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Current TVR Projects

Evaluation of safety and correlative immunogenicity studies of CMVPepVax co-injected with PF03512676 adjuvant in recipients of allogeneic stem cell transplant
 
CMVPepVax to protect stem cell transplant recipients from Cytomegalovirus infection-University of Minnesota collaborative study
 
Control of CMV infection in allogeneic stem cell transplant recipients using attenuated MVA-based CMV subunit vaccine
 
A Phase I study of a p53-MVA vaccine for advanced colon, gastric and pancreatic cancer
 
HCMV vaccine Produced from BAC-MVA that blocks epithelial and fibroblast entry
 
Evaluation of protective CMV vaccines in rhesus macaques
 
IDO-silencing Salmonella therapy for the treatment of primary and metastatic PDAC
 
WT1 as a biomarker topredict relapse in patients with acute leukemia and MDS
 
Project 9
Optimizing shRNA approaches for control of Lymphoma using Salmonella delivery systems
 

Project 1

Evaluation of safety and correlative immunogenicity studies of CMVPepVax co-injected with PF03512676 adjuvant in recipients of allogeneic stem cell transplant

Allogeneic hematopoietic cell transplantation (HCT) is an effective therapy for a range of life-threatening hematologic malignancies. Since the inception of HCT four decades ago, more than 800,000 patients have been transplanted worldwide. The majority of allogeneic HCT recipients are patients with leukemia, lymphoma, myeloma, myelodysplasia, bone marrow failure conditions, severe red blood cell disorders or solid tumors. In allogeneic HCT, hematopoietic cells are obtained from suitably HLA matched related or unrelated volunteer donors (URD) or from umbilical cord blood. Pretransplant, the patient is treated with chemotherapy, with or without radiation therapy, to eradicate cancerous cells, and for suppressing the patient’s immune system to prevent it from attacking donor hematopoietic cells. As a result, patients are vulnerable to pathogens termed opportunistic infections. Among them is cytomegalovirus (CMV) infection, which is the cause of significant morbidity at early and late times post-HCT in the recovery of immune-compromised recipients. CMV is a highly prevalent β-herpes virus that rarely causes disease in healthy individuals. In contrast, HCT patients are vulnerable to herpes virus infections, including CMV, as a result of immunosuppression associated with treatment strategies aimed at preventing rejection or graft-versus-host disease (GVHD). Despite advances in development of antiviral drugs and substantial reduction of CMV disease with pre-emptive antiviral treatment, CMV remains one of the most difficult-to-treat infections post-HCT, which strongly impacts the course of recovery and success rate of this curative treatment for cancer. Furthermore, antiviral therapy has major side effects, including nephrotoxicity, neutropenia and delayed immune reconstitution, which exposes HCT recipients to other opportunistic viral, bacterial and fungal infections. Additionally, costs associated with usage of antivirals are significant, with a single course reaching $25,000. Next-generation prophylactic antiviral drugs are undergoing clinical testing and might effectively reduce CMV infection rates, although a phase III study assessing a promising antiviral did not show a reduction in CMV infection. Thus, alternative strategies to control CMV are eagerly sought, since use of antivirals does not address the major risks of late-onset CMV disease, including reactivation and failure to reconstitute CMV-specific immunity. Substituting toxic antivirals with a vaccine that harnesses the abundant native immune response to CMV may improve outcomes for HCT recipients. Our group has identified a repertoire of CD8 T cell epitopes from the CMV-pp65 protein that can expand human CMV-pp65-specific memory CD8 T cells in vitro. In HLA A*0201 transgenic mice, two candidate vaccine peptides containing the HLA A*0201  pp65495-503 CD8+ T cell epitope fused to universal T-help epitopes (either the synthetic PADRE or a natural Tetanus sequence) showed favorable immunogenicity profiles. The vaccine peptides were named PADRE-CMV and Tet-CMV, respectively, and were developed with support of the National Cancer Institute sponsored Rapid Access to Interventional Development (NCI-RAID, currently called NCI-NExT). Co-injection with PF-03512676 adjuvant (a synthetic single stranded DNA containing bacterial CpG DNA motifs with immunostimulatory activity, produced by Pfizer) further augmented activity at a lower vaccine dose. cGMP-grade PADRE-CMV (NSC-721433) and Tet-CMV (NSC-721434) vials were produced, tested for stability and preclinically assessed for toxicology at all investigated dosages (Southern Research Institute). After obtaining approval from FDA (BB-IND13124), PADRE-CMV and Tet-CMV, with or without PF-03512676 adjuvant were clinically evaluated for safety and immunogenicity. The phase Ib dose-escalation clinical trial (registry number: NCT00722839@www.clinicaltrials.gov) was conducted in HLA A*0201 healthy adults and indicated that the CMV peptides co-injected with PF-03512676 were safe and immunogenic. In particular, Tet-CMV + PF-03512676 had a favorable safety profile and led to substantial expansion of pp65495-503 T cells after two subcutaneous vaccine injections. The achievement of the central goal of our phase Ib study in healthy adults supports further evaluation of Tet-CMV combined with PF-03512676 (renamed CMVPepVax)  in the HCT setting. A summary of the results of the trial was published in 2012 (see La Rosa et al, 2012). These promising results are the basis for CMVPepVax as a therapeutic vaccine, to improve outcomes of HCT recipients with uncontrolled CMV viremia.
 
Summary of IRB12022-approved Phase Ib Randomized Open Label Clinical Trial in HCT recipients. The phase Ib pilot trial is powered to evaluate safety of administering CMVPepVax to HLA matched allogeneic (MRD or URD) patients at risk for CMV complications (NCT01588015@www.clinicaltrials.gov). The target enrollment is ≤36 patients with the goal of assessing feasibility to conduct a larger phase II trial (see Project 2). Computer generated 1:1 randomization assigns each patient either to the vaccine or to the non-interventional (prospective) immune monitoring arm. In the vaccine arm, patients will be vaccinated twice (d28 and d56 post-HCT) with CMVPepVax. Safety (10 endpoint) will include continuous post-immunization assessment until d100 for GVHD and as necessary until d180 for any AE in ≤18 immunized patients. We initiated this trial and have administered vaccine to three patients and enrolled an additional four observational patients. CMV-specific vaccine function (20 endpoint) will be monitored in all enrolled patients in both trial arms (n≤36) biweekly from d28-100 post-HCT and every 30d thereafter by measuring numbers of CD8+ T cells binding to HLA-tetramers. Additional correlative studies will include assessment of PD-1 expression on CMV-specific T cells (as a measure of exhaustion), measuring proliferative capacity (CFSE dilution method) by cell division and cell death. Reduction of apoptosis markers and increased proliferation of CMV-specific T cells is expected in vaccinated compared to unvaccinated patients. Immune assessments will be done in batch at the conclusion of six months of observation. Pending success of the pilot trial, NCI will provide a fresh lot of vaccine to support a large multi-center phase II study jointly with the University of Minnesota Comprehensive Cancer Center (see Project 2).

