The Laboratory of Vaccine Research (LVR) was originally formed by Dr. Diamond in 2000 to address priorities in vaccine research that would potentially impact patient outcomes at the City of Hope (COH) and other cancer centers worldwide. The LVR later evolved into the Division of Translational Vaccine Research (TVR) in 2008, which has, since then, focused on the clinical translation of vaccine and therapeutic strategies to combat herpes viral infections, hematologic malignancies, and solid tumors. Our comprehensive program has now developed molecular vaccines and therapies that incorporate various technologies such as peptides and viral or bacterial vectors to directly elicit, or encode antigens that elicit, viral- or cancer-specific immune responses. Currently, the TVR has produced several agents that have advanced beyond pre-clinical testing into Phase I and II trials. The mission of the TVR is to continue progress in the development and testing of treatments with clinical benefit for cancer patients. In 2014, the TVR was transformed into the Department of Experimental Therapeutics (ET). The mission of the ET department will encompass the work of the TVR and broaden its scope to include more basic studies in basic and tumor immunology.
Allogeneic hematopoietic cell transplantation (HCT) is a therapy for which COH is a world leader and is effective for a range of life-threatening hematologic malignancies. However, one of the most difficult-to-treat complications can occur during the first 100 days post-HCT, which is infection with the highly prevalent beta-herpes virus known as human cytomegalovirus (HCMV). HCMV rarely causes disease in healthy individuals, but can be life-threatening in HCT patients as a result of immunosuppression associated with treatment strategies aimed at preventing rejection or graft-versus-host disease (GVHD). To improve outcomes for HCT recipients, the TVR aims to substitute toxic antivirals with a vaccine that induces long-lasting, memory immune responses to HCMV, since antivirals are unable to generate adaptive immunity capable of preventing HCMV infection and disease.
In allogeneic HCT, hematopoietic cells are obtained from suitable HLA matched related or unrelated volunteer donors (URD). Pretransplant patients are 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 and 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 therapy, the 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 first generation vaccine approach relied on a non-living synthetic portion of the virus called a peptide that has cleared its safety hurdle after a successful clinical trial in healthy volunteers. 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) program. After obtaining approval from the FDA, PADRE-CMV and Tet-CMV, with or without PF-03512676 adjuvant (a synthetic single stranded DNA containing bacterial CpG DNA motifs with immunostimulatory activity, produced by Pfizer, Inc.), were clinically evaluated for safety and immunogenicity in a Phase Ib dose-escalation clinical trial. 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. These promising results are the basis for CMVPepVax as a therapeutic vaccine, to improve outcomes of HCT recipients with uncontrolled CMV viremia. The phase Ib pilot trial was powered to evaluate safety of administering CMVPepVax to HLA matched allogeneic (MRD or URD) patients at risk for CMV complications (Project 1). To capitalize on the success of the pilot Phase Ib trial, NCI approved a fresh lot of vaccine to support a large multi-center Phase II study jointly with the University of Minnesota Comprehensive Cancer Center. The goal of this Phase II clinical trial is to assess efficacy of CMVPepVax, in protecting against CMV reactivation and disease (Project 2).
As a viral vector that can incorporate foreign antigens and protect against a challenge pathogen, modified vaccinia Ankara (MVA) virus is hypothesized to act as a powerful immunotherapeutic tool against multiple strains of CMV regardless of an individual’s HLA type (Projects 3-6). The potential value of MVA for the clinic stems from its ability to elicit strong humoral and T cell responses against diverse antigens. Studies in rodents and macaques affirm the safety of MVA, including protection against more virulent forms of poxviruses. There are over 150 active clinical studies using MVA that are documented on the USPHS website http://clinicaltrials.gov/. Recent trials have shown MVA is well tolerated and immunogenic when administered to HCT recipients, indicating minimal human toxicity in either short term or long term studies. Currently, there is no vaccine strategy against CMV applicable to HCT recipients that uses a recombinant MVA incorporating multiple cellular response antigens. Three CMV gene products, UL83 (pp65), UL122 (IE2), and UL123 (IE1) have been selected as targets for cell mediated immune response. We have termed this vaccine as CMV-MVA Triplex, which was manufactured and is currently being tested at the City of Hope. This study will compare the immune response of CMV-MVA Triplex vaccine used in persons with no prior CMV immunity and in those with prior CMV immunity. The primary goal of this first in humans clinical trial is to establish the safety of the CMV-MVA Triplex vaccine given to healthy volunteers (Project 3). A future study is being finalized to investigate the safety and protective function of the vaccine in our HCT population. Additional studies are envisioned in the solid organ transplant setting.
