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Howard L Kaufman

Publications and source records attributed to Howard L Kaufman.

At least 19 recordsLinked to original sources
PubMed2006

4-1BB ligand enhances tumor-specific immunity of poxvirus vaccines.

PURPOSE: Recombinant poxvirus vaccines have been explored as tumor vaccines. The immunogenicity of these vaccines can be enhanced by co-expressing costimulatory molecules and tumor-associated antigens. While the B7-CD28 interaction has been most comprehensively investigated, other costimulatory molecules utilize different signaling pathways and might provide further cooperation in T cell priming and survival. 4-1BB (CD137) is a TNF family member and is critical for activation and long-term maintenance of primed T cells. This study was conducted to determine if a poxvirus expressing the ligand for 4-1BB (4-1BBL) could further improve the immune and therapeutic responses of a previously reported poxvirus vaccine expressing a triad of costimulatory molecules (B7.1, ICAM-1, and LFA-3). EXPERIMENTAL DESIGN: A recombinant vaccinia virus expressing 4-1BBL was generated and characterized in an in vitro infection system. This vaccine was then used alone or in combination with a vaccinia virus expressing CEA, B7.1, ICAM-1, and LFA-3 in CEA-transgenic mice bearing established MC38 tumors. Tumor growth and immune responses against CEA and other tumor-associated antigens were determined. The level of anti-apoptotic proteins in responding T cells was determined by flow cytometry on tetramer selected T cells. RESULTS: The combination of 4-1BBL with B7.1-based poxvirus vaccination resulted in significantly enhanced therapeutic effects against CEA-expressing tumors in a CEA-transgenic mouse model. This was associated with an increased level of CEA-specific CD4(+) and CD8(+) T cell responses, induction of antigen spreading to p53 and gp70, increased accumulation of CEA-specific T cells in the tumor microenvironment, and increased expression of bcl-X(L) and bcl-2 in CD4(+) and CD8(+) T cells in vaccinated mice. CONCLUSION: 4-1BBL cooperates with B7 in enhancing anti-tumor and immunologic responses in a recombinant poxvirus vaccine model. The inclusion of costimulatory molecules targeting distinct T cell signaling pathways provides a mechanism for enhancing the therapeutic effectiveness of tumor vaccines.

4-1BB Ligand↗
PubMed2006

Characterization of CD4+CD25+ regulatory T cells in patients treated with high-dose interleukin-2 for metastatic melanoma or renal cell carcinoma.

PURPOSE: To characterize the number and functional status of CD4+CD25+ regulatory T cells (Tregs) in patients with metastatic melanoma (MM) and renal cell carcinoma (RCC) treated with high-dose bolus interleukin-2 (IL-2). PATIENTS AND METHODS: Patients with MM or RCC treated with high-dose bolus IL-2 (600,000 IU/kg every 8 hours) at a single center provided pre- and post-treatment whole blood specimens. Peripheral blood mononuclear cells were isolated by Ficoll density gradient centrifugation, separated into cellular subsets, and analyzed by flow cytometry or used for in vitro proliferation assays. RESULTS: Between September 2003 and July 2005 57 patients were enrolled in the study with 48 patients available for analysis (45 MM, 12 RCC). Tregs were defined as CD4+CD25(hi) T cells, and this subset was significantly elevated in the cancer patients compared with normal donors (7.75% v 2.24%). The CD4(+)CD25(hi) T-cell pool in the patients constitutively expressed intracellular FoxP3, CTLA-4, and produced high amounts of IL-10. The Tregs were CCR7+ with 50% representing naïve and 50% central-memory T cells. The cells were functionally suppressive in mixed in vitro proliferation assays. Following IL-2 administration, the number and frequency of Tregs increased in patients with progressive disease but returned to normal levels in patients with objective clinical responses. CONCLUSION: The number of Tregs, defined as CD4+CD25(hi) T cells is increased in patients with MM and RCC. High-dose IL-2 resulted in a significant decrease of Tregs in those patients achieving an objective clinical response to IL-2 therapy.

Adult↗
PubMed2006

Chemokines in tumor immunotherapy.

