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Kwong-Yok Tsang

Publications and source records attributed to Kwong-Yok Tsang.

15 recordsLinked to original sources
PubMed2006

Combination chemotherapy and radiation of human squamous cell carcinoma of the head and neck augments CTL-mediated lysis.

PURPOSE: The combination of systemic multiagent chemotherapy (5-fluorouracil + cisplatin) and tumor irradiation is standard of care for head and neck squamous cell carcinoma (HNSCC). Furthermore, it has been shown that sublethal doses of radiation or chemotherapeutic drugs in diverse cancer types may alter the phenotype or biology of neoplastic cells, making them more susceptible to CTL-mediated cytotoxicity. However, little is known about the potential synergistic effect of drug plus radiation on CTL killing. Here, we examined whether the combination of two chemotherapeutics and ionizing radiation enhanced CTL-mediated destruction of HNSCC more so than either modality separately, as well as the basis for the enhanced tumor cell lysis. EXPERIMENTAL DESIGN: Several HNSCC cell lines with distinct biological features were treated with sublethal doses of cisplatin and 5-fluorouracil for 24 hours and with 10-Gy irradiation. Seventy-two hours postirradiation, tumor cells were exposed to an antigen-specific CD8+ CTL directed against carcinoembryonic antigen or MUC-1. RESULTS: In three of three tumor cell lines tested, enhanced CTL activity was observed when the two modalities (chemotherapy and radiation) were combined as compared with target cells exposed to either modality separately. CTL-mediated lysis was MHC restricted and antigen specific and occurred almost entirely via the perforin pathway. Moreover, the combination treatment regimen led to a 50% reduction in Bcl-2 expression whereas single modality treatment had little bearing on the expression of this antiapoptotic gene. CONCLUSIONS: Overall, these results reveal that (a) CTL killing can be enhanced by combining multiagent chemotherapy and radiation and (b) combination treatment enhanced or sensitized HNSCC to the perforin pathway, perhaps by down-regulating Bcl-2 expression. These studies thus form the rational basis for clinical trials of immunotherapy concomitant with the current standard of care of HNSCC.

Antigens, Neoplasm↗
PubMed2006

Costimulatory molecules as adjuvants for immunotherapy.

Tumor-associated antigens (TAAs) are by definition either weakly immunogenic or functionally nonimmunogenic. Therefore, efforts have concentrated on the development of vaccine strategies in which the presentation of TAAs to the immune system results in far greater activation of T cells than that occurring naturally in the host. Several strategies are being explored in our laboratory and others to enhance the immunogenicity of TAAs. These are: (a) placing the gene coding for the tumor antigen, as a transgene, into poxvirus vectors. (b) The use of diversified prime and boost vaccine strategies employing two different types of poxvirus vectors. (c) The use of T-cell costimulation; accomplished by placing transgenes for different T-cell costimulation molecules into viral vectors along with the transgenes for the TAA. (d) Altering the amino acid sequence of the TAA to enhance the host immune response. (e) The use of cytokines, and in particular GM-CSF, as a biologic adjuvant. This review will focus on the current state of the use of costimulatory molecules as adjuvants for immunotherapy, and in particular, as immunomodulators for cancer vaccines.

Adjuvants, Immunologic↗
PubMed2006

TRICOM vector based cancer vaccines.

