Biomedical subjects

Jeffrey Schlom

Publications and source records attributed to Jeffrey Schlom.

At least 19 recordsLinked to original sources

PubMed2006

Acquisition of antigen presentasome (APS), an MHC/costimulatory complex, is a checkpoint of memory T-cell homeostasis.

Immunologic memory is associated with the activation and expansion of antigen-specific T cells, followed by clonal deletion and survival of a small number of memory T cells. This study establishes that effector and rested memory T cells can acquire major histocompatibility complex (MHC)/CD80 molecules (antigen presentasome [APS]) upon activation in vitro and after vaccination in vivo. We demonstrate for the first time that acquisition of APS by rested memory T cells is correlated with increased levels of apoptosis in vivo and up-regulation of caspase-3, bcl-x, bak, and bax in our in vitro studies. Moreover, our results demonstrate that memory T cells with acquired APS can indeed become cytotoxic T lymphocytes and kill other cells through perforin-mediated lysis. In addition, they retained the production of interferon gamma and T-helper 2 (Th2) type cytokines. The acquisition of APS by memory T cells might be an important checkpoint leading to the clonal deletion of the majority of effector T cells, possibly allowing the surviving cells to become long-term memory cells by default.

Animals↗

PubMed2006

Radiation modulates the peptide repertoire, enhances MHC class I expression, and induces successful antitumor immunotherapy.

Radiotherapy is one of the most successful cancer therapies. Here the effect of irradiation on antigen presentation by MHC class I molecules was studied. Cell surface expression of MHC class I molecules was increased for many days in a radiation dose-dependent manner as a consequence of three responses. Initially, enhanced degradation of existing proteins occurred which resulted in an increased intracellular peptide pool. Subsequently, enhanced translation due to activation of the mammalian target of rapamycin pathway resulted in increased peptide production, antigen presentation, as well as cytotoxic T lymphocyte recognition of irradiated cells. In addition, novel proteins were made in response to gamma-irradiation, resulting in new peptides presented by MHC class I molecules, which were recognized by cytotoxic T cells. We show that immunotherapy is successful in eradicating a murine colon adenocarcinoma only when preceded by radiotherapy of the tumor tissue. Our findings indicate that directed radiotherapy can improve the efficacy of tumor immunotherapy.

Adenocarcinoma↗

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

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

A randomized phase II study of concurrent docetaxel plus vaccine versus vaccine alone in metastatic androgen-independent prostate cancer.

PURPOSE: Docetaxel has activity against androgen-independent prostate cancer and preclinical studies have shown that taxane-based chemotherapy can enhance antitumor response of vaccines. The primary objective of this study was to determine if concurrent docetaxel (with dexamethasone) had any effect on generating an immune response to the vaccine. Secondary end points were whether vaccine could be given safely with docetaxel and the clinical outcome of the treatment regimen. EXPERIMENTAL DESIGN: The vaccination regimen was composed of (a) recombinant vaccinia virus (rV) that expresses the prostate-specific antigen gene (rV-PSA) admixed with (b) rV that expresses the B7.1 costimulatory gene (rV-B7.1), and (c) sequential booster vaccinations with recombinant fowlpox virus (rF-) containing the PSA gene (rF-PSA). Patients received granulocyte macrophage colony-stimulating factor with each vaccination. Twenty-eight patients with metastatic androgen-independent prostate cancer were randomized to receive either vaccine and weekly docetaxel or vaccine alone. Patients on the vaccine alone arm were allowed to cross over to receive docetaxel alone at time of disease progression. The ELISPOT assay was used to monitor immune responses for PSA-specific T cells. RESULTS: The median increase in these T-cell precursors to PSA was 3.33-fold in both arms following 3 months of therapy. In addition, immune responses to other prostate cancer-associated tumor antigens were also detected postvaccination. Eleven patients who progressed on vaccine alone crossed over to receive docetaxel at time of progression. Median progression-free survival on docetaxel was 6.1 months after receiving vaccine compared with 3.7 months with the same regimen in a historical control. CONCLUSION: This is the first clinical trial to show that docetaxel can be administered safely with immunotherapy without inhibiting vaccine specific T-cell responses. Furthermore, patients previously vaccinated with an anticancer vaccine may respond longer to docetaxel compared with a historical control of patients receiving docetaxel alone. Larger prospective clinical studies will be required to validate these findings.

Acid Phosphatase↗

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

Cancer vaccines: preclinical studies and novel strategies.

