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Last Updated: 09/21/21

SPORE in Cervical Cancer

Johns Hopkins University

Principal Investigator(s):

T.-C. Wu, MD, PhD
T.-C. Wu, MD, PhD

Principal Investigator(s) Contact Information

T.-C. Wu, MD, PhD
Professor of Pathology
Director, Gynecologic Pathology Division
Johns Hopkins University
1550 Orleans St, CRB II Rm 309
Baltimore, MD 21287
(410) 614-3899

Overview

Johns Hopkins is home to the Specialized Program of Research Excellence (SPORE) in Cervical Cancer and aims to explore groundbreaking cervical cancer research, prevention, and treatment. Johns Hopkins has been the home to this project since 2003. The goal of the Cervical Cancer SPORE is to reduce the incidence, morbidity, and mortality related to cervical cancer by developing next-generation therapeutic human papillomavirus (HPV) vaccines for clinical translation. These projects are translational in nature and address diagnosis, detection, prevention, treatment, and risk assessment for cervical cancer.

Our SPORE includes the following three research projects:

  • Project 1 Thermostable RG1-VLPs, a candidate broadly protective HPV vaccine for the prevention of cervical cancer
  • Project 2 Electroporation delivery of pNGVL4aCRTE6E7L2 DNA for the treatment of HPV16+ CIN2/3 patients
  • Project 3 Phase I safety and immunogenicity study of HPV16-specific therapeutic protein, TA-CIN, administered intratumorallly with chemoradiation in patients with cervical cacncer stratified by HPV16 infection.

This program is supported by an Administrative/Communication Core (Core A), a Biostatistics/Bioinformatics Core (Core B), a Tissue/Pathology/Immunology CORE (Core C), and innovates and renews through a Developmental Research Program (DRP) and a Career Enhancement Program (CEP).

Project 1: Thermostable RG1-VLPs, a candidate broadly protective HPV vaccine for the prevention of cervical cancer

Project Co-Leaders:
Richard Roden, PhD (Basic Co-leader)
Robert Garcea, MD (Applied Co-leader)
Warner Huh, MD (Clinical Co-leader)

>85% of cervical cancers occur in developing country populations that are hard to reach with a vaccine, or lack access to either cervical screening or HPV vaccination. Our overall goal is to develop an affordable HPV vaccine that both extends the breadth of protection to all oncogenic types and is stable at ambient temperature. This is an important opportunity to reduce the global burden of cervical cancer, regardless of race, income or location. We generated a monoclonal antibody (mAb) RG1 reactive against the HPV16 L2 protein and able to cross-neutralize several key oncogenic HPV types. The HPV16L2 RG1 epitope was cloned into the DE surface loop of HPV16 L1.

Based on data produced by the Cervical Cancer SPORE, we have obtained a patent in several countries, a commercial licensee (Pathovax LLC) and an NCI PREVENT award for our novel RG1-VLP based vaccine. The PREVENT program is producing GMP grade RG1-VLPs at Paragon Inc., Baltimore, MD, for our use, and will fund a preclinical toxicology study in support of the IND. Pathovax LLC has initiated a head-to-head comparison with Gardasil 9, and shown that vaccination of rabbits with RG1-VLPs adjuvanted with aluminum hydroxide (alum) provides robust protection against experimental challenge with all HPV types tested to date.

Aim 1: Develop a GLP freeze-dry protocol for a powder formulation of RG1-VLPs in alum and study its in vitro temperature stability, and in murine models test its immunogenicity and protective efficacy in comparison to Gardasil 9.

Aim 2: To perform a Dose Escalation Phase I Trial of the Safety and Immunogenicity of RG1-VLP in 36 healthy female volunteers with the inclusion of a control Gardasil 9 arm in the study.

Aim 3: To analyze the levels of protective antibodies in the serum of patients from the phase I study induced by RG1-VLP vaccination or Gardasil 9. We will utilize the passive transfer assay to measure protective responses, as well as L2 and L1 VLP ELISA and in vitro neutralization assays to quantify antigen-specific neutralizing antibody titers in serum.