For the immune system to mount an effective antitumor T-cell response, an adequate number of T-cells specific for the antigens expressed by the malignancy must be activated [1]. Since most antigens expressed by tumors are "self"-antigens, tumor antigens often lack endogenous immunogenicity and thus do not sufficiently activate T-cells to levels that can mediate tumor eradication. In addition, virtually all solid tumor cells lack the costimulatory molecules necessary to activate tumor-specific T-cells. Approaches that stimulate immune responses to these tumor antigens have the potential to alter this poor responsiveness. This theory has promoted the use of active immunotherapy to generate immune responses against tumor-associated antigens (TAAs) for the treatment of cancer. As one such vaccine strategy, we have utilized poxviruses as delivery vehicles for TAAs in combination with T-cell costimulatory molecules. Initial studies have demonstrated that the insertion of costimulatory molecule trangenes into viral vectors, along with a TAA transgene, greatly enhances the immune response to the antigen. Using this approach, a TRIad of COstimulatory Molecules (TRICOM; B7-1, ICAM-1 and LFA-3) has been shown to enhance T-cell responses to TAAs to levels far greater than any one or two of the costimulatory molecules in combination. In this article, preclinical findings and recent clinical applications of TRICOM-based vaccines as a cancer immunotherapy are reviewed.

Animals↗
PubMed2005

Induction of higher-avidity human CTLs by vector-mediated enhanced costimulation of antigen-presenting cells.

The efficacy of antigen-specific CD8(+) CTLs depends not only on the quantity of CTLs generated but also perhaps, more importantly, on the avidity of the CTLs. To date, however, no strategy has been shown to preferentially induce higher-avidity human CTLs. In the present study, antigen-presenting cells (APC) generated from human peripheral blood mononuclear cells were infected with a recombinant avipox vector (rF-) containing the transgenes for a triad of costimulatory molecules (human B7.1, intercellular adhesion molecule-1, and LFA-3, designated as rF-TRICOM) and then used to elicit peptide-specific CTLs from autologous T cells. Compared with peptide-pulsed noninfected APCs or peptide-pulsed APCs infected with wild-type vector, peptide-pulsed APCs infected with rF-TRICOM induced not only more CTLs but also higher-avidity CTLs; this was shown by tetramer staining, tetramer dissociation, IFN-gamma production, and cytolytic assays. Peptide-pulsed rF-TRICOM-infected dendritic cells were also shown to induce CTLs with a >10-fold higher avidity than CTLs induced using CD40L-matured dendritic cells; the use of peptide-pulsed CD40L-matured dendritic cells infected with rF-TRICOM as APCs induced CTLs of even greater avidity. To our knowledge, these studies are the first to show a methodology to induce higher-avidity human CTLs and have implications for the development of more efficient vaccines for a range of human cancers.

Antibody Affinity↗
PubMed2005

Combining a recombinant cancer vaccine with standard definitive radiotherapy in patients with localized prostate cancer.

PURPOSE: Many patients with clinically localized prostate cancer develop biochemical failure despite excellent local therapy perhaps due to occult metastatic disease. One potential solution is the utilization of a well-tolerated systemic therapy (e.g., vaccine) in concert with local therapy. EXPERIMENTAL DESIGN: We present a randomized phase II clinical trial designed to determine if a poxviral vaccine encoding prostate-specific antigen (PSA) can induce a PSA-specific T-cell response when combined with radiotherapy in patients with clinically localized prostate cancer. Thirty patients were randomized in a 2:1 ratio into vaccine plus radiotherapy or radiotherapy-only arms. Those patients in the combination arm received a "priming" vaccine with recombinant vaccinia (rV) PSA plus r V containing the T-cell costimulatory molecule B7.1 (rV-B7.1) followed by monthly booster vaccines with recombinant fowlpox PSA. The vaccines were given with local granulocyte-macrophage colony-stimulating factor and low-dose systemic interleukin-2. Standard external beam radiation therapy was given between the fourth and the sixth vaccinations. RESULTS: Seventeen of 19 patients in the combination arm completed all eight vaccinations and 13 of these 17 patients had increases in PSA-specific T cells of at least 3-fold versus no detectable increases in the radiotherapy-only arm (P < 0.0005). There was also evidence of de novo generation of T cells to well-described prostate-associated antigens not found in the vaccine, providing indirect evidence of immune-mediated tumor killing. The vaccine was well tolerated. CONCLUSION: This vaccine regimen can be safely given in patients undergoing radiation therapy for localized prostate cancer, with the majority of patients generating a PSA-specific cellular immune response to vaccine.

