system versus tumor: shifting the balance in favor of DCs and effective immunity.

Despite the initial excitement over cancer vaccines, the clinical effectiveness of immunotherapy has been disappointing. The suppressive milieu present within established tumors inhibits effective immune responses, although new strategies are emerging to manipulate the local tumor microenvironment and shift the balance back to a proinflammatory environment, promote DC activation, and enhance tumor immunity.

Animals↗
PubMed2004

Poxvirus vaccines for cancer and HIV therapy.

The poxviridae have a long history of causing disease in society, and their biological effects in humans and other mammals have been extensively studied. In the 1980s, genetic engineering techniques were applied to vaccinia in order to create replicating recombinant vectors that could express inserted genes encoding influenza virus proteins. In animal models, these recombinant viruses were able to deliver their foreign antigens to the immune system and elicit a specific adaptive immune response. Since then, improvements in our understanding of immunobiology, as well as technical advances in bioengineering, have led to the creation and clinical testing of a large number of recombinant poxviruses as candidate vaccines. Poxviruses can infect a broad range of cells, replicate with high efficiency and elicit strong immune responses - factors that make them especially well-suited as vaccines for the prevention and treatment of human immunodeficiency virus (HIV) and cancer. Both of these diseases are characterised by chronic antigen expression in the setting of focal or global deficits in the immune system that hamper the generation of protective immunity. This review traces the history of poxviruses as pathogens and immunogens, examines some of the approaches that have been taken to design poxviral vaccines for HIV and cancer and summarises the results of existing clinical trials of these vectors. In addition, the review aims to identify some of the factors that may shape the development of future therapies based on recombinant poxviruses.

AIDS Vaccines↗
PubMed2004

Adjuvant therapy for malignant melanoma.

Malignant melanoma is increasing in incidence worldwide, and many patients remain at a significant risk of recurrence following surgical resection. Over the past 30 years, interferon-alpha has been the only agent approved for adjuvant therapy of melanoma. This review summarizes the rationale for adjuvant therapy, and discusses the roles of interferon, immunotherapy, chemotherapy and radiation therapy in the adjuvant setting. New approaches and novel combinations that appear promising for the adjuvant therapy of malignant melanoma are also outlined.

Antineoplastic Agents↗
PubMed2004

TG-4010 Transgene.

Transgene is developing TG-4010, a second-generation modified vaccinia virus Ankara encoding MUC1 and interleukin-2 for the potential treatment of a variety of cancer types. Phase II trials are underway for non-small-cell lung cancer, metastatic renal cancer and prostate cancer.

Animals↗
PubMed2003

Local delivery of poxvirus vaccines for melanoma.

The development of vaccines for melanoma has been accelerated by the identification of melanoma-associated antigens, a better understanding of basic immunologic principles, and the ability to construct complex vectors for immunization. The location and context in which T-cell priming occurs significantly influences the type and magnitude of immune response. Furthermore, there is a delicate balance between the generation of tumor-specific immunity and the emergence of tumor escape variants. We have focused on the direct intra-tumoral delivery of poxvirus vaccines expressing costimulatory molecules as a strategy for overcoming local immunosuppression in the treatment of established melanoma. Poxviruses provide potent danger signals and, in the presence of costimulation, local administration provides a mechanism to prime tumor-specific T-cell responses. The clinical application of this approach will likely depend on the ability to induce systemic anti-tumor immunity following local injection and we are evaluating this in current clinical trials. These studies may have important implications for the design of vaccine strategies for melanoma and other tumors.

Cancer Vaccines↗
PubMed2003

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↗
PubMed2003

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↗
PubMed2003

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↗
PubMed2003

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↗
PubMed2002

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↗
PubMed2002

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↗
PubMed2002

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↗