Clinical Trials /

HPV-16/18 E6/E7-Specific T Lymphocytes, Relapsed HPV-Associated Cancers, HESTIA

NCT02379520

Description:

Subjects have a type of cancer that has been associated with an infection with a virus called human papilloma virus (HPV). The cancer has come back, has not gone away after standard treatment or the subject cannot receive standard treatment. This is a research study using special immune system cells called HPVST cells, a new experimental treatment. Investigators want to find out if they can use this type of treatment in patients with HPV-cancers. They have discovered a way to grow large number of HPV-specific T cells from the blood of patients with HPV-cancers. They want to see if these special white blood cells, called HPVST cells, that will have been trained to kill HPV infected cells can survive in the blood and affect the tumor. They will also see if they can make the T cells more active against the HPV-cancers by engineering them to be resistant to the TGF-beta chemical that these HPV-cancers produce. They will grow these HPVST cells from the patient's blood. The purpose of this study is to find the biggest dose of HPVSTs that is safe, to see how long they last in the body, to learn what the side effects are and to see if the HPVSTs will help people with HPV associated cancers. If the treatment with HPVST cells alone proves safe (Group A), additional group of patients (Group B) will receive Nivolumab in addition to HPVST cells in a lymphodepleted environment. Nivolumab is an antibody therapy that helps T cells control the tumor and it is FDA approved for the treatment of certain types of cancers, including Hodgkin's lymphoma. Lymphodepletion will decrease the level of circulating T cells prior to infusion of HPVST cells, thereby giving them room to expand. The purpose of this part of the study is to find out if TGF-beta resistant HPVST cells in combination with Nivolumab are safe, how long they last in the body and if they are more effective than HPVST cells alone in controlling the tumor.

Related Conditions:
  • Malignant Solid Tumor
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

HPV-16/18 E6/E7-Specific T Lymphocytes, Relapsed HPV-Associated Cancers, HESTIA

Title

  • Brief Title: HPV-16/18 E6/E7-Specific T Lymphocytes, Relapsed HPV-Associated Cancers, HESTIA
  • Official Title: HPV-16/18 E6/E7-Specific T Lymphocytes in Patients With Relapsed HPV-Associated Cancers
  • Clinical Trial IDs

    NCT ID: NCT02379520

    ORG ID: H-36021 HESTIA

    Trial Conditions

    Human Papillomavirus-Related Carcinoma

    Human Papillomavirus Positive Oropharyngeal Carcinoma

    Human Papillomavirus Positive Cervical Carcinoma

    Human Papillomavirus Positive Anal Carcinoma

    Human Papillomavirus Positive Vulvar Carcinoma

    Human Papillomavirus Positive Penile Carcinoma

    Trial Interventions

    Drug Synonyms Arms

    Trial Purpose

    Subjects have a type of cancer that has been associated with an infection with a virus
    called human papilloma virus (HPV). The cancer has come back, has not gone away after
    standard treatment or the subject cannot receive standard treatment.

    The is a research study using special immune system cells called HPVST cells, a new
    experimental treatment.

    Investigators want to find out if they can use this type of treatment in patients with
    HPV-cancers. They have discovered a way to grow large number of HPV-specific T cells from
    the blood of patients with HPV-cancers. They want to see if these special white blood cells,
    called HPVST cells, that will have been trained to kill HPV infected cells can survive in
    the blood and affect the tumor. They will also see if they can make the T cells more active
    against the HPV-cancers by engineering them to be resistant to the TGF-beta chemical that
    these HPV-cancers produce. They will grow these HPVST cells from the patient's blood.

    The purpose of this study is to find the biggest dose of HPVSTs that is safe, to see how
    long they last in the body, to learn what the side effects are and to see if the HPVSTs will
    help people with HPV associated cancers.

    Detailed Description

    HPV is found in the cancer cells of more than half the patients with certain types of
    cancer, suggesting that it may play a role in causing the cancer. The virus makes proteins
    in the tumor cells that should allow the diseased cells to be recognized and killed by a
    part of the body's own immune system called T cells. Unfortunately, tumors are able to avoid
    being killed by making molecules that turn off these T cells. So, the cancer cells infected
    by HPV are able to hide from the body's immune system and escape destruction.