Personnel
Ryotaro Nakamura, M.D.
Principal Investigator of IRB12022
 
Jennifer Drake, C.C.R.P.
Study Coordinator

Cindy Slape, R.N.
Clinical Research Nurse
 
Corinna La Rosa, Ph.D.
Associate Research Professor
Conducts the laboratory investigations

Staff of the Department of Hematology & Hematopoietic Cell Transplantation
 

Project 2

CMVPepVAX to protect stem cell transplant recipients from CMV infection
 
Pending success of the pilot trial, the National Cancer Institute will provide a fresh lot of CMVPepVax to support a multicenter phase II study jointly with the University of Minnesota Comprehensive Cancer Center. We propose two phase II trials in hematopoietic cell transplantation (HCT) with the goal of preventing cytomegalovirus (CMV) reactivation. We will conduct a randomized placebo-controlled phase II study (Trial 1) powered to test the primary endpoint of reduced CMV reactivation in  matched related donor (MRD) HCT. Nested within this trial, we will assess immunologic efficacy of vaccinating the MRD to augment levels and function of CMV immunity that are concurrently boosted by the vaccine in HCT recipients. Immunologic 20 endpoints will be quantified by frequency measurements of CMV-specific T cells using HLA tetramers and functional studies with T-box transcription factors, T-bet and Eomes that will assess improved effector function in vaccinated patients. Trial 2 will test protective function of CMVPepVax in higher risk unrelated donor (URD) or umbilical cord blood (UCB) recipients. This randomized trial will address a broad range of URD settings, stratified as low risk 8/8 HLA match, or higher risk 7/8 match URD, or lesser matched UCB grafts, all resulting in a higher risk of CMV reactivation compared to MRD. URD recipients will be immunized at City of Hope while UCB recipients will be exclusively immunized at the University of Minnesota, and results of Trial 2 participants will be combined to assess protective efficacy. The goal is to capitalize on our phase I success with CMVPepVax by conducting phase II studies that will not only establish the therapeutic benefit for HCT recipients at risk for complications of CMV infection, but as well define the immunologic basis for this protection.
 
Personnel
Ryotaro Nakamura, M.D.
Principal Investigator of IRB12022

Jeff Longmate, Ph.D.
Director, Department of Biostatistics
 
Jennifer Drake, C.C.R.P.
Study Coordinator

Cindy Slape, R.N.
Clinical Research Nurse
 
Corinna La Rosa, Ph.D.
Associate Research Professor
Conducts the laboratory investigations

Staff of the Department of Hematology & Hematopoietic Cell Transplantation
Recruits and consents patients
 
Michael Verneris, M.D.
Pediatric Leukemia Program Director, University of Minnesota
Principal Investigator at the University of Minnesota site

Jeff Miller, M.D.
Director, Cancer Experimental Therapeutics Initiative (CETI), University of Minnesota
Co-investigator at the University of Minnesota site
 

Control of CMV infection in allogeneic stem cell transplant recipients using attenuated MVA-based CMV subunit vaccine

While we are seeking to confirm a therapeutic benefit of CMVPepVax in hematopoietic cell transplant (HCT) recipients, broadening the population that would benefit from a vaccination strategy is best approached by employing a delivery vector that expresses full length cytomegalovirus (CMV) antigens. We have used modified vaccinia Ankara (MVA) virus for that purpose in collaboration with NCI-NExT to manufacture a candidate for clinical testing. The clinical manufacturing of CMV-MVA took place at City of Hope, and IND-directed toxicology at SRI (Birmingham, Ala.). We propose three clinical trials that will comprehensively evaluate our clinical vaccine candidate. Trial 1 will be conducted in healthy volunteers stratified by age and poxvirus exposure who are equivalent health-wise to immunocompetent HCT donors as required by the Food and Drug Administration and will establish the safety and dose level for a second  trial in HCT. A double-blind phase II trial is proposed in which 150 HLA matched MRD will be randomized equally to receive either vaccine or placebo. Immune responses and clinical correlates of vaccine-stimulated protection will be followed in recipients whose donors are enrolled in Trial 2. In Trial 3, we propose to directly immunize 150 HCT recipients undergoing unrelated (8/8 HLA matches) URD-HCT. This approach is justified since recipients are at high-risk for CMV reactivation and do not have consistently accessible donors. Trials 2 and 3 will each enroll 150 HCT subjects, randomized equally to vaccine or placebo and both will have 90% power to detect a 50% reduction in viremia (60% to 30%) in the vaccine arm. Safety monitoring employing defined stopping rules will guard against adverse events for recipients in both trials. Combined results from carrying out both Trials 2 and 3 will provide a precise immunoprophylaxis strategy for control of CMV disease in the HCT setting. We will discover the optimal formula for immunizing both donors and recipients to prevent CMV viremia and minimize usage of potentially toxic antiviral agents. Success with this CMV vaccine would have a significant clinical and cost-saving effect on recipient management after MRD or URD HCT. The next two projects involve our rapid development of a prophylactic clinical CMV vaccine that has strong relevance to the pediatric population.
 