Aged↗
PubMed2005

Antiandrogen, vaccine and combination therapy in patients with nonmetastatic hormone refractory prostate cancer.

PURPOSE: There is no current standard treatment for patients with prostate cancer who have received hormonal therapy but have an increasing prostate specific antigen (PSA) without radiographic evidence of metastasis. This trial was designed to analyze toxicity, immunogenicity and time to treatment failure using vaccine, antiandrogen therapy or their sequential use. MATERIALS AND METHODS: A total of 42 patients were randomized to receive vaccine vs antiandrogen therapy with nilutamide. The vaccine consisted of recombinant vaccinia viruses containing the PSA and B7.1 costimulatory genes as prime vaccinations, and avipox-PSA as boosters. After 6 months patients with an increasing PSA and no metastasis may receive a combination of both treatments. RESULTS: Three patients on nilutamide were removed from study secondary to grade 3 toxicities but no grade 3 toxicities were attributed to vaccine. In the vaccine arm median time to treatment failure was 9.9 months with 13 of 21 decreases in PSA velocity vs 7.6 months with 16 of 21 decreases in PSA velocity in the nilutamide arm (p =0.28). Of the patients in the nilutamide arm 8 had vaccine added at the time of PSA progression. Median time to treatment failure with combined therapy was 5.2 months, with a median duration from study entry of 15.9 months. Of the patients in the vaccine arm 12 had nilutamide added at the time of PSA progression. Median time to treatment failure with combined therapy was 13.9 months and a median of 25.9 months from initiation of therapy. CONCLUSIONS: Further studies are merited to investigate the role of combining vaccine with antiandrogen therapy or vaccine followed by vaccine plus antiandrogen therapy in this patient population.

Aged↗
PubMed2004

Phase I study of sequential vaccinations with fowlpox-CEA(6D)-TRICOM alone and sequentially with vaccinia-CEA(6D)-TRICOM, with and without granulocyte-macrophage colony-stimulating factor, in patients with carcinoembryonic antigen-expressing carcinomas.

PURPOSE: Our previous clinical experience with vaccinia and replication-defective avipox recombinant carcinoembryonic antigen (CEA) vaccines has demonstrated safety and clinical activity with a correlation between CEA-specific immune response and survival. Preclinical evidence demonstrated that the addition of the transgenes for three T-cell costimulatory molecules (B7-1, ICAM-1, LFA-3, designated TRICOM) results in a significant improvement in antigen-specific T-cell responses and antitumor activity. We describe here the first trial in humans of the CEA-TRICOM vaccines (also including an enhancer agonist epitope within the CEA gene). PATIENTS AND METHODS: Fifty-eight patients with advanced CEA-expressing cancers were accrued to eight cohorts that involved vaccinations with the following: replication-defective fowlpox recombinant (rF)-CEA(6D)-TRICOM; primary vaccination with recombinant vaccinia (rV)-CEA(6D)-TRICOM plus rF-CEA(6D)-TRICOM booster vaccinations; and rV-CEA(6D)-TRICOM and then rF-CEA(6D)-TRICOM, plus granulocyte-macrophage colony-stimulating factor (GM-CSF) with vaccines, or with divided doses of vaccine with GM-CSF. Vaccines were administered every 28 days for six doses and then once every 3 months. Reverting to treatments every 28 days was allowed if patients progressed on the 3-month schedule. RESULTS: In this phase I study, no significant toxicity was observed. Twenty-three patients (40%) had stable disease for at least 4 months, with 14 of these patients having prolonged stable disease (> 6 months). Eleven patients had decreasing or stable serum CEA, and one patient had a pathologic complete response. Enhanced CEA-specific T-cell responses were observed in the majority of patients tested. CONCLUSION: We demonstrated that the CEA-TRICOM vaccines are safe and can generate significant CEA-specific immune responses, and they seem to have clinical benefit in some patients with advanced cancer.