Project 3: Electroporation delivery of pNGVL4aCRTE6E7L2 DNA for treatment of HPV16+ CIN2/3 patients

Project Co-Leaders:
Kimberly Levinson, MD, MPH (Clinical Co-leader)
Richard Roden, PhD (Basic Co-leader)
Chien-Fu Hung, PhD (Basic Co-leader)
Warner Huh, MD (Clinical Co-leader)

The increased rates of HPV-associated malignancy in HIV+ patients and organ transplant recipients, as well as a wealth of preclinical studies, suggest the importance of cellular immunity in controlling infection. To accelerate the impact of HPV vaccination even in HIV+ patients, here our goal is to develop a combined therapeutic and preventive approach to eradicate established infection and/or HPV-associated precancerous lesions by inducing cell-mediated immunity, as well as to elicit broadly protective humoral immunity to prevent new HPV infections. We have previously developed a candidate therapeutic and preventive DNA vaccine, pNGVL4aCRTE6E7L2 (CRTE6E7L2), which encodes calreticulin linked to HPV16 E6, E7, and L2 proteins. Due to the prevalence and diversity of HPV types and the lack of antiviral agents for HPV, development of broad-spectrum prophylactic vaccines against all 14 high-risk HPV is an attractive strategy in the prevention of the HPV-associated cancer in HIV+ patients. Nevertheless, our focus remains on HPV16 as it is the most common type in cervical cancer and is dominant in other anogenital and head and neck malignancies. Our overall goal is to use the Ichor TriGrid™ Delivery System Electroporation Device, which has been used safely in multiple clinical trials, for i.m. administration of the CRTE6E7L2 DNA vaccine at escalating doses in both HIV- and HIV+ patients with HPV16-associated high-grade cervical intraepithelial neoplasia grades 2 and 3, and to examine the safety, virologic, and disease outcomes.

Aim 1: To evaluate the safety and toxicity of CRTE6E7L2 administered via electroporation in HIV- and HIV+ patients with HPV16+ CIN2/3.

Aim 2: To characterize the HPV16 E6/E7-specific cell-mediated and humoral immune responses in HIV- and HIV+ patients with HPV16+ CIN2/3 vaccinated with CRTE6E7L2 via electroporation.

Aim 3: To characterize L2-specific humoral immune responses in HIV- and HIV+ patients with HPV16-associated CIN2/3 upon vaccination with CRTE6E7L2 DNA vaccine via electroporation.

Aim 4: To determine the HPV viral load and histopathological changes in the lesion and its microenvironment in HIV- and HIV+ patients with HPV16-associated CIN2/3 upon treatment with CRTE6E7L2 DNA vaccine via electroporation.

Project 4: A Phase I safety & immunogenicity study of an HPV16-specific therapeutic protein, TA-CIN, administered intratumorally with chemoradiation in patients with cervical cancer stratified by HPV16 infection

Project Co-leaders:
TC Wu, MD, MPH, PhD (Co-Leader)
Stephanie Gaillard, MD, PhD (Clinical Co-Leader)
Charles (Trey) Leath III, MD, MSPH (Clinical Co-Leader)

The current standard-of-care for inoperable, locally advanced, stage IIB-IVA cervical cancer includes the chemotherapeutic drug, cisplatin, in conjunction with local radiation therapy. However, the five-year survival in most patients affected by stage IIB-IVA cervical cancer is ~30% (58%-63% for stage II patients, 32-35% for stage III patients, and 16% for stage IVA patients). Therefore, an innovative treatment strategy, such as immunotherapy, is needed improve patient outcomes. We have discovered that chemoradiation transiently converts the tumor microenvironment into a site permissive for the activation of an adaptive immune response. We found that chemotherapy or radiation therapy combined with intratumoral antigenic peptide administration was sufficient could lead to synergistic therapeutic antitumor effects compared to either treatment alone. Furthermore, this combination treatment leads to the presentation of antigenic peptide by immunosuppressive stromal cells of the tumor, which are thus rendered susceptible to antigen-specific CD8+ T cell-mediated killing, potentially contributing to the control of tumor regardless of the type of HPV infection. Together, this results in potent antigen-specific CD8+ T cell immune responses and antitumor effects. Our overall hypothesis is that intratumoral TA-CIN vaccination combined with chemoradiotherapy will enhance HPV antigen-specific immune responses that will accumulate in the tumor microenvironment and promote the killing of immunosuppressive stromal cell and/or tumor cells, leading to better control of HPV-related tumors.