Personnel
Ryotaro Nakamura, M.D.
Staff physician, Department of Hematology & Hematopoietic Cell Transplantation
Principal Investigator for Trials 2 and 3

John A. Zaia, M.D.
Chair, Department of Virology
Principal Investigator of IRB 08173
 
Jennifer Drake, C.C.R.P.
Study Coordinator

Cindy Slape, R.N.
Clinical Research Nurse
 
Corinna La Rosa, Ph.D.
Associate Research Professor
Conducts the laboratory investigations

Joy Martinez
Senior Research Associate
Conducts stability testing and coordinates release testing
 
Staff of the Department of Hematology & Hematopoietic Cell Transplantation
Recruits and consents patients
 

Project 4

A Phase I study of a p53-MVA vaccine for advanced colon, gastric and pancreatic cancer

Despite recent advances in targeted therapies, the outlook for patients with advanced GI cancer remains bleak, and new treatments are urgently needed. Cancer vaccines have potential to improve outcomes for cancer patients and are being actively developed. The p53 protein is a well-characterized suppressor of uncontrolled cell division. Mutations in the gene occur in ≥50% of all patients with solid tumors, whereby it acquires oncogenic properties, and leads to high levels of dysfunctional p53 protein within malignant cells. The concentration of normal, non-mutant p53 in healthy cells is low, making p53 an attractive target for selective killing of tumor cells. Our preclinical studies have shown that immunization of mice with p53-MVA vaccine causes rejection of established tumors and generation of systemic tumor immunity.  In addition, p53-MVA was used to generate cytotoxic T cells from the blood of cancer patients that are capable of killing tumor cells. Recombinant MVA vaccines have an impressive safety record, being administered in numerous clinical trials with only mild side-effects. Along with a medical oncologist, we have initiated a first in human, Phase 1 dose-escalation study evaluating the safety and immunogenicity of clinical grade p53-MVA vaccine in patients with gastric, colon and pancreatic cancers. The first 3 patients have already completed a course of vaccination with low dose p53-MVA. As no severe toxicities have been observed, the next group of 4 patients received a higher dose of p53-MVA which is more likely to produce clinical effects. CT scans were used to evaluate progression of disease and blood draws were taken for safety and immunological assessments throughout the vaccination phase. A Phase 2 clinical trial will involve p53-MVA vaccination early after diagnosis, when beneficial outcomes are more attainable. In this clinical trial, the p53MVA vaccine will be given concurrently with the standard chemotherapy drug gemcitabine, with the aim of extending survival. These studies will greatly advance our vaccine program for patients with GI cancer who currently have few alternatives.
 
Personnel
Vincent Chung, MD
Staff Physician, Department of Medical Oncology & Therapeutics Research
Enrolls and consents patients

Nicola Hardwick, PhD
Post-Doctoral Fellow, Division of Translational Vaccine Research
Conducts the laboratory investigations
 
Department of Medical Oncology Staff Physicians
Enrolls and consents patients
 
Read the study abstract.

Project 5

HCMV vaccine produced from BAC-MVA that blocks epithelial and fibroblast entry.

The culmination of years of study on the original fibroblast (Fibro) pathway of human cytomegalovirus (HCMV) entry was a clinical trial in which a formulated gB vaccine was repeatedly administered to HCMV-negative women and 50% protection against primary infection was found. We have reproduced this success using RhCMV-negative RM by demonstrating 50% protection against a virulent RhCMV challenge, using an modified vaccinia Ankara virus (MVA) vaccine composed of RhgB and the tegument protein Rhpp65. We hypothesize that to further improve vaccine success; efficient inhibition of CMV entry into Epi/EC will be required. We recently published that vaccination of RhCMV-negative RM with RhUL128C-MVA produced high titer neutralizing antibodies (NAb) that inhibit virulent RhCMV natural isolates from infecting Epi/EC and Fibro, confirming RhUL128C function. Based on these novel results in the RhCMV/RM model, we constructed an HCMV counterpart to RhUL128C in bacterial artificial chromosome (BAC)-MVA, and the reconstituted MVA virus used to vaccinate BALB/c mice generated NAb to prevent in vitro HCMV infection of Epi/EC. In future studies, H-UL128C-MVA will be used to vaccinate RM and properties of NAb generated against the pentamer complex in sera and saliva from vaccinated and control groups will be assessed in preventing natural HCMV isolate infection of ARPE-19 cells. Avidity assays of post-vaccination sera will be assessed using urea denaturation after binding to pentamer containing lysates. We will choose a regimen for inhibition of two HCMV entry pathways by including vaccines expressing H-UL128C and HCMV pp65/gB subunits either as two individual vaccines or a single multiple insert form. The formulation and regimen will be selected based on generation of superior NAb avidity and titers that interfere with in vitro HCMV infection of ARPE-19 cells and Fibro. The anticipated result of these studies will be an HCMV-based subunit vaccine ready for clinical development.
 
Personnel
Felix Wussow, Ph.D.
Post-doctoral Fellow, Division of Translational Vaccine Research

Flavia Chiupessi, Ph.D.
Post-doctoral Fellow, Division of Translational Vaccine Research
 
Peter A Barry, Ph.D.
Vice Chair for Research, Department of Pathology and Laboratory Medicine, UC Davis
Principal Investigator of the UC Davis consortium site
 

Project 6 - Evaluation of Protective CMV Vaccines in Rhesus Macaques

The 35 year quest for a vaccine that confers protective efficacy against congenital infection with human cytomegalovirus (HCMV) remains unmet. Complexities in HCMV natural history, incompletely defined correlates of immune protection, and financial and logistical factors in designing sufficiently powered clinical trials all contribute to the absence of a licensed prophylactic HCMV vaccine. There is now increased recognition from studies in both humans and rhesus macaques (RM) that (1) the mechanism of HCMV and rhesus CMV (RhCMV) entry into cells, such as endothelial and epithelial cells, is distinct from the mechanism of fibroblast entry, and (2) seroimmune individuals develop neutralizing antibodies (NAb) against the viral proteins mediating epithelial/endothelial cell tropism. Recent findings have shown that a pentameric virion complex formed by the glycoproteins gH, gL, UL128, UL130 and UL131A (UL128C) is required for HCMV entry into epithelial/endothelial cells (Epi/EC) and is the target of potent NAb in HCMV-seropositive individuals. Using bacterial artificial chromosome (BAC)  technology, we have generated a modified vaccinia Ankara virus (MVA) that stably coexpresses all five rhesus CMV (RhCMV) proteins homologous to HCMV UL128C, termed MVA-RhUL128C. All eight RhCMV-naïve rhesus macaques (RM) vaccinated with MVA-RhUL128C developed NAb that blocked infection of monkey kidney epithelial cells (MKE) and rhesus fibroblasts. NAb titers induced by MVARhUL128C measured on both cell types at two to six weeks postvaccination were comparable to levels observed in naturally infected RM. In contrast, MVA expressing a subset of RhUL128C proteins or RhgB glycoprotein only minimally stimulated NAb that inhibited infection of MKE. In addition, following subcutaneous RhCMV challenge at eight weeks postvaccination, animals vaccinated with MVA-RhUL128C showed reduced plasma viral loads. These results indicate that MVA expressing the RhUL128C induces NAb inhibiting RhCMV entry into both Epi/EC and fibroblasts and limits RhCMV replication in RM. This novel approach is the first step in developing a prophylactic HCMV vaccine designed to interfere with virus entry into major cell types permissive for viral replication, a required property of an effective vaccine.
 