The development of cancer vaccines, aimed to enhance the immune response against a tumor, is a promising area of research. A better understanding of both the molecular mechanisms that govern the generation of an effective immune response and the biology of a tumor has contributed to substantial progress in the field. Areas of intense investigation in cancer immunotherapy will be discussed here, including: (1) the discovery and characterization of novel tumor antigens to be used as targets for vaccination; (2) the investigation of different vaccine-delivery modalities such as cellular-based vaccines, protein- and peptide-based vaccines, and vector-based vaccines; (3) the characterization of biological adjuvants to further improve the immunogenicity of a vaccine; and (4) the investigation of multimodal therapies where vaccines are being combined with other oncological treatments such as radiation and chemotherapy. A compilation of data from preclinical studies conducted in vitro as well as in animal models is presented here. The results from these studies would certainly support the development of new vaccination strategies toward cancer vaccines with enhanced clinical efficacy.

Animals↗

PubMed2006

Pharmacokinetics and tumor localization of (111)in-labeled HuCC49DeltaC(H)2 in BALB/c mice and athymic murine colon carcinoma xenograft.

The primary limitation of IgG antibodies for radioimmunotherapy of solid tumors is their prolonged serum half-life, leading to dose-limiting bone marrow toxicity at doses providing inadequate radiation to the tumor. A humanized C(H)2 domain-deleted variant of the anti-TAG-72 antibody CC49 (HuCC49DeltaC(H)2) has faster blood clearance, compared to the IgG, while retaining tumor targeting. We compared the pharmacokinetics and tumor uptake of (111)In-HuCC49DeltaC(H)2 in BALB/c mice and a colon carcinoma (LS-174T) mouse xenograft with that of (111)In-labeled chimeric CC49 (cCC49), an antibody with pharmacokinetics similar to the humanized CC49 parent. Immuno-conjugates of HuCC49DeltaC(H)2 and cCC49 prepared with the (111)In chelator Mx-DTPA (1-isothiocyantobenzyl-3-methyldiethylenetriaminepentaacetic acid) retained low nM affinity and radiolabeling protocols provided greater than 95% radio-incorporation with (111)In while retaining greater than 80% immunoreactivity. Blood clearance of (111)In-HuCC49DeltaC(H)2 in BALB/c mice was monoexponential (t(1/2) 5.4 hours) and faster than (111)In-cCC49 (biexponential clearance; t1/2Delta 1.5 hours; t1/2beta 162 hours). The (111)In-HuCC49DeltaC(H)2 also cleared more rapidly from the blood in the murine xenograft. At 1 hour postinjection, blood concentrations for (111)In-HuCC49DeltaC(H)2 and (111)In-cCC49 were comparable (25.5 injected dose per g [%ID/g] and 21.3 %ID/g, respectively); tumor uptake for (111)In- HuCC49DeltaC(H)2 was 7.9 %ID/g, compared to 7.5 %ID/g for (111)In-cCC49. However, at 24 hours, blood concentration for (111)In-HuCC49DeltaC(H)2 was less than (111)In-cCC49 (0.9 %ID/g versus 5.2 %ID/g, respectively) with comparable tumor retention (14.4 %ID/g versus 19.0 %ID/g, respectively). Faster blood clearance of (111)In-HuCC49DeltaC(H)2 and tumor localization comparable to that of (111)In-cCC49 provided a fourfold improved tumor-to-blood ratio for (111)In-HuCC49DeltaC(H)2 at 24 hours postinjection.

Animals↗

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

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

Vaccines with enhanced costimulation maintain high avidity memory CTL.

