Phase 1b and Phase 2 evaluation of protective efficacy, safety and correlative immunogenicity studies of CMVPepVax co-injected with PF03512676 adjuvant in recipients of allogeneic stem cell transplant
Hematopoietic cell transplant (HCT) patients are susceptible to herpes virus infections. A particularly dangerous form is known as cytomegalovirus (CMV) which can cause disease in patients treated with immunosuppressive drugs. The immunocompromised HCT recipient is vulnerable to uncontrolled viremia caused by CMV infection. Small molecule pharmacologic agents limiting virus replication have become leading methods of therapy for CMV viremia. Toxicity is a factor in their usage, and the cost of these small molecule drugs known as antivirals is significant, with a single course of treatment reaching $25,000. Alternatively, it has been known for 25 years that cellular immunity is a key protective mechanism guarding HCT recipients against the morbidity of CMV viremia. For instance, CMV-pp65-specific CD8+ T-cells can protect HCT recipients from CMV complications. We have identified a repertoire of CTL epitopes from the CMV-pp65 protein, which can be used to expand human CMV-pp65-specific 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 with universal T-helper 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, Inc.) further augmented activity at a lower vaccine dose.
After obtaining approval from the FDA (BB-IND13124), PADRE-CMV and Tet-CMV, with or without PF-03512676 adjuvant were clinically evaluated for safety and immunogenicity. The Phase Ib trial (NCT00722839 @www.clinicaltrials.gov) was conducted in HLA A*0201 healthy adults. Results of the trial indicated that the CMV vaccines co-injected with PF-03512676 were safe and immunogenic. In particular, Tet-CMV + PF-03512676 had a favorable safety profile that led to a substantial expansion of pp65495-503 T cells after two subcutaneous vaccine injections. A summary of the results of the trial was published in 2012 (see La Rosa et al, 2012).
A single center Phase 1b pilot trial has been completed and evaluated the safety of administering CMVPepVax to HLA matched related (MRD) or unrelated (URD) donor HCT patients at risk for CMV complications ([email protected]
). Computer generated 1:1 randomization assigned each patient either to the vaccine or to the non-interventional (prospective) immune monitoring arm. In the vaccine arm, patients were vaccinated twice (day 28 and 56 post-HCT) with CMVPepVax. Safety (primary endpoint) included continuous post-immunization assessment until day 100 for CMV viremia (>500 genome copies/mL) and GVHD as necessary, until day 180 for any adverse event in 18 immunized patients. CMV-specific vaccine function (secondary endpoint) was monitored in all enrolled patients in both trial arms (n = 36) biweekly from day 28-100 post-HCT and every 30 days thereafter by measuring numbers of CD8+ T-cells binding to HLA-multimers.
We safely administered CMVPepVax to 18 patients and enrolled (n=18) observational patients for this study. Results of this trial, recently published in Lancet Haematology (Nakamura et al, 2016) indicated favorable tolerability, safety, increases in CMV-specific pp65495-503 CD8+ T cells without elevation of GVHD incidence and grade, in immunized patients. Importatnly, the trial also showed significant clinical benefit in the CMVPepVax vaccinated recipients, who experienced improved survival with reduced CMV reactivation and usage of toxic antivirals. Based on the successful data of the pilot trial, NCI-NExT provided a newly manufactured lot of CMVPepVax to support the ongoing multi-center Phase 2 efficacy trial, which started enrollment in June 2015. Currently, this randomized, blinded, placebo-controlled Phase 2 study will test the primary endpoint of reduced CMV reactivation, defined as viral load >500 genome copies/mL, in MRD and URD HCT recipients (see previous paragraph for clinical trial specifications). Immunologic secondary endpoints will be quantified by frequency measurements of CMV-specific T and NK cells, and functional studies that will assess improved effector function in vaccinated patients. The goal is to capitalize on our Phase 1 success with CMVPepVax by conducting Phase 2 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. This study is supported by a five year NIH-NCI award.