Personnel
Felix Wussow, Ph.D.
Post-doctoral Fellow, Division of Translational Vaccine Research

Flavia Chiupessi, Ph.D.
Post-doctoral Fellow, Division of Translational Vaccine Research
 
Peter A Barry, Ph.D.
Vice Chair for Research, Department of Pathology and Laboratory Medicine, UC Davis
Principal Investigator of the UC Davis consortium site
 

TVR Project 7 - IDO-silencing Salmonella therapy for the treatment of primary and metastatic PDAC.

Advanced pancreatic ductal adenocarcinoma (PDAC) is often inoperable, and is only transiently responsive to existing therapies. Overexpression of indoleamine 2,3-dioxygenase (IDO) in PDAC plays a major role in accelerating disease progression by suppressing antitumor immunity. Current IDO inhibitors inadequately reverse immunosuppression while systemic off target effects contribute to their toxicity. ShIDO-ST is a novel Salmonella typhimurium (ST)-based therapy that expresses a small hairpin (sh)RNA to specifically silence tumor-derived IDO with decreased toxicity. ST as an shRNA delivery vehicle offers superior penetration against desmoplastic PDAC tissue and anti-metastatic function due to its motility and affinity for poorly vascularized, hypoxic tissue. The combination of IDO silencing and abundant ST tumor colonization increases intratumoral local reactive oxygen species through the recruitment and activation of polymorphonuclear neutrophils (PMN), which can cause oxidative stress-induced apoptosis of tumor cells, cancer stem cells (CSC), and vascular stroma to inhibit PDAC progression. PMN are also known to have anti-metastatic function, thus providing additional protection against tumor spread. To best assess the capabilities of this therapeutic class to suppress tumor growth, we will apply it to the KrasG12D;Trp53R127H;Brca1;Pdx1-Cre genetically engineered mouse model (KPC-GEMM) that recapitulates desmoplasia and metastasis characteristic of human PDAC. Incorporation of luciferase into the KPC-GEMM model allows for longitudinal measurements of tumor growth and metastasis by intravital imaging systems (IVIS). We have obtained breeding pairs of these mice by MTA with OSUMC. To improve penetration of tumors by shIDO-ST, we are investigating PEGylated human recombinant hyaluronidase (PEGPH20, Halozyme Inc. by MTA), which depletes hyaluronan abundant in PDAC tissue and increases vascular permeability. The long-term objective is to develop shIDO-ST into a suitable, effective therapy for the treatment of patients with advanced inoperable PDAC that can also be explored with other solid tumors.

Personnel
Edwin R. Manuel, Ph.D.
Staff Scientist, Division of Translational Vaccine Research
Conducts investigations and interprets findings

Joseph Kim, M.D.
Director, Surgical Oncology Training Program
Provides tissues and background on GI malignancies

Massimo d’Apuzzo, M.D.
Neuropathologist and Anatomic Pathologist, Division of Pathology
Interprets ultrastructural information from tumors

Vincent Chung, M.D.
Staff Physician, Department of Medical Oncology & Therapeutics Research
Enrolls and consents patients

 

Project 8 – WT1 as a biomarker to predict relapse in patients with acute leukemia and MDS.

Relapse is a major obstacle to maximizing curative potential of allogeneic HCT (aHCT) therapy for acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL)) and myelodysplastic syndrome (MDS). It has been shown that relapse can be detected through longitudinal application of quantitative PCR (qPCR) measurement techniques before patients (Pts) develop symptoms and that early intervention to delay or stop relapse can improve patient outcome. However, such tests apply only to a small percentage of Pts with fusion gene transcripts and specific mutations. WT1 has been investigated as a tumor marker in a variety of studies which have shown its association with disease progression and relapse. In our pilot work, based on WT1 kinetics data in a small cohort of Pts, we have shown the striking correspondence of increasing WT1 transcript levels with future relapse and the specific time frame between molecular relapse detected by the WT1 PCR test and hematologic relapse confirmed by clinical observations. Our plan is to establish ranges of WT1 transcript levels characteristic of Pts after aHCT that do not relapse, a high threshold level that can serve as a specific biomarker for relapse with close to or 100% specificity, and a less stringent threshold level with lower specificity to identify more Pts that relapse and at earlier times. We will also define the time interval when relapse is detected molecularly by qPCR methods, and later confirmed morphologically by standard clinical methods. Our hypothesis is that many of the Pts that will ultimately relapse will have a period of minimal residual disease that may be detected by repeated elevations of WT1 not exceeding the determined WT1 threshold levels. The ultimate purpose of our study is to apply this important biomarker as part of standard diagnostic procedures for detection of relapse in the highest-risk individuals – acute leukemia and MDS Pts undergoing aHCT.