The avidity of Ag-specific CTL is a critical determinant for clearing viral infection and eliminating tumor. Although previous studies have demonstrated that vaccines using enhanced costimulation will enhance the level and avidity of Ag-specific T cells from naive mice, there are conflicting data about the effects of vaccines using enhanced costimulation (vector or dendritic cell based) on the survival of memory T cells. In this study we have first extended previous observations that primary vaccination with a recombinant vaccinia virus (rV-) expressing a model Ag (LacZ) and a triad of T cell costimulatory molecules (B7-1, ICAM-1, and LFA-3 (designated TRICOM)) enhances the level and avidity of T cells from naive vaccinated C57BL/6 (Thy1.2) mice. Adoptive transfer of Thy1.1 memory CD8(+) T cells into naive Thy1.2 C57BL/6 mice was followed by booster vaccinations with a recombinant fowlpox (rF-)-expressing LacZ (rF-LacZ) or booster vaccinations with rF-LacZ/TRICOM. Analysis of levels of beta-galactosidase tetramer-positive T cells and functional assays (IFN-gamma expression and lytic activity) determined that booster vaccinations with rF-LacZ/TRICOM were superior to booster vaccinations with rF-LacZ in terms of both maintenance and enhanced avidity of memory CD8(+) T cells. Antitumor experiments using a self-Ag (carcinoembryonic Ag (CEA) vaccines in CEA transgenic mice bearing CEA-expressing tumors) also demonstrated that the use of booster vaccinations with vaccines bearing enhanced costimulatory capacity had superior antitumor effects. These studies thus have implications in the design of more effective vaccine strategies.

Animals↗

PubMed2005

Identification of novel human CTL epitopes and their agonist epitopes of mesothelin.

PURPOSE: Mesothelin is overexpressed in many pancreatic and ovarian cancers, mesotheliomas, and other tumor types. Clinical trials are ongoing using immunotoxins to target mesothelin, and patients immunized with allogeneic pancreatic tumor cell lines have shown immune responses to previously defined mesothelin epitopes. The purpose of this study was to define novel mesothelin CTL epitopes and, more importantly, agonist epitopes that would more efficiently activate human T cells to more efficiently lyse human tumors. EXPERIMENTAL DESIGN AND RESULTS: Two novel mesothelin HLA-A2 epitopes were defined. T-cell lines generated from one of these epitopes were shown to lyse pancreatic and ovarian tumor cells. Several agonist epitopes were defined and were shown to (a) have higher affinity and avidity for HLA-A2, (b) activate mesothelin-specific T cells from normal individuals or cancer patients to a greater degree than the native epitope in terms of induction of higher levels of IFN-gamma and the chemokine lymphotactin, and (c) lyse several mesothelin-expressing tumor types in a MHC-restricted manner more effectively than T cells generated using the native peptide. External beam radiation of tumor cells at nontoxic levels was shown to enhance the expression of mesothelin and other accessory molecules, resulting in a modest but statistically significant increase in tumor cell lysis by mesothelin-specific T cells. CONCLUSIONS: The identification of novel CTL agonist epitopes supports and extends observations that mesothelin is a potential target for immunotherapy of pancreatic and ovarian cancers, as well as mesotheliomas.

Carcinoma, Squamous Cell↗

PubMed2005

Potential approach to immunotherapy of chronic lymphocytic leukemia (CLL): enhanced immunogenicity of CLL cells via infection with vectors encoding for multiple costimulatory molecules.

Chronic lymphocytic leukemia (CLL) is a disease of CD5(+) B lymphocytes (designated as CLL cells) that are inefficient antigen-presenting cells. Their poor ability to present antigens to the T cells, largely due to an inadequate costimulatory capacity, is manifested as a failure to stimulate proliferation of both allogeneic and autologous T cells. We have investigated the ability of in vitro manipulated CLL cells, via hyperexpression of a triad of costimulatory molecules (B7-1, intercellular adhesion molecule 1 [ICAM-1], and leukocyte-function-associated antigen 3 [LFA-3], designated TRICOM), to stimulate effective antitumor T-cell responses. A recombinant modified vaccinia virus strain Ankara (MVA), which is a highly attenuated, replication-impaired virus variant, was successfully used to infect and deliver the simultaneous expression of the 3 human costimulatory molecules in TRICOM on the surface of the CLL cells. Proliferation of allogeneic and autologous T cells was observed when MVA-TRICOM-infected CLL cells were used as stimulators in proliferation assays. Cytotoxic T lymphocytes, generated in vitro by stimulation of autologous T cells with MVA-TRICOM-infected CLL cells, showed cytotoxicity against unmodified/uninfected CLL cells. Therefore, our findings suggest that the use of CLL cells infected ex vivo with MVA-TRICOM or direct injection of MVA-TRICOM in patients with CLL has potential for the immunotherapy of CLL.

Aged↗

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

The requirement of multimodal therapy (vaccine, local tumor radiation, and reduction of suppressor cells) to eliminate established tumors.