Fetal infection by HCMV during and after pregnancy poses a serious health risk to the developing child. Thus, a vaccine that confers protective immunity against congenital CMV infection is another significant focus of the TVR. In collaboration with the University of California at Davis and the California National Primate Research Center (CNPRC), the TVR is utilizing rhesus macaques (RM) as a primate model for HCMV infection and testing congenital vaccine concepts. The close phylogenetic relation of humans and RM makes them a pivotal animal model for this study. In addition, the rhesus (Rh)CMV genome is largely co-linear to that of HCMV and encodes orthologs for all 5 subunits of the gH/gL-pentameric complex, termed gH/gL-PC (UL128, UL130, UL131A, gH and gL). Previous studies have shown that neutralizing antibodies (NAb) are crucial in the host immune response to control or prevent the infection with HCMV. Promising progress in the development of an HCMV vaccine has been made by a strategy based on a recombinant form of the envelope glycoprotein B (gB), a dominant NAb target in HCMV-positive individuals. Based on these findings, scientists in the Division have developed a bacterial artificial chromosome (BAC)-derived Modified Vaccinia Ankara (MVA) vaccine vector co-expressing all 5 subunits of the gH/gL-PC (MVA-gH/gL-PC), which is considered as the major target of NAb that block the infection of epithelial and endothelial cells (EC). Focus of current work involves the characterization and isolation of the gH/gL-PC, and identification of gH/gL-PC-specific NAb responses and their epitope targets. Generation of a multi-antigenic BAC-derived MVA vaccine vector that incorporates the gH/gL-PC in combination with other dominant NAb targets (gB, gH/gL, gH/gL/gO, gM, gN) and major targets of the cell-mediated arm of immunity such as pp65 and IE1 are also major efforts (Projects 5 and 6).
Advanced pancreatic ductal adenocarcinoma (PDAC) is the 4th leading cause of cancer-related deaths in the United States and can be attributed to deficiencies in early detection methods and effective therapies. Overexpression of indoleamine 2,3-dioxygenase (IDO) in PDAC plays a major role in accelerating disease progression by suppressing antitumor immunity. shIDO-ST is a novel Salmonella typhimirium (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. Using bioluminescent forms of cell lines derived from pancreatic tumors, the TVR is able to employ advanced imaging techniques to follow therapeutic strategies in which Salmonella therapy is combined with proprietary adjuvant causing remarkable complete rejection of transplantable tumors (Project 7). To further understand the molecular mechanisms leading to PDAC tumor cell death, Project 9 focuses on inhibitory immune-checkpoints receptors such as programmed death 1 (PD1) and its ligand (PD-L1) whose expression have been significantly associated with various types of cancer, including PDAC. Studies are being conducted to best assess anti-PD1 mAb using genetically engineered orthotopic Kras and p53 mutant (KPC) PDAC mouse models that recapitulates desmoplasia and metastasis characteristic of human PDAC. The long-term objective of this study is to better understand the molecular mechanism of PD-1 action that causes clinical remission of many solid tumors.
The p53 protein is a well-characterized suppressor of uncontrolled cell division. Mutations in the gene occur > 50% of all patients with solid tumors, whereby it acquires oncogenic properties, and leads to high levels of dysfunctional p53 protein with 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. To generate robust anti-p53 immune responses, a vaccine delivery platform was developed based on a highly attenuated virus referred to as Modified Vaccinia Ankara (MVA). Preclinical studies developed in our Division have shown that immunization of mice with p53-MVA vaccine causes rejection of established tumors and generation of systemic tumor immunity. In addition, when p53-MVA was used to generate cytotoxic T cells from the blood of cancer patients, these were capable of killing tumor cells in vitro. Recombinant MVA vaccinies have an impressive safety record, being administered in numerous clinical trials with only mild-side effects. Earlier this year, a first in human, Phase I clinical trial evaluating the safety and immunogenicity of clinical grade p53MVA vaccine in patients with colon and pancreatic cancers was completed. A planned phase II clinical trial will involve p53-MVA vaccination early after diagnosis to test efficacy of the vaccine as a multimodal therapy in combination with standard chemotherapy or with immunologic check point inhibitors such as CTLA-4 or PD-1 (Project 4).
The role of suppressive hematopoietic cells in tumor immune evasion and cancer progression is well known. One method of depleting these suppressive cell types is with standard chemotherapy agents such as gemcitabine, which is reported to induce positive immunomodulatory effects in pancreatic cancer patients. Gemcitabine is often used to treat platinum resistant ovarian cancer, which has a very poor outcome. Our forthcoming clinical study will evaluate the p53MVA vaccine in combination with gemcitabine in chemotherapy-refractory ovarian cancer patients with the aim of enhancing the stimulatory action of p53MVA and delivering clinical benefit (Project 4).
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). WT1 has been investigated as a tumor marker in a variety of studies which have shown its association with disease progression and relapse. TVR personnel are applying this important biomarker as part of standard diagnostic procedures for detection of relapse in the highest-risk individuals – acute leukemia and MDS patients undergoing aHCT (Project 9). Furthermore, we are using WT1 as a potential therapeutic vaccine antigen in combination with adjuvants and checkpoint inhibitors, such as PD1, for patients with hematologic malignancies. The hope is that an effective adaptive immune response is generated that can recognize and ablate tumors and metastases over-expressing the WT1 oncogene.