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SU2C-Farrah Fawcett Foundation HPV Translational Research Team Progress Update

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SU2C-Farrah Fawcett Foundation Human Papillomavirus (HPV) Translational Research Team Progress Report

Therapeutic CD8 vaccines against conserved E7 HPV epitopes identified by MS

Funding: $1.2 million

Leader: Ellis L. Reinherz, MD, Dana-Farber Cancer Institute
Co-Leader: Robert I. Haddad, MD, Dana-Farber Cancer Institute


Fast Facts on Human papillomavirus:

  • Human papillomavirus (HPV) is a sexually-transmitted virus that causes cancer in 26,000 men and women a year.
  • HPV causes several types of cancers including anal, cervical, vulvar, vaginal, penile, and head and neck cancer.
  • More than 90% of anal and cervical cancers are attributed to HPV.

Fast Facts on Prevention Tips:

  • Preventative measures against HPV include condom use, vaccination, and screening.
  • Vaccination against HPV is recommended for all boys and girls age 11-12.

 

Project Background

Worldwide, persistent infection with certain types of human papillomavirus (HPV) is responsible for more than five percent of all new human cancer cases. These viruses play a significant role in cancers of the cervix, vulva, vagina, anus, penis, head, and neck. Although vaccines can help prevent infection with the HPV types that cause the most cancer cases, these vaccines do not benefit people once they have already become infected.

Once a cancer-causing type of HPV has established itself, immune cells called cytolytic T lymphocytes (CTLs) are required to eradicate the virus-infected precancerous or cancerous cells. CTLs distinguish between the body’s own good cells and those that are abnormal by recognizing “tags” on the surface of the abnormal cells. More specifically, “tags” called epitopes on the abnormal cells are detected by molecules called T cell receptors (TCRs) on the CTL. Using their TCRs, CTLs can distinguish between normal and abnormal cells with great specificity. Since CTLs are able to distinguish abnormal epitopes in a sea of 100,000 normal epitopes, these cells are ideal for development of therapeutic vaccines that stimulate the right CTLs to attack virus-infected, pre-cancerous, or cancerous cells.

The multidisciplinary research team led by Reinherz and Haddad includes molecular and cellular immunologists, an ion physicist, a computer scientist, a vaccinologist, a molecular oncologist, and translational scientists. The team focuses on patients with HPV-driven cancers (including cervical, anal, and head and neck cancer) who relapse following initial therapy. These patients have few treatment options, and the Team’s aim is to develop novel immunotherapy approaches that will address this huge unmet need.

The researchers have developed a highly sensitive ion physics method to find epitopes on cancer cells that are entirely specific for the cancer and hence not found on the normal cells in the body. CTLs in the patient’s body can be programmed by vaccination to detect these epitopes and then attack and kill the cancer. One epitope CTL target that the Team has already identified has been incorporated into a new therapeutic vaccine that will be tested in patients in a clinical trial as part of this research grant. The team will also use their epitope-identification technology to find other epitopes for the development of additional immunotherapeuties. Finally, they will identify the T cell receptors on CTLs that provide the best immune response in order to re-engineer the patients’ own immune cells in the laboratory for use as a cancer treatment.

The innovative approaches to be pursued here will lead to novel immunotherapies that have the potential to dramatically improve outcomes for patients with HPV-driven cancers who relapse following initial therapy.

Status Update:

6 Months:
During the first 6 months, the Team reports that:

  • They have developed a protocol for the proposed vaccination clinical trial and are awaiting approval from the Dana-Farber Cancer Institute, the first of several approvals required.
  • They have been preparing the necessary materials for the clinical trial.
  • They have optimized a new method to evaluate key epitopes of HPV-related cancers.
  • They are working on methods to isolate cells from tumors that will eventually be used for analyzing cell markers.

During the next 6 months, the Team will continue to optimize their clinical trial protocol and work on obtaining approval to conduct the study. They will also continue to work on optimizing methods to identify and evaluate key markers of HPV-related cancers.

12 Months:
During this 6-month reporting period, the Team has continued its progress on this grant. They report that:

  • They held a teleconference with the Food and Drug Administration (FDA) discussing the study design for the proposed vaccination clinical trial. Upon recommendation from the SU2C review committee, the primary endpoint for this clinical trial was changed and preliminarily approved by the FDA.
  • Once the vaccine is available, the proposed clinical trial will be reviewed by experts at the Team’s institution to ensure patient safety.. The Team anticipates the review to begin by the end of June 2015.
  • They have optimized their new mass spectrometry instruments, which are the instruments used to find epitopes on HPV related-cancers, and are ready to evaluate patients’ tumor samples.

They have published a scientific paper describing the methods they developed to understand how cancer cells change when exposed to a vaccine.

During the next six months, the Team will continue to study how a person’s body responds to vaccines in the laboratory. They will continue efforts to ensure their proposed clinical trial meets all necessary safety requirements. Finally, they will use the new method they developed to understand how cancer cells respond to vaccines to study immune cells associated with HPV.

18 Months:
The Team has made considerable progress in the 12-18 month period of the grant.

  • The team has scheduled drug procurement and regulatory approvals for the planned clinical trial. Currently, the Team anticipates that the HPV-16 E711-19 vaccine will be available for patient use in April 2016. The protocol is under IRB review and the Team anticipates submission to the FDA by mid-April 2016.
  • The Team has acquired state-of-the-art new equipment and is optimizing and refining the sensitivity for detecting specific flags on cells associated with HPV cancers. Detection sensitivity is vital to select the most suitable patient for the trial and for subsequent evaluation of how the vaccine therapy is working.

24 Months:
The Team reports the following progress in the 19-24 month period of the grant:

  • The clinical trial protocol has been approved by the Institutional Review Board (IRB) and the US Food and Drug Administration (FDA). It is slated to open in the next six months.
  • Laboratory work continues to optimize the preparation of patient samples for evaluation of immune response to the vaccine.
  • The optimization of patient sample evaluation continues, utilizing highly sensitive machinery/technology, called mass spectrometry, as well as digital imaging technology.


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