PURPOSE: Numerous immune-based strategies are currently being evaluated for cancer therapy in preclinical models and clinical trials. Whereas many strategies look promising in preclinical models, they are often evaluated before or shortly following tumor implantation. The elimination of well-established tumors often proves elusive. Here we show that a multimodal immune-based therapy can be successfully employed to eliminate established tumors. EXPERIMENTAL DESIGN: This therapy consists of vaccines directed against a self-tumor-associated antigen, the use of external beam radiation of tumors to up-regulate Fas on tumor cells, and the use of a monoclonal antibody (mAb) to reduce levels of CD4+CD25+ suppressor cells. RESULTS: We show here for the first time that (a) antigen-specific immune responses induced by vaccines were optimally augmented when anti-CD25 mAb was given at the same time as vaccination; (b) anti-CD25 mAb administration in combination with vaccines equally augmented T-cell immune responses specific for a self-antigen as well as those specific for a non-self antigen; (c) whereas the combined use of vaccines and anti-CD25 mAb enhanced antigen-specific immune responses, it was not sufficient to eliminate established tumors; (d) the addition of external beam radiation of tumors to the vaccine/anti-CD25 mAb regimen was required for the elimination of established tumors; and (e) T cells from mice receiving the combination therapy showed significantly higher T-cell responses specific not only for the antigen in the vaccine but also for additional tumor-derived antigens (p53 and gp70). CONCLUSIONS: These studies reported here support the rationale for clinical trials employing multimodal immune-based therapies.

Animals↗

PubMed2005

Multiple costimulatory modalities enhance CTL avidity.

Recent studies in both animal models and clinical trials have demonstrated that the avidity of T cells is a major determinant of antitumor and antiviral immunity. In this study, we evaluated several different vaccine strategies for their ability to enhance both the quantity and avidity of CTL responses. CD8(+) T cell quantity was measured by tetramer binding precursor frequency, and avidity was measured by both tetramer dissociation and quantitative cytolytic function. We have evaluated a peptide, a viral vector expressing the Ag transgene alone, with one costimulatory molecule (B7-1), and with three costimulatory molecules (B7-1, ICAM-1, and LFA-3), with anti-CTLA-4 mAb, with GM-CSF, and combinations of the above. We have evaluated these strategies in both a foreign Ag model using beta-galactosidase as immunogen, and in a "self" Ag model, using carcinoembryonic Ag as immunogen in carcinoembryonic Ag transgenic mice. The combined use of several of these strategies was shown to enhance not only the quantity, but, to a greater magnitude, the avidity of T cells generated; a combination strategy is also shown to enhance antitumor effects. The results reported in this study thus demonstrate multiple strategies that can be used in both antitumor and antiviral vaccine settings to generate higher avidity host T cell responses.

Adjuvants, Immunologic↗

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

Phase I study of immunization with dendritic cells modified with fowlpox encoding carcinoembryonic antigen and costimulatory molecules.

PURPOSE: To determine the safety and immunologic and clinical efficacy of a dendritic cell vaccine modified to hyperexpress costimulatory molecules and tumor antigen. EXPERIMENTAL DESIGN: In this phase I study, we administered one or two cycles of four triweekly s.c./intradermal injections of ex vivo generated dendritic cells modified with a recombinant fowlpox vector encoding carcinoembryonic antigen (CEA) and a triad of costimulatory molecules [rF-CEA(6D)-TRICOM]. Controls consisted of immature dendritic cells loaded with tetanus toxoid and a HLA A2-restricted peptide derived from cytomegalovirus pp65 protein. RESULTS: Fourteen patients (11 with colorectal cancer and 3 with non-small cell lung cancer) were enrolled and 12 completed at least one cycle of immunization. There were no grade 3/4 toxicities directly referable to the immunizations. One patient had a decrease in the CEA level from 46 to 6.8 and a minor regression in adenopathy that occurred several months after completion of the immunizations. Five other patients were stable through at least one cycle of immunization (3 months). Direct analysis of peripheral blood mononuclear cells using the ELISpot assay showed an increase in the frequency of CEA-specific T cells in 10 patients (range, 10-541 CEA-specific cells/10(5) peripheral blood mononuclear cells). There was a trend for a greater peak frequency of CEA-specific T cells among those with either a minor response or a stable disease following at least one cycle of therapy. A second cycle was not associated with higher T-cell frequencies. Cytokine flow cytometry showed CEA-specific immune response among both CD4(+) and CD8(+) T cells in all immune responders. CONCLUSION: This immunization strategy is safe and activates potent CEA-specific immune responses.

B7-1 Antigen↗