Personnel

Anna Israyelyan, Ph.D.
Postdoctoral Fellow, Division of Translational Vaccine Research

Weimin Tsai
Research Associate II, Division of Hematology/Bone Marrow Transplantation

Lia Aquino
Clinical Research Analyst, Clinical Trials Office

Leanne Streja, Ph.D.
Senior Programmer Analyst, Department of Information Sciences

 

Translational Vaccine Research Projects

Current TVR Projects

Evaluation of safety and correlative immunogenicity studies of CMVPepVax co-injected with PF03512676 adjuvant in recipients of allogeneic stem cell transplant
 
CMVPepVax to protect stem cell transplant recipients from Cytomegalovirus infection-University of Minnesota collaborative study
 
Control of CMV infection in allogeneic stem cell transplant recipients using attenuated MVA-based CMV subunit vaccine
 
A Phase I study of a p53-MVA vaccine for advanced colon, gastric and pancreatic cancer
 
HCMV vaccine Produced from BAC-MVA that blocks epithelial and fibroblast entry
 
Evaluation of protective CMV vaccines in rhesus macaques
 
IDO-silencing Salmonella therapy for the treatment of primary and metastatic PDAC
 
WT1 as a biomarker topredict relapse in patients with acute leukemia and MDS
 
Project 9
Optimizing shRNA approaches for control of Lymphoma using Salmonella delivery systems
 

Project 1

Project 1

Evaluation of safety and correlative immunogenicity studies of CMVPepVax co-injected with PF03512676 adjuvant in recipients of allogeneic stem cell transplant

Allogeneic hematopoietic cell transplantation (HCT) is an effective therapy for a range of life-threatening hematologic malignancies. Since the inception of HCT four decades ago, more than 800,000 patients have been transplanted worldwide. The majority of allogeneic HCT recipients are patients with leukemia, lymphoma, myeloma, myelodysplasia, bone marrow failure conditions, severe red blood cell disorders or solid tumors. In allogeneic HCT, hematopoietic cells are obtained from suitably HLA matched related or unrelated volunteer donors (URD) or from umbilical cord blood. Pretransplant, the patient is treated with chemotherapy, with or without radiation therapy, to eradicate cancerous cells, and for suppressing the patient’s immune system to prevent it from attacking donor hematopoietic cells. As a result, patients are vulnerable to pathogens termed opportunistic infections. Among them is cytomegalovirus (CMV) infection, which is the cause of significant morbidity at early and late times post-HCT in the recovery of immune-compromised recipients. CMV is a highly prevalent β-herpes virus that rarely causes disease in healthy individuals. In contrast, HCT patients are vulnerable to herpes virus infections, including CMV, as a result of immunosuppression associated with treatment strategies aimed at preventing rejection or graft-versus-host disease (GVHD). Despite advances in development of antiviral drugs and substantial reduction of CMV disease with pre-emptive antiviral treatment, CMV remains one of the most difficult-to-treat infections post-HCT, which strongly impacts the course of recovery and success rate of this curative treatment for cancer. Furthermore, antiviral therapy has major side effects, including nephrotoxicity, neutropenia and delayed immune reconstitution, which exposes HCT recipients to other opportunistic viral, bacterial and fungal infections. Additionally, costs associated with usage of antivirals are significant, with a single course reaching $25,000. Next-generation prophylactic antiviral drugs are undergoing clinical testing and might effectively reduce CMV infection rates, although a phase III study assessing a promising antiviral did not show a reduction in CMV infection. Thus, alternative strategies to control CMV are eagerly sought, since use of antivirals does not address the major risks of late-onset CMV disease, including reactivation and failure to reconstitute CMV-specific immunity. Substituting toxic antivirals with a vaccine that harnesses the abundant native immune response to CMV may improve outcomes for HCT recipients. Our group has identified a repertoire of CD8 T cell epitopes from the CMV-pp65 protein that can expand human CMV-pp65-specific memory CD8 T cells in vitro. In HLA A*0201 transgenic mice, two candidate vaccine peptides containing the HLA A*0201  pp65495-503 CD8+ T cell epitope fused to universal T-help epitopes (either the synthetic PADRE or a natural Tetanus sequence) showed favorable immunogenicity profiles. The vaccine peptides were named PADRE-CMV and Tet-CMV, respectively, and were developed with support of the National Cancer Institute sponsored Rapid Access to Interventional Development (NCI-RAID, currently called NCI-NExT). Co-injection with PF-03512676 adjuvant (a synthetic single stranded DNA containing bacterial CpG DNA motifs with immunostimulatory activity, produced by Pfizer) further augmented activity at a lower vaccine dose. cGMP-grade PADRE-CMV (NSC-721433) and Tet-CMV (NSC-721434) vials were produced, tested for stability and preclinically assessed for toxicology at all investigated dosages (Southern Research Institute). After obtaining approval from FDA (BB-IND13124), PADRE-CMV and Tet-CMV, with or without PF-03512676 adjuvant were clinically evaluated for safety and immunogenicity. The phase Ib dose-escalation clinical trial (registry number: NCT00722839@www.clinicaltrials.gov) was conducted in HLA A*0201 healthy adults and indicated that the CMV peptides co-injected with PF-03512676 were safe and immunogenic. In particular, Tet-CMV + PF-03512676 had a favorable safety profile and led to substantial expansion of pp65495-503 T cells after two subcutaneous vaccine injections. The achievement of the central goal of our phase Ib study in healthy adults supports further evaluation of Tet-CMV combined with PF-03512676 (renamed CMVPepVax)  in the HCT setting. A summary of the results of the trial was published in 2012 (see La Rosa et al, 2012). These promising results are the basis for CMVPepVax as a therapeutic vaccine, to improve outcomes of HCT recipients with uncontrolled CMV viremia.
 
Summary of IRB12022-approved Phase Ib Randomized Open Label Clinical Trial in HCT recipients. The phase Ib pilot trial is powered to evaluate safety of administering CMVPepVax to HLA matched allogeneic (MRD or URD) patients at risk for CMV complications (NCT01588015@www.clinicaltrials.gov). The target enrollment is ≤36 patients with the goal of assessing feasibility to conduct a larger phase II trial (see Project 2). Computer generated 1:1 randomization assigns each patient either to the vaccine or to the non-interventional (prospective) immune monitoring arm. In the vaccine arm, patients will be vaccinated twice (d28 and d56 post-HCT) with CMVPepVax. Safety (10 endpoint) will include continuous post-immunization assessment until d100 for GVHD and as necessary until d180 for any AE in ≤18 immunized patients. We initiated this trial and have administered vaccine to three patients and enrolled an additional four observational patients. CMV-specific vaccine function (20 endpoint) will be monitored in all enrolled patients in both trial arms (n≤36) biweekly from d28-100 post-HCT and every 30d thereafter by measuring numbers of CD8+ T cells binding to HLA-tetramers. Additional correlative studies will include assessment of PD-1 expression on CMV-specific T cells (as a measure of exhaustion), measuring proliferative capacity (CFSE dilution method) by cell division and cell death. Reduction of apoptosis markers and increased proliferation of CMV-specific T cells is expected in vaccinated compared to unvaccinated patients. Immune assessments will be done in batch at the conclusion of six months of observation. Pending success of the pilot trial, NCI will provide a fresh lot of vaccine to support a large multi-center phase II study jointly with the University of Minnesota Comprehensive Cancer Center (see Project 2).