Aim 1: To evaluate the safety and toxicity of TA-CIN administered intratumorally in both HPV16 (+) and HPV16 (-) stage IIB-IVA cervical cancer patients.

Aim 2: To characterize the HPV16 E6/E7-specific T cell-mediated and L2-specific humoral immune responses as well as HPV16 viral load in stage IIB-IVA cervical cancer patients intratumorally vaccinated with TA-CIN.

Aim 3: To determine the phenotypes of immune cells infiltrating the lesion bed, expression of PD-1 and PD-L1 in the tumor microenvironment, and apoptotic lesion cell death in HPV16-associated stage IIB-IVA cervical cancer patients receiving intratumoral TA-CIN vaccination.

Aim 4: To characterize the HPV16 E6/E7 antigen-specific CD8+ T cell-mediated immune responses and therapeutic antitumor effects in a spontaneous HPV16 E6/E7-expressing cervicovaginal carcinoma model treated with intratumoral TA-CIN vaccination with or without checkpoint blockade treatment.

Administrative/Communication Core

Core Directors:
TC Wu, MD, MPH, PhD
Warner Huh, MD

The Administration/Communication Core is responsible for managing and overseeing the SPORE, disseminating information within the SPORE, and external interactions. The organizational structure provided by the Core and the administrative oversight, review, and monitoring features of each component highlight the importance of this Core to the SPORE.

Core A serves the entire project in several key areas of coordination and oversight. The objectives of the Administrative/Communication Core are:

  1. Provide administrative oversight and support to all activities of the SPORE, including Projects, Cores and Programs.
  2. Ensure compliance with all general, federal and local regulations and requirements.
  3. Oversee all communication and consultation with the NCI personnel in the preparation of all required reports and publications.
  4. Coordinate with other SPORE programs to promote and maintain communication and integration, and oversee the distribution of materials between SPORE institutions.
  5. Enhance interaction and communications between JHU, UAB, and UCB by convening all meetings including the Steering Committee, the Internal and External Advisory Board Committees, monthly investigators meetings, quarterly research meetings, lectures and symposia.
  6. Coordinate data control and quality assurance issues in conjunction with the Internal Scientific Advisory Board and Tissue/Pathology/Immunology and Biostatistics/Bioinformatics Cores.
  7. Assume responsibility for maintenance of fiscal and budgetary functions.
  8. Establish and monitor policies for the recruitment of individuals from disadvantaged groups in all clinical studies and as SPORE investigators.
  9. Ensure protection of human subjects from research risks with implementation of a data safety and monitoring plan where appropriate.
  10. Implement policies to determine the success of ongoing projects with a clear plan describing how underperforming projects or cores would be replaced as well as a mechanism to identify new projects.
  11. Implement policies for replacement of key personnel and projects and cores when required.
  12. Assume responsibility for all issues related to technology transfer and management of intellectual property rights under the requirements of the Bayh-Dole Act NIH funding agreements.
  13. Ensure that the SPORE interactions with commercial entities uphold the principles of academic freedom, including the ability of SPORE investigators to collaborate freely and to send and receive biomedical research materials without undue restriction to other scientific investigators.

Biostatistics and Bioinformatics Core

Core Directors:
Chenguang Wang, PhD (Core Co-Director)
Sejong Bae, PhD (Core Co-Director)
Anne Rostich, PhD (Core Co-Director)

The Biostatistics/Bioinformatics Core (Core B) will provide centralized biostatistics and bioinformatics services, as well as collaborative research and data management support for the research projects of the Cervical Cancer SPORE. Core B will support the Cervical Cancer SPORE by providing innovative statistical and bioinformatics services via seamless consultation as well as database management that is in compliance with NIH and FDA regulations.

Through consultation and collaboration, Core B will provide SPORE investigators with assistance and direction in their experimental design, data collection, and interim and final statistical data analysis. Core B will lead the effort to design a clinical and basic research database with user-friendly interface for data entry, data retrieval, patient or sample tracking and procedures to ensure data quality, integrity, and confidentiality. Core B will serve as the focal point from which SPORE investigators and career enhancement awardees, including basic scientists, clinicians, and epidemiologists, can draw biostatistics and bioinformatics expertise for the communications and analyses of their research projects.