Adult↗
PubMed2004

Sublethal irradiation of human tumor cells modulates phenotype resulting in enhanced killing by cytotoxic T lymphocytes.

Local radiation of tumor masses is an established modality for the therapy of a range of human tumors. It has recently been recognized that doses of radiation, lower than or equal to those that cause direct cytolysis, may alter the phenotype of target tissue by up-regulating gene products that may make tumor cells more susceptible to T-cell-mediated immune attack. Previously, we demonstrated that radiation increased Fas (CD95) gene expression in carcinoembryonic antigen (CEA)-expressing murine tumor cells, which consequently enhanced their susceptibility to CEA-specific CTL-mediated killing. The present study was designed to determine whether these phenomena also occur with human tumor cells. Here, 23 human carcinoma cell lines (12 colon, 7 lung, and 4 prostate) were examined for their response to nonlytic doses of radiation (10 or 20 Gy). Seventy-two hours postirradiation, changes in surface expression of Fas (CD95), as well as expression of other surface molecules involved in T-cell-mediated immune attack such as intercellular adhesion molecule 1, mucin-1, CEA, and MHC class I, were examined. Twenty-one of the 23 (91%) cell lines up-regulated one or more of these surface molecules postirradiation. Furthermore, five of five irradiated CEA(+)/A2(+) colon tumor cells lines demonstrated significantly enhanced killing by CEA-specific HLA-A2-restricted CD8(+) CTLs compared with nonirradiated counterparts. We then used microarray analysis to broaden the scope of observed changes in gene expression after radiation and found that many additional genes had been modulated. These up-regulated gene products may additionally enhance the tumor cells' susceptibility to T-cell-mediated immune attack or serve as additional targets for immunotherapy. Overall, the results of this study suggest that nonlethal doses of radiation can be used to make human tumors more amenable to immune system recognition and attack and form the rational basis for the combinatorial use of cancer vaccines and local tumor irradiation.

Carcinoembryonic Antigen↗
PubMed2004

A human cytotoxic T-lymphocyte epitope and its agonist epitope from the nonvariable number of tandem repeat sequence of MUC-1.

PURPOSE: MUC-1/DF-3 remains an attractive target for vaccine therapy. It is overexpressed in the majority of human carcinomas and multiple myeloma. Clinical trials using MUC-1-based vaccines have demonstrated safety, clinical responses, and the induction of T-cell responses directed against MUC-1. Previous studies in experimental models and in clinical trials have demonstrated that altering the amino acid sequence of a "self" epitope can lead to the generation of an enhancer agonist epitope capable of eliciting stronger T-cell responses than the native epitope can. EXPERIMENTAL DESIGN AND RESULTS: We describe here the identification of six novel class I HLA-A2 epitopes of MUC-1 that reside outside of the variable number of tandem repeat region. Each is shown to have the ability to activate human T cells as measured by IFN-gamma production. One epitope (ATWGQDVTSV, at amino acid position 92-101 and designated P-92), which demonstrated the highest level of binding to HLA-A2 and which induced the highest level of IFN-gamma in human T cells, was further studied for the generation of potential enhancer agonist epitopes. Of four potential agonists identified, one epitope (ALWGQDVTSV, designated P-93L) was identified as an enhancer agonist. Compared with the native P-92 peptide, the P-93L agonist (a). bound HLA-A2 at lower peptide concentrations, (b). demonstrated a higher avidity for HLA-A2 in dissociation assays, (c). when used with antigen-presenting cells, induced the production of more IFN-gamma by T cells than with the use of the native peptide, and (d). was capable of more efficiently generating MUC-1-specific human T-cell lines from normal volunteers and pancreatic cancer patients. Most importantly, the T-cell lines generated using the agonist epitope were more efficient than those generated with the native epitope in the lysis of targets pulsed with the native epitope and in the lysis of HLA-A2 human tumor cells expressing MUC-1. CONCLUSIONS: In addition to the identification of novel MUC-1 epitopes outside the variable number of tandem repeat region, the studies reported here describe the first agonist epitope of MUC-1. The employment of this agonist epitope in peptide-, protein-, and vector-based vaccines may well aid in the development of effective vaccines for a range of human cancers.