Personnel
Ryotaro Nakamura, M.D.
Principal Investigator of IRB12022
 
Jennifer Drake, C.C.R.P.
Study Coordinator

Cindy Slape, R.N.
Clinical Research Nurse
 
Corinna La Rosa, Ph.D.
Associate Research Professor
Conducts the laboratory investigations

Staff of the Department of Hematology & Hematopoietic Cell Transplantation
 

Project 2

Project 2

CMVPepVAX to protect stem cell transplant recipients from CMV infection
 
Pending success of the pilot trial, the National Cancer Institute will provide a fresh lot of CMVPepVax to support a multicenter phase II study jointly with the University of Minnesota Comprehensive Cancer Center. We propose two phase II trials in hematopoietic cell transplantation (HCT) with the goal of preventing cytomegalovirus (CMV) reactivation. We will conduct a randomized placebo-controlled phase II study (Trial 1) powered to test the primary endpoint of reduced CMV reactivation in  matched related donor (MRD) HCT. Nested within this trial, we will assess immunologic efficacy of vaccinating the MRD to augment levels and function of CMV immunity that are concurrently boosted by the vaccine in HCT recipients. Immunologic 20 endpoints will be quantified by frequency measurements of CMV-specific T cells using HLA tetramers and functional studies with T-box transcription factors, T-bet and Eomes that will assess improved effector function in vaccinated patients. Trial 2 will test protective function of CMVPepVax in higher risk unrelated donor (URD) or umbilical cord blood (UCB) recipients. This randomized trial will address a broad range of URD settings, stratified as low risk 8/8 HLA match, or higher risk 7/8 match URD, or lesser matched UCB grafts, all resulting in a higher risk of CMV reactivation compared to MRD. URD recipients will be immunized at City of Hope while UCB recipients will be exclusively immunized at the University of Minnesota, and results of Trial 2 participants will be combined to assess protective efficacy. The goal is to capitalize on our phase I success with CMVPepVax by conducting phase II studies that will not only establish the therapeutic benefit for HCT recipients at risk for complications of CMV infection, but as well define the immunologic basis for this protection.
 
Personnel
Ryotaro Nakamura, M.D.
Principal Investigator of IRB12022

Jeff Longmate, Ph.D.
Director, Department of Biostatistics
 
Jennifer Drake, C.C.R.P.
Study Coordinator

Cindy Slape, R.N.
Clinical Research Nurse
 
Corinna La Rosa, Ph.D.
Associate Research Professor
Conducts the laboratory investigations

Staff of the Department of Hematology & Hematopoietic Cell Transplantation
Recruits and consents patients
 
Michael Verneris, M.D.
Pediatric Leukemia Program Director, University of Minnesota
Principal Investigator at the University of Minnesota site

Jeff Miller, M.D.
Director, Cancer Experimental Therapeutics Initiative (CETI), University of Minnesota
Co-investigator at the University of Minnesota site
 

Project 3

Control of CMV infection in allogeneic stem cell transplant recipients using attenuated MVA-based CMV subunit vaccine

While we are seeking to confirm a therapeutic benefit of CMVPepVax in hematopoietic cell transplant (HCT) recipients, broadening the population that would benefit from a vaccination strategy is best approached by employing a delivery vector that expresses full length cytomegalovirus (CMV) antigens. We have used modified vaccinia Ankara (MVA) virus for that purpose in collaboration with NCI-NExT to manufacture a candidate for clinical testing. The clinical manufacturing of CMV-MVA took place at City of Hope, and IND-directed toxicology at SRI (Birmingham, Ala.). We propose three clinical trials that will comprehensively evaluate our clinical vaccine candidate. Trial 1 will be conducted in healthy volunteers stratified by age and poxvirus exposure who are equivalent health-wise to immunocompetent HCT donors as required by the Food and Drug Administration and will establish the safety and dose level for a second  trial in HCT. A double-blind phase II trial is proposed in which 150 HLA matched MRD will be randomized equally to receive either vaccine or placebo. Immune responses and clinical correlates of vaccine-stimulated protection will be followed in recipients whose donors are enrolled in Trial 2. In Trial 3, we propose to directly immunize 150 HCT recipients undergoing unrelated (8/8 HLA matches) URD-HCT. This approach is justified since recipients are at high-risk for CMV reactivation and do not have consistently accessible donors. Trials 2 and 3 will each enroll 150 HCT subjects, randomized equally to vaccine or placebo and both will have 90% power to detect a 50% reduction in viremia (60% to 30%) in the vaccine arm. Safety monitoring employing defined stopping rules will guard against adverse events for recipients in both trials. Combined results from carrying out both Trials 2 and 3 will provide a precise immunoprophylaxis strategy for control of CMV disease in the HCT setting. We will discover the optimal formula for immunizing both donors and recipients to prevent CMV viremia and minimize usage of potentially toxic antiviral agents. Success with this CMV vaccine would have a significant clinical and cost-saving effect on recipient management after MRD or URD HCT. The next two projects involve our rapid development of a prophylactic clinical CMV vaccine that has strong relevance to the pediatric population.
 