The Specific Aims of the Biostatistics/Bioinformatics Core are:

  1. To provide biostatistics and bioinformatics consultation and support by assisting in experimental design and data collection, visualization, analysis, quantitative modeling, interpretation, and publication for all SPORE projects.
  2. To provide biostatistics and bioinformatics support for the Tissue/Pathology/Immunology Core (Core C), the Developmental Research Program awardees, and the Career Enhancement Program awardees.
  3. To develop new or adapt existing biostatistics and bioinformatics methods as needed and appropriate.

Tissue and Pathology/Immunology Core

Core Directors:
Todd Stevens, MD (Core Co-Director)
Raphael Viscidi, MD (Core Co-Director)
Russel Vang, MD (Core Co-Director)

The acquisition and preservation of well-annotated, high-quality human tissues and biologic fluids, and the in situ analysis of the immune response therein, is pivotal to the success of all four HPV vaccine-based SPORE projects. This Shared Resource aims to support all four HPV vaccine-based SPORE projects as well as external collaborators.

We have built upon our successes in the prior funding period by expanding the resources of the Core C Shared Resource to strengthen guidance for pathologic interpretation and tissue-based analyses of immune responses, including specimens obtained from patients enrolled in SPORE-related protocols through recruitment of new members of this Shared Resource, serves as Director. This core will work closely with the Biostatistics/Bioinformatics Core (Core B) to ensure appropriate data management and controls via our web-based database as well as, study design, assay validation, and the processing and analysis of immunologic data sets.

  1. Collect, process, store, and ship tissues and biologic fluids for translational research without compromising sample integrity, traceability, or patient care
  2. Provide well-characterized tumors, precursor lesions and normal tissues with respect to site of origin, World Health Organization histologic subtype, differentiation, and fraction of neoplastic and stromal tissues with matching PBMC or serum samples as required
  3. Support the generation of tissue microarrays with a wide range of biologic potential (e.g. normal, dysplasia, carcinoma) and/or relevant clinical parameters (e.g. before and after vaccination) and laser-capture microdissection as needed
  4. Support HPV typing of samples
  5. Provide well-defined mechanisms for prioritization of the expeditious distribution of requested resources to investigators within and external to the Cervical Cancer SPORE per institutional guidelines.
  6. Provide expert advice, execution and interpretation of multi-parameter immunohistochemical studies including digital microscopic photography and image processing
  7. Provide pathological interpretation of stained tissue and cytologic samples
  8. Provide expert support and sample organization for the execution and interpretation of human serologic assays
  9. Provide expert experimental support, sequencing and interpretation of human TCR sequences in tissue and blood
  10. Organize blinded sample sets to ship to sites that include appropriate controls to ensure data integrity, reproducibility and comparability.

Developmental Research Program

Program Directors:
TC Wu, MD, MPH, PhD (Director)
Drew Pardoll, MD, PhD (Co-Director)

The Developmental Research Program is an important mechanism for nurturing new ideas and techniques relevant to cervical cancer to reach the level of full projects in the SPORE, and attracting new faculty members to work on cervical cancer. The Program takes advantage of the broad expertise of researchers at JHU, UCB, and UAB, bringing in researchers from different fields (i.e. radiology, immunology, molecular biology and genetics etc.). The Program provides funds for pilot projects with potential for development into full-fledged translational research avenues, collaborations, and new methodologies for integration into other Research Projects.

Career Enhancement Program

Program Directors:
TC Wu, MD, MPH, PhD (Director)
Donald Buchsbaum, PhD (CEP Co-Director)

The Career Enhancement Program is critical to the rejuvenation of the Cervical Cancer SPORE Program by recruiting the best junior faculty to focus on cervical cancer research. We plan to attract, select, and mentor promising junior investigators with a special emphasis on recruiting qualified women, individuals from underrepresented racial and ethnic groups, as well as individuals with disabilities. The Cervical Cancer SPORE will support Career Enhancement Program awardees’ rigorous and innovative translational research projects addressing cervical cancer.

Institutional SPORE Website

https://labs.pathology.jhu.edu/ccspore/