Nakamura R, La Rosa C, Longmate J, Drake J, Slape C, Zhou Q, Lampa MG, O’Donnell M, Cai J-L, Farol L, Salhotra A, Snyder DS, Aldoss I, Forman SJ, Miller JS, Zaia JA, Diamond DJ. Viraemia, immunogenicity, and survival outcomes of CMV chimeric epitope vaccine supplemented with PF03512676 (CMVPepVax) in allogeneic haematopoietic stem-cell transplantation: randomised phase 1b trial. The Lancet Haematology. 3(2): e87-98, 2016. doi: 10.1016/S2352-3026(15)00246-X. PMC4926626
Cichocki F, Cooley S, Davis Z, DeFor TE, Schlums H, Zhang B, Brunstein CG, Blazar BR, Wagner J, Diamond DJ, Verneris MR, Bryceson YT, Weisdorf DJ, Miller JS. CD56dimCD57+NKG2C+ NK cell expansion is associated with reduced leukemia relapse after reduced intensity HCT. Leukemia, 30(2):456-63, 2015.
Wang X, Wong CW, Urak R, Mardiros A, Budde LE, Chang W-C, Thomas SH, Brown CE, La Rosa C, Diamond DJ, Jensen MC, Nakamura R, Zaia JA, Forman SJ. CMVpp65 vaccine enhances the antitumor efficacy of adoptively transferred CD19-redirected CMV-specific T cells. Clinical Cancer Research, 21(13):2993-3002, 2015. PMID:25838392
La Rosa C, Longmate J, Lacey SF, Kaltcheva T, Sharan R, Marsano D, Kwon P, J Drake, Williams B, Denison S, Broyer S, Couture L, Nakamura R, Kelsey MI, Krieg AM, Diamond DJ, and Zaia JA. Clinical Evaluation of Safety and Immunogenicity of PADRE-CMV and Tetanus-CMV fusion peptide vaccines with or without PF03512676 adjuvant. Journal of Infectious Diseases, 205:1294-1304, 2012. PMC3308906
La Rosa C, Wang Z, Brewer JC, Lacey SF, Villacres MC, Sharan R, Krishnan R, Crooks M, Markel S, Maas R, and Diamond DJ. Pre-clinical Development of an Adjuvant-Free Peptide Vaccine with Activity Against CMV pp65 in HLA Transgenic Mice. Blood 100(10):3681-3689, 2002. PM:12393676
Lacey SF, Gallez-Hawkins G, Crooks M, Spielberger R, Forman SJ, Zaia JA and Diamond DJ. Characterization of Cytotoxic Function of CMV-pp65-Specific CD8+ T-lymphocytes Identified by HLA Tetramers in Recipients and Donors of Stem Cell Transplants. Transplantation 74 (5):722-732, 2002. PM:12352893
BenMohamed, L., Denis, M., Auge, C., Primus, J., and Diamond D.J. Intranasal administration of a synthetic lipopeptide without adjuvant induces systemic immune responses. Immunology 106:113-121, 2002.
La Rosa C, Krishnan R, Markel S, Schneck JP, Houghten R, Pinilla C, and Diamond DJ. Enhanced Immune Activity of CTL Epitope Analogues Derived from Positional Scanning Synthetic Combinatorial Libraries. Blood 97(6):1776-1786, 2001.
Longmate J, York J, La Rosa C, Krishnan R, Zhang M, Senitzer D, and Diamond DJ. Population coverage by HLA class-I restricted cytotoxic T-lymphocyte epitopes. Immunogenetics 52 (3-4):165-173, 2001. PM:11220618
Zaia JA, Sissons P, Riddell S, and Diamond DJ. Status of CMV prevention and treatment in 2000. In Hematology 2000, pp 339-356, 2000.
BenMohamed L, Krishnan R, Auge C, Low L, Primus J, and Diamond DJ. CTL response to human cytomegalovirus minimal epitope vaccination in HLA-A2.1/HLA-DR1 transgenic mice: Dependence of class I MHC-restricted immune response on TH epitope interaction with MHC CLASS II. Human Immunology, 61(8):764-779, 2000.