Personnel
Ryotaro Nakamura, M.D.
Staff physician, Department of Hematology & Hematopoietic Cell Transplantation
Principal Investigator for Trials 2 and 3

John A. Zaia, M.D.
Chair, Department of Virology
Principal Investigator of IRB 08173
 
Jennifer Drake, C.C.R.P.
Study Coordinator

Cindy Slape, R.N.
Clinical Research Nurse
 
Corinna La Rosa, Ph.D.
Associate Research Professor
Conducts the laboratory investigations

Joy Martinez
Senior Research Associate
Conducts stability testing and coordinates release testing
 
Staff of the Department of Hematology & Hematopoietic Cell Transplantation
Recruits and consents patients
 

Project 4

Project 4

A Phase I study of a p53-MVA vaccine for advanced colon, gastric and pancreatic cancer

Despite recent advances in targeted therapies, the outlook for patients with advanced GI cancer remains bleak, and new treatments are urgently needed. Cancer vaccines have potential to improve outcomes for cancer patients and are being actively developed. The p53 protein is a well-characterized suppressor of uncontrolled cell division. Mutations in the gene occur in ≥50% of all patients with solid tumors, whereby it acquires oncogenic properties, and leads to high levels of dysfunctional p53 protein within malignant cells. The concentration of normal, non-mutant p53 in healthy cells is low, making p53 an attractive target for selective killing of tumor cells. Our preclinical studies have shown that immunization of mice with p53-MVA vaccine causes rejection of established tumors and generation of systemic tumor immunity.  In addition, p53-MVA was used to generate cytotoxic T cells from the blood of cancer patients that are capable of killing tumor cells. Recombinant MVA vaccines have an impressive safety record, being administered in numerous clinical trials with only mild side-effects. Along with a medical oncologist, we have initiated a first in human, Phase 1 dose-escalation study evaluating the safety and immunogenicity of clinical grade p53-MVA vaccine in patients with gastric, colon and pancreatic cancers. The first 3 patients have already completed a course of vaccination with low dose p53-MVA. As no severe toxicities have been observed, the next group of 4 patients received a higher dose of p53-MVA which is more likely to produce clinical effects. CT scans were used to evaluate progression of disease and blood draws were taken for safety and immunological assessments throughout the vaccination phase. A Phase 2 clinical trial will involve p53-MVA vaccination early after diagnosis, when beneficial outcomes are more attainable. In this clinical trial, the p53MVA vaccine will be given concurrently with the standard chemotherapy drug gemcitabine, with the aim of extending survival. These studies will greatly advance our vaccine program for patients with GI cancer who currently have few alternatives.
 
Personnel
Vincent Chung, MD
Staff Physician, Department of Medical Oncology & Therapeutics Research
Enrolls and consents patients

Nicola Hardwick, PhD
Post-Doctoral Fellow, Division of Translational Vaccine Research
Conducts the laboratory investigations
 
Department of Medical Oncology Staff Physicians
Enrolls and consents patients
 
Read the study abstract.

Project 5

Project 5

HCMV vaccine produced from BAC-MVA that blocks epithelial and fibroblast entry.

The culmination of years of study on the original fibroblast (Fibro) pathway of human cytomegalovirus (HCMV) entry was a clinical trial in which a formulated gB vaccine was repeatedly administered to HCMV-negative women and 50% protection against primary infection was found. We have reproduced this success using RhCMV-negative RM by demonstrating 50% protection against a virulent RhCMV challenge, using an modified vaccinia Ankara virus (MVA) vaccine composed of RhgB and the tegument protein Rhpp65. We hypothesize that to further improve vaccine success; efficient inhibition of CMV entry into Epi/EC will be required. We recently published that vaccination of RhCMV-negative RM with RhUL128C-MVA produced high titer neutralizing antibodies (NAb) that inhibit virulent RhCMV natural isolates from infecting Epi/EC and Fibro, confirming RhUL128C function. Based on these novel results in the RhCMV/RM model, we constructed an HCMV counterpart to RhUL128C in bacterial artificial chromosome (BAC)-MVA, and the reconstituted MVA virus used to vaccinate BALB/c mice generated NAb to prevent in vitro HCMV infection of Epi/EC. In future studies, H-UL128C-MVA will be used to vaccinate RM and properties of NAb generated against the pentamer complex in sera and saliva from vaccinated and control groups will be assessed in preventing natural HCMV isolate infection of ARPE-19 cells. Avidity assays of post-vaccination sera will be assessed using urea denaturation after binding to pentamer containing lysates. We will choose a regimen for inhibition of two HCMV entry pathways by including vaccines expressing H-UL128C and HCMV pp65/gB subunits either as two individual vaccines or a single multiple insert form. The formulation and regimen will be selected based on generation of superior NAb avidity and titers that interfere with in vitro HCMV infection of ARPE-19 cells and Fibro. The anticipated result of these studies will be an HCMV-based subunit vaccine ready for clinical development.
 
Personnel
Felix Wussow, Ph.D.
Post-doctoral Fellow, Division of Translational Vaccine Research

Flavia Chiupessi, Ph.D.
Post-doctoral Fellow, Division of Translational Vaccine Research
 
Peter A Barry, Ph.D.
Vice Chair for Research, Department of Pathology and Laboratory Medicine, UC Davis
Principal Investigator of the UC Davis consortium site
 

Project 6

Project 6 - Evaluation of Protective CMV Vaccines in Rhesus Macaques

The 35 year quest for a vaccine that confers protective efficacy against congenital infection with human cytomegalovirus (HCMV) remains unmet. Complexities in HCMV natural history, incompletely defined correlates of immune protection, and financial and logistical factors in designing sufficiently powered clinical trials all contribute to the absence of a licensed prophylactic HCMV vaccine. There is now increased recognition from studies in both humans and rhesus macaques (RM) that (1) the mechanism of HCMV and rhesus CMV (RhCMV) entry into cells, such as endothelial and epithelial cells, is distinct from the mechanism of fibroblast entry, and (2) seroimmune individuals develop neutralizing antibodies (NAb) against the viral proteins mediating epithelial/endothelial cell tropism. Recent findings have shown that a pentameric virion complex formed by the glycoproteins gH, gL, UL128, UL130 and UL131A (UL128C) is required for HCMV entry into epithelial/endothelial cells (Epi/EC) and is the target of potent NAb in HCMV-seropositive individuals. Using bacterial artificial chromosome (BAC)  technology, we have generated a modified vaccinia Ankara virus (MVA) that stably coexpresses all five rhesus CMV (RhCMV) proteins homologous to HCMV UL128C, termed MVA-RhUL128C. All eight RhCMV-naïve rhesus macaques (RM) vaccinated with MVA-RhUL128C developed NAb that blocked infection of monkey kidney epithelial cells (MKE) and rhesus fibroblasts. NAb titers induced by MVARhUL128C measured on both cell types at two to six weeks postvaccination were comparable to levels observed in naturally infected RM. In contrast, MVA expressing a subset of RhUL128C proteins or RhgB glycoprotein only minimally stimulated NAb that inhibited infection of MKE. In addition, following subcutaneous RhCMV challenge at eight weeks postvaccination, animals vaccinated with MVA-RhUL128C showed reduced plasma viral loads. These results indicate that MVA expressing the RhUL128C induces NAb inhibiting RhCMV entry into both Epi/EC and fibroblasts and limits RhCMV replication in RM. This novel approach is the first step in developing a prophylactic HCMV vaccine designed to interfere with virus entry into major cell types permissive for viral replication, a required property of an effective vaccine.
 