Amino Acid Sequence↗
PubMed2004

Human B cells that hyperexpress a triad of costimulatory molecules via avipox-vector infection: an alternative source of efficient antigen-presenting cells.

Dendritic cells (DCs) are the most potent of the antigen-presenting cells (APCs). Preparation of sufficient numbers of mature DCs, however, is both costly and time-consuming. We have examined here the possibility of using an alternative source of APCs that would be easier to obtain, would not require extensive culture, and thus would be more applicable to human immunotherapy protocols. We show here that freshly isolated human B cells can be efficiently infected by a replication-defective fowlpox recombinant vector, designated rF-TRICOM (TRIad of COstimulatory Molecules), to markedly increase surface expression of the human costimulatory molecule B7-1 and moderately increase expression of intercellular adhesion molecule-1 (ICAM-1) and leukocyte function-associated antigen-3 (LFA-3). Peptide-pulsed rF-TRICOM-infected B cells were highly efficient in activating antigen-specific human T cells and shown to be superior to the use of CD40L in enhancing APC potency. Moreover, when infection of freshly isolated B cells with rF-TRICOM was combined with CD40L, a still further marked enhancement of the antigen-presenting potency was observed. Ex vivo-generated antigen-specific T cells activated in this manner might be applied to experimental protocols or used for adoptive transfer in immunotherapy protocols.

Antigen-Presenting Cells↗
PubMed2003

Enhanced expression of lymphotactin by CD8+ T cells is selectively induced by enhancer agonist peptides of tumor-associated antigens.

Human tumor-associated antigens (TAAs) are weak immunogens. One strategy for increasing the immunogenicity of TAAs is to generate altered peptide ligands. In the studies reported here, microarray technology has been used to compare gene expression profiles of a human T cell line that was derived from the peripheral blood of a cancer patient vaccinated with a carcinoembryonic antigen (CEA)-based vaccine. We compared the gene expression profiles of this CEA-specific CD8 T cell line when (a) stimulated with the native peptide used to derive this line vs. no peptide, and (b) stimulated with its TCR enhancer agonist epitope vs. no peptide. The results demonstrate that the effect on the T cell line, when stimulated with the agonist peptide, is not an enhanced quantitative expression of the same genes or gene sets induced by the native peptide, but is rather a nearly reciprocal upregulation of different gene sets. The gene for the chemokine lymphotactin, which was overexpressed only in T cells stimulated with the agonist peptide, stood out above all others. This finding was extended using other T cell lines, and another set of agonist and native peptides from another TAA. ELISPOT and ELISA assays for lymphotactin confirmed and extended these findings. These studies suggest a potential role for lymphotactin in the T-cell activation processes and subsequent anti-tumor events.

Animals↗
PubMed2003

Strategies for the development of PSA-based vaccines for the treatment of advanced prostate cancer.

Prostate cancer is the second leading cause of cancer death in males in the USA. Vaccine strategies represent a novel therapeutic approach. One potential target for a prostate cancer vaccine is prostate-specific antigen (PSA), due to its restricted expression in prostate cancer and normal prostatic epithelial cells. A number of PSAspecific epitopes have been identified that can activate cytotoxic T-lymphocytes (CTLs) and in turn lead to the killing of tumor targets by the peptide-specific CTLs. Strategies have now been employed in clinical trials using RNA-pulsed dendritic cell vaccines, recombinant protein vaccines, and recombinant viral vector delivery of vaccines. Newer approaches incorporating costimulatory molecules that enhance Tcell activation are also being investigated.