The chemokines are a family of small molecules that mediate cell migration, activation, differentiation, angiogenesis, and perhaps other functions. The chemokines have been classified by their amino acid composition, functional activity, and receptor binding properties. The chemokines receptors are 7 transmembrane G proteins and there is considerable redundancy in ligand specificity. The role of chemokines in cancer is not well understood, but there is accumulating evidence that they play a major role in both tumorigenesis and the host immune response to tumors. Thus, chemokines and their receptors represent potential therapeutic targets for drug development. This article will briefly review the current understanding of chemokines biology of defined chemokines that are thought to be involved in tumor growth, metastasis, and the host immune response against cancer.

Amino Acids↗
PubMed2006

Viral vaccines for cancer immunotherapy.

The understanding that tumor cells can be recognized and eliminated by the immune system has led to intense interest in the development of cancer vaccines. Viruses are naturally occurring agents that cause human disease but have the potential to prevent disease when attenuated forms or subunits are used as vaccines before exposure. A large number of viruses have been engineered as attenuated vaccines for the expression of tumor antigens, immunomodulatory molecules, and as vehicles for direct destruction of tumor cells or expression of highly specific gene products. This article focuses on the major viruses that are under development as cancer vaccines, including the poxviruses, adenoviruses, adeno-associated viruses, herpesviruses, retroviruses, and lentiviruses. The biology supporting these viruses as vaccines is reviewed and clinical progress is reported.

Genetic Vectors↗
PubMed2006

Local delivery of vaccinia virus expressing multiple costimulatory molecules for the treatment of established tumors.

Successful immunotherapy of established tumors depends on overcoming the suppressive influence of the local tumor microenvironment. The direct injection of vaccinia virus expressing the B7.1 (CD80) costimulatory molecule into melanoma lesions resulted in local and systemic immunity with associated clinical responses. Therefore, we sought to evaluate the effects of a vaccinia virus expressing three costimulatory molecules, B7.1, ICAM-1, and LFA-3 (rV-TRICOM), in patients with metastatic melanoma. A standard dose escalation phase I clinical trial was performed. Thirteen patients were enrolled and 12 were available for follow-up. Local vaccination was feasible, with only low-grade injection site reactions associated with mild fatigue and myalgia reported. There was one occurrence of grade 1 vitiligo. Overall there was a 30.7% objective clinical response, with one patient achieving a complete response for more than 22 months. An inverse association was detected between anti-vaccinia antibody and anti-vaccinia T cell responses. Patients who failed to respond to vaccination but received high-dose interleukin-2 had a trend toward improved survival. Collectively, these results confirm the safety profile and feasibility of direct injection of vaccinia virus expressing multiple costimulatory molecules in patients with established tumors. Further clinical investigation is needed to better define the role of antigen, adjuvant cytokines, costimulation, and cross-presentation in the host immune response to local vaccination with vaccinia viruses expressing immunomodulatory molecules.

Adult↗
PubMed2006

The tumour microenvironment and implications for cancer immunotherapy.

Tumour cells exist in a complex milieu of cellular and non-cellular components comprising fibroblasts, endothelial cells, immune cells and metabolites of cellular respiration. An elaborate interplay between these components and tumour cells exists with implications for immunological recognition of tumour cells. Tumours have been shown to alter their antigen and cytokine profiles, desensitise and impair immune defences, signal fibroblasts to facilitate metastasis, and take advantage of acidic and hypoxic conditions that impede normal cells. This paper aims to review the roles of the stroma, extracellular matrix and chemistry of the microenvironment on tumour growth, with particular emphasis on interactions with the immune system, and to highlight some of the novel therapeutic strategies that target the tumour microenvironment.

Antineoplastic Agents↗
PubMed2006

Development of the PANVAC-VF vaccine for pancreatic cancer.