Personnel
Felix Wussow, Ph.D.
Post-doctoral Fellow, Division of Translational Vaccine Research

Flavia Chiupessi, Ph.D.
Post-doctoral Fellow, Division of Translational Vaccine Research
 
Peter A Barry, Ph.D.
Vice Chair for Research, Department of Pathology and Laboratory Medicine, UC Davis
Principal Investigator of the UC Davis consortium site
 

Project 7

TVR Project 7 - IDO-silencing Salmonella therapy for the treatment of primary and metastatic PDAC.

Advanced pancreatic ductal adenocarcinoma (PDAC) is often inoperable, and is only transiently responsive to existing therapies. Overexpression of indoleamine 2,3-dioxygenase (IDO) in PDAC plays a major role in accelerating disease progression by suppressing antitumor immunity. Current IDO inhibitors inadequately reverse immunosuppression while systemic off target effects contribute to their toxicity. ShIDO-ST is a novel Salmonella typhimurium (ST)-based therapy that expresses a small hairpin (sh)RNA to specifically silence tumor-derived IDO with decreased toxicity. ST as an shRNA delivery vehicle offers superior penetration against desmoplastic PDAC tissue and anti-metastatic function due to its motility and affinity for poorly vascularized, hypoxic tissue. The combination of IDO silencing and abundant ST tumor colonization increases intratumoral local reactive oxygen species through the recruitment and activation of polymorphonuclear neutrophils (PMN), which can cause oxidative stress-induced apoptosis of tumor cells, cancer stem cells (CSC), and vascular stroma to inhibit PDAC progression. PMN are also known to have anti-metastatic function, thus providing additional protection against tumor spread. To best assess the capabilities of this therapeutic class to suppress tumor growth, we will apply it to the KrasG12D;Trp53R127H;Brca1;Pdx1-Cre genetically engineered mouse model (KPC-GEMM) that recapitulates desmoplasia and metastasis characteristic of human PDAC. Incorporation of luciferase into the KPC-GEMM model allows for longitudinal measurements of tumor growth and metastasis by intravital imaging systems (IVIS). We have obtained breeding pairs of these mice by MTA with OSUMC. To improve penetration of tumors by shIDO-ST, we are investigating PEGylated human recombinant hyaluronidase (PEGPH20, Halozyme Inc. by MTA), which depletes hyaluronan abundant in PDAC tissue and increases vascular permeability. The long-term objective is to develop shIDO-ST into a suitable, effective therapy for the treatment of patients with advanced inoperable PDAC that can also be explored with other solid tumors.

Personnel
Edwin R. Manuel, Ph.D.
Staff Scientist, Division of Translational Vaccine Research
Conducts investigations and interprets findings

Joseph Kim, M.D.
Director, Surgical Oncology Training Program
Provides tissues and background on GI malignancies

Massimo d’Apuzzo, M.D.
Neuropathologist and Anatomic Pathologist, Division of Pathology
Interprets ultrastructural information from tumors

Vincent Chung, M.D.
Staff Physician, Department of Medical Oncology & Therapeutics Research
Enrolls and consents patients

 

Project 8

Project 8 – WT1 as a biomarker to predict relapse in patients with acute leukemia and MDS.

Relapse is a major obstacle to maximizing curative potential of allogeneic HCT (aHCT) therapy for acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL)) and myelodysplastic syndrome (MDS). It has been shown that relapse can be detected through longitudinal application of quantitative PCR (qPCR) measurement techniques before patients (Pts) develop symptoms and that early intervention to delay or stop relapse can improve patient outcome. However, such tests apply only to a small percentage of Pts with fusion gene transcripts and specific mutations. WT1 has been investigated as a tumor marker in a variety of studies which have shown its association with disease progression and relapse. In our pilot work, based on WT1 kinetics data in a small cohort of Pts, we have shown the striking correspondence of increasing WT1 transcript levels with future relapse and the specific time frame between molecular relapse detected by the WT1 PCR test and hematologic relapse confirmed by clinical observations. Our plan is to establish ranges of WT1 transcript levels characteristic of Pts after aHCT that do not relapse, a high threshold level that can serve as a specific biomarker for relapse with close to or 100% specificity, and a less stringent threshold level with lower specificity to identify more Pts that relapse and at earlier times. We will also define the time interval when relapse is detected molecularly by qPCR methods, and later confirmed morphologically by standard clinical methods. Our hypothesis is that many of the Pts that will ultimately relapse will have a period of minimal residual disease that may be detected by repeated elevations of WT1 not exceeding the determined WT1 threshold levels. The ultimate purpose of our study is to apply this important biomarker as part of standard diagnostic procedures for detection of relapse in the highest-risk individuals – acute leukemia and MDS Pts undergoing aHCT.

Personnel

Anna Israyelyan, Ph.D.
Postdoctoral Fellow, Division of Translational Vaccine Research

Weimin Tsai
Research Associate II, Division of Hematology/Bone Marrow Transplantation

Lia Aquino
Clinical Research Analyst, Clinical Trials Office

Leanne Streja, Ph.D.
Senior Programmer Analyst, Department of Information Sciences

 
Overview
Beckman Research Institute of City of Hope is responsible for fundamentally expanding the world’s understanding of how biology affects diseases such as cancer, HIV/AIDS and diabetes.
 
 
Research Departments/Divisions

City of Hope is a leader in translational research - integrating basic science, clinical research and patient care.
 

Research Shared Services

City of Hope embodies the spirit of scientific collaboration by sharing services and core facilities with colleagues here and around the world.
 

Our Scientists

Our research laboratories are led by the best and brightest minds in scientific research.
 

City of Hope’s Irell & Manella Graduate School of Biological Sciences equips students with the skills and strategies to transform the future of modern medicine.
Develop new therapies, diagnostics and preventions in the fight against cancer and other life-threatening diseases.
 
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