Cancer Vaccines↗
PubMed2003

Differential gene expression profiles in a human T-cell line stimulated with a tumor-associated self-peptide versus an enhancer agonist peptide.

PURPOSE: Previous studies have shown that a specific 9-mer amino acid epitope (designated CAP-1) of the human "self" tumor-associated carcinoembryonic antigen can be used to stimulate CD8+ T cells from peripheral blood mononuclear cells of carcinoma patients vaccinated with pox vector-based carcinoembryonic antigen vaccines. A T-cell receptor agonist epitope of CAP-1 (designated CAP1-6D) has been shown to enhance the stimulation of T cells over levels obtained using CAP-1. The purpose of this study was to analyze gene expression profiles in T cells stimulated with the native CAP-1 versus the agonist CAP1-6D peptide. EXPERIMENTAL DESIGN: Microarray analyses were conducted to analyze differential gene expression profiles of a T-cell line stimulated with native versus agonist peptides. RESULTS: Numerous genes and gene clusters are identified as differentially expressed as a consequence of stimulation with the agonist peptide versus the native peptide; two genes, however, stand out in magnitude: the chemokine lymphotactin and granzyme B. In particular, lymphotactin expression is >12 times more pronounced in agonist-stimulated T cells. An ELISA assay was developed that confirmed marked lymphotactin secretion in T cells when stimulated with the agonist versus the native peptide. A chemotaxis assay also demonstrated the biological activity of the lymphotactin produced. CONCLUSIONS: To our knowledge, these are the first studies of gene expression profiles of a defined T-cell line in response to stimulation with a defined antigen. They are also the first to compare, via cDNA microarray, responses of a T-cell line to (a) a tumor-associated self-antigen and (b) a native epitope versus an agonist epitope.

Antigens, Neoplasm↗
PubMed2002

Identification and characterization of a human agonist cytotoxic T-lymphocyte epitope of human prostate-specific antigen.

One potential target of vaccine therapy for human prostate cancer is the prostate-specific antigen (PSA). One strategy to enhance the immunogenicity of a self-antigen such as PSA is to develop agonist epitopes that are potentially more immunogenic. The studies described here report the design and analysis of an agonist epitope designated PSA-3A ("A" for agonist) of the PSA-3 CTL epitope. Studies demonstrate that when compared with the native PSA-3 epitope, the PSA-3A agonist demonstrates enhanced binding to the MHC class I A2 allele as well as enhanced stability of the peptide-MHC complex. T-cell lines generated with either the PSA-3 or the PSA-3A peptide showed higher levels of lysis of targets pulsed with the PSA-3A peptide than those targets pulsed with the PSA-3 peptide; this was observed when both the concentration of peptide and the ratio of effector to target cells were titrated. T cells stimulated with dendritic cells (DCs) pulsed with PSA-3A peptide produced higher levels of IFN-gamma than did DCs pulsed with PSA-3 peptide; however, no increase in apoptosis was seen in T cells stimulated with the PSA-3A agonist compared with those stimulated with PSA-3. Human T-cell lines generated with the PSA-3A agonist had the ability to lyse human prostate carcinoma cells expressing native PSA in an MHC-restricted manner. Recombinant vaccinia viruses were also constructed that contained the entire PSA transgene with and without the single amino acid change that constitutes the PSA-3A epitope; DCs infected with the recombinant vector containing the agonist amino acid change within the entire PSA gene (designated rV-PSA-3A) were more effective than DCs infected with the rV-PSA vector in enhancing IFN-gamma production by T cells. Finally, the PSA-3A agonist was shown to induce higher levels of T-cell activation, compared with the PSA-3 peptide, in an in vivo model using HLA-A2.1/K(b) transgenic mice. These studies thus demonstrate the potential use of the PSA-3A agonist epitope in both peptide- and vector-mediated immunotherapy protocols for prostate cancer.

Animals↗