PANVAC-VF is a vaccine regimen composed of a priming dose of recombinant vaccinia virus and booster doses of recombinant fowlpox virus expressing carcinoembryonic antigen, mucin-1 and a triad of costimulatory molecules (TRICOM), which include B7.1, intercellular adhesion molecule-1 and leukocyte function-associated antigen-3. Vaccination is administered by subcutaneous injection followed by 4 days of local recombinant adjuvant granulocyte-macrophage colony-stimulating factor at the vaccination site. The vaccine has been developed for patients with advanced pancreatic cancer and has now entered a randomized Phase III clinical trial. This review will describe the background of recombinant poxvirus technology for tumor vaccine development, detail the key preclinical studies supporting the regimen, review the clinical trials supporting the current Phase III study, and highlight the key challenges and future obstacles to successful implementation of PANVAC-VF for pancreatic cancer.

Adjuvants, Immunologic↗
PubMed2005

Targeting the local tumor microenvironment with vaccinia virus expressing B7.1 for the treatment of melanoma.

Immunotherapy for the treatment of metastatic melanoma remains a major clinical challenge. The melanoma microenvironment may lead to local T cell tolerance in part through downregulation of costimulatory molecules, such as B7.1 (CD80). We report the results from the first clinical trial, to our knowledge, using a recombinant vaccinia virus expressing B7.1 (rV-B7.1) for monthly intralesional vaccination of accessible melanoma lesions. A standard 2-dose-escalation phase I clinical trial was conducted with 12 patients. The approach was well tolerated with only low-grade fever, myalgias, and fatigue reported and 2 patients experiencing vitiligo. An objective partial response was observed in 1 patient and disease stabilization in 2 patients, 1 of whom is alive without disease 59 months following vaccination. All patients demonstrated an increase in postvaccination antibody and T cell responses against vaccinia virus. Systemic immunity was tested in HLA-A*0201 patients who demonstrated an increased frequency of gp100 and T cells specific to melanoma antigen recognized by T cells 1 (MART-1), also known as Melan-A, by ELISPOT assay following local rV-B7.1 vaccination. Local immunity was evaluated by quantitative real-time RT-PCR, which suggested that tumor regression was associated with increased expression of CD8 and IFN-gamma. The local delivery of vaccinia virus expressing B7.1 was well tolerated and represents an innovative strategy for altering the local tumor microenvironment in patients with melanoma.

Adult↗
PubMed2005

Initial clinical response predicts outcome and is associated with dose schedule in metastatic melanoma and renal cell carcinoma patients treated with high-dose interleukin 2.

BACKGROUND: High-dose interleukin (IL)-2 is an effective agent for the treatment of metastatic malignant melanoma and renal cell carcinoma. This study evaluated the outcomes of patients receiving two commonly used intravenous IL-2 schedules that have never been directly compared. METHODS: Forty-seven metastatic malignant melanoma and renal cell carcinoma patients were identified from a prospective database who underwent high-dose IL-2 therapy (720,000 or 600,000 IU/kg) during 1999 to 2003. Disease-specific survival (DSS) was calculated by the Kaplan-Meier method with the log-rank test on an intention-to-treat basis. Multivariate Cox regression analysis of prognostic variables associated with outcome was performed. Factors associated with initial response and prevention of disease progression were determined. RESULTS: Objective response (5 partial and 5 mixed) or disease stabilization was noted in 9 (20%) and 10 (22%), respectively, of 46 assessable patients after 1 course of therapy. Four patients (22%) achieved disease-free status after the third course of IL-2 (n = 1) or surgical resection of confined metastatic disease (n = 3). At 19.1 months' median follow-up, factors associated with improved DSS included an initial clinical response to IL-2 therapy (P < .001) and a higher administered dose (P = .04). Patients who received 720,000 IU/kg were more likely to experience an initial major objective response (P = .03) and disease stabilization (P = 0.03) independent of the tumor treated. Objective response early in the course of therapy was the only independent predictor of tumor-related mortality (P = .004). CONCLUSIONS: The initial clinical response to IL-2 therapy is an independent predictor of improved outcome associated with DSS and the 720,000 IU/kg dose. These results support further prospective trials with increased IL-2 dose schedules in a larger cohort of patients.

Adolescent↗
PubMed2005

The lymphoid chemokine CCL21 costimulates naive T cell expansion and Th1 polarization of non-regulatory CD4+ T cells.