Diamond DJ, York J, Sun J, Wright C, and Forman SJ. Development of an candidate HLA A*0201 restricted peptide-based vaccine against human CMV infection. Blood (Rapid Communication), 90: 1751-1767, 1997. PM:9292508
10/2014 – 7/2019
CMVPepVax to Protect HCT Recipients from Cytomegalovirus Infection
NExT Proposal 253529
Approved for funding
Production of a clinical lot of Tet-CMV vaccine for HCT recipients
3/2012 - 11/2013
Cancer Center Support Grant
Evaluation of safety and correlative immunogenicity studies of a CMV peptide vaccine co-injected with PF03512676 adjuvant in recipients of allogeneic HCT
10/1992 - 3/2012
Bone Marrow Transplantation for Hematologic Malignancy: Project III “Acquisition of Immunity to CMV”
3/1998 - 2/2009
Peptide vaccine to prevent CMV disease after HSCT
6/2004 - 9/2005
Design of an in vivo Assay to Measure the Potency of the PADRE-CMV and Tetanus-CMV Peptides
9/2001 - 8/2004
HLA Tetramer-Guided Analysis of CMV Immunity After BMT
10/2000 - 12/2002
NCI, SAIC Frederick
Preclinical Evaluation of Mono- and dilipidated Vaccines for Activity Against Cytomegalovirus
9/1997 – 8/2002
Therapeutic Vaccine to Limit CMV Infection After BMT
BB-IND13124 “CMV Fusion Peptide (PADRE T-cell helper epitope and Tetanus T-cell helper epitope; synthetic; Bachem California) Vaccine with and without Oligodeoxynucleotide Immunomodulator (CPG 7909; Coley Pharmaceutical Group, Inc.)”
Diamond, D.J. Diagnostic reagents for human cytomegalovirus and methods of use. Patent # 7,160,685, January 9, 2007
Diamond, D.J. CTL Epitope Analogs. Patent # 6,951,651, October 4, 2005
Diamond, D.J. Immuno-Reactive Peptide CTL Epitopes of Human Cytomegalovirus. Patent # 6,843,992, January 18, 2005
Diamond, D.J. Diagnostic Reagents for Human Cytomegalovirus and Methods of use. Patent # 6,733,973, May 11, 2004
Diamond, D.J. HCMV-reactive T cells and uses thereof. Patent # 6,727,093, April 27, 2004
Diamond, D.J. Immuno-Reactive Peptide CTL Epitopes of Human Cytomegalovirus. Patent # 6,726,910, April 27, 2004
Diamond, D.J. CTL Epitope Analogs. Patent # 6,632,435. October 14, 2003.
Diamond, D.J. Immuno-Reactive Peptide CTL Epitopes of Human Cytomegalovirus. Patent # 6,562,345, May 13, 2003
Diamond, D.J. Immunoreactive peptide CTL epitopes of cytomegalovirus pp150. Patent # 6,544,521, April 8, 2003 Diamond, D.J. Immuno-Reactive Peptide CTL Epitopes of Human Cytomegalovirus. Patent # 6,251,399, June 26, 2001
Diamond, D. J. and York, J. Immuno-reactive Peptide CTL Epitopes of Human Cytomegalovirus. Patent # 6,156, 317, December 5, 2000
Diamond, D.J. and York, J. Immuno-reactive Peptide CTL Epitopes of Human Cytomegalovirus. Patent # 6,074,645, June 13, 2000
John A. Zaia, M.D.: PI of the Phase Ib Trial in healthy adults
Ryotaro Nakamura, M.D.: PI of the Phase Ib and II Trial in HCT recipients; Clinical Staff of Department of Hematology and HCT
Stephen J. Forman, M.D.: Chair, Hem/HCT (City of Hope National Medical Center)
Corinna LaRosa, Ph.D.: Director of the laboratory correlative studies for vaccine clinical trials
Michael Verneris, M.D.: PI of the Phase II trial in HCT recipients
Jeffrey S. Miller, M.D.: co-PI (University of Minnesota Medical Center).
Pfizer, Inc.: Vaccine Research, supplier of PF-03512676 adjuvant.
For inquiries about this project or employment opportunities, please contact Melanie Lampa.