CCL21 (SLC/6Ckine) is constitutively expressed by secondary lymphoid tissue and attracts CCR7-expressing mature dendritic cells and naive T cells. Recent studies demonstrated that intra-tumoral delivery of CCL21 induces tumor regression in a T cell dependent manner. CCL21 is known to mediate T cell trafficking but little is known about its function as a costimulatory molecule. Herein, we demonstrate that CCL21 costimulates expansion of CD4+ and CD8+ T cells and induces Th1 polarization. These effects were specific for naive T cells, and we show that CD4+CD25+ regulatory T cells were hyporesponsive to CCL21 induced migration, and unresponsive to CCL21 costimulation. These unique functions of CCL21 to both attract naive T cells as well as costimulate their proliferation and differentiation, suggests that CCL21 is a pivotal molecule for priming T cell responses and has therapeutic implications for local delivery of CCL21. The coordinated effects of CCL21 on T cell migration and activation may also represent a more comprehensive paradigm for the activity of other chemokines as well.

Animals↗
PubMed2005

Pox viral vaccine approaches.

Recent advances in understanding tumor-specific immunity have introduced new excitement in the clinical development of vaccines for the treatment of cancer. A better understanding of basic immunologic principles has led to a variety of techniques for enhancing tumor-specific immunity through vaccination. Approaches to antigen-specific immunotherapy have included: (1) peptides, usually in combination with various immunological adjuvants; (2) soluble proteins; (3) dendritic cells pulsed with specific antigens; (4) monoclonal antibodies; (5) recombinant plasmid DNA; (6) autologous and allogeneic tumor cells; and (7) recombinant viral vectors. This review will focus on the use of viral vectors, which offer unique advantages as both gene delivery vectors and as agents supplying additional adjuvant activity for vaccination. Viral vectors are particularly attractive for immunotherapy since they mimic natural infection and can induce potent immune responses. Replicating and nonreplicating members of the poxvirus family have been widely studied for expression of tumor antigens and other immunomodulatory genes, such as cytokines and costimulatory molecules. Although a large number of TAAs are available for insertion into viral vectors, this review will discuss the preclinical and clinical development of prostate-specific antigen (PSA) and carcinoembryonic antigen (CEA) poxviral vaccines, as models of the pox viral vaccine approach.

Antibody Formation↗
PubMed2005

Manipulating the local tumor microenvironment with poxviruses expressing costimulatory molecules.

The identification of tumor-associated antigens and new insights into the molecular and cellular basis of tumor immunology have generated a variety of vaccine strategies. Although promising in animal models, data from early-phase clinical trials have not been encouraging. These studies have documented the ability of vaccines to prime T cells, but these responses have not correlated with therapeutic effectiveness. Because the location of T-cell activation and effector activity may impact T-cell function significantly, attention has been placed on the tumor microenvironment. There is now evidence that T-cell responses may be altered in the setting of established tumor growth. To alter the balance between local immune responses and tumor growth, a vaccine regimen using direct intratumoral delivery of poxvirus vaccines expressing costimulatory molecules was developed. An initial series of clinical trials has documented the safety profile of this approach and has suggested that local and systemic immunity can be induced. Herein, we review the general rationale for this approach, discuss the results of ongoing clinical trials, and highlight critical questions that can be addressed in well-designed preclinical and clinical studies.

Cancer Vaccines↗
PubMed2005

Gene therapy with poxvirus vectors.

Poxviruses represent a heterogenous group of DNA viruses that have been utilized to express a multitude of foreign genes. An improved understanding of the virally encoded genes involved in regulating the host immune response has led to specially designed vectors with varying levels of immune induction. Vaccinia virus is the prototypical recombinant poxvirus and can generate potent antibody and T-cell responses. This property has led to the use of recombinant vaccinia viruses as a vaccine against HIV and cancer. The isolation of viruses that do not replicate in mammalian cells provides a source of recombinant vectors for when transient gene expression may be required for a longer period of time. The identification of molecular mediators of host immunity, such as cytokines, co-stimulatory molecules and chemokines, provides another method for manipulating innate and adaptive immune responses to recombinant poxvirus vectors and expressed transgenes. This review focuses on the current status of recombinant poxviruses as vectors for gene therapy of human disease.

AIDS Vaccines↗