    The investigators have previously studied cancers caused by a different virus, called
    Epstein-Barr virus (EBV). These EBV-cancers are like HPV-cancers, since they turn off the T
    cells that would otherwise destroy them, and so can keep growing. They investigators have
    found, however, that if they removed the T cells from the blood of patients with EBV-cancers
    and grew them outside the body, they could increase the number and the activity of T cells
    directed against the tumors. When these T cells were given back to the patients, the T cells
    eliminated the cancers in over half the recipients. Investigators also found that they could
    engineer the T cells to be even more active against the EBV-cancer cells by making them
    resist an inhibitory chemical called TGF-beta, which is produced by these cancer cells.

    Investigators will collect up to 240 mL of blood. Then they will use this blood to grow T
    cells. First they will grow them in a special type of cell called a dendritic cell, which
    stimulates the T cells. These dendritic cells will then be loaded with bits of proteins from
    the HPV virus called E6 and E7. These dendritic cells will be used to stimulate T cells.
    This stimulation trains the T cells to kill cells with the HPV proteins E6 and E7 on their
    surface. Next, the investigators will grow these HPV-specific T cells by more stimulation
    with dendritic cells and HPV proteins, and, when needed, a special type of cell called K562.
    These K562 cells were treated with radiation so they cannot grow.

    To make these T cells resistant to the TGF-beta released by the tumor, investigators will
    put a new gene in them in the laboratory called a mutant TGF-beta receptor. In cells with
    this new gene, TGF-beta released by the tumor cells will not be able to bind to the mutant
    TGF-beta receptor on the T cell. Investigators hope this will improve the chances that after
    the T cells are injected they will be able to keep working and kill the tumor cells. This
    gene is added to the cells using a mouse retrovirus that has been changed to stop it from
    causing infections. Retroviruses enter the cell's DNA (genetic material) to make permanent
    changes to the cell.

    After making these cells, they will be frozen. For treatment, the cells will be thawed and
    injected in a vein over 5 to 10 minutes. Initially, one dose of T cells will be given.

    If, after the 1st infusion, there is a reduction in the size of the subject's cancer (or no
    increase) on CT or MRI scans as assessed by a radiologist, the subject can receive
    additional doses if it would be to his/her benefit, if s/he would like to receive more
    doses, and if there is enough product remaining to give any additional injections (at the
    same or a lower dose).

    This is a dose escalation study. The dose the patient will get will depend on how many
    participants get the agent beforehand and how they react.

    Investigators will follow the patient during and after the injections at predetermined time
    points which may require blood draws and other examinations.

    Trial Arms

    Name Type Description Interventions
    HPV Specific T Cells Experimental Human Papillomavirus Specific T cells

    Eligibility Criteria

    Inclusion Criteria:

    PROCUREMENT

    1. Diagnosis of a cancer for which the presence of a high risk HPV type has been
    documented in a biopsy sample

    2. Cancer is:

    - recurrent or persistent after standard therapy

    - OR patient is unable to receive standard therapy

    3. Karnofsky score 50%

    4. Informed consent

    TREATMENT

    1. Diagnosis of a cancer for which the presence of a high risk HPV type has been
    documented in a biopsy sample

    2. Cancer is:

    - recurrent or persistent after standard therapy

    - OR patient is unable to receive standard therapy

    3. Life expectancy 6 weeks.

    4. Age 18 years.

    5. Karnofsky score 50%

    6. Bilirubin < 3 upper limit of normal (ULN), AST < 5 ULN, Hgb > 8.0 g/dL and serum
    creatinine < 3 ULN

    7. Pulse oximetry of > 90% on room air.

    8. Informed consent

    9. Sexually active patients must be willing to utilize one of the more effective birth
    control methods during the study and for 3 months after the study is concluded. The
    male partner should use a condom.

    Exclusion Criteria:

    PROCUREMENT

    1. Known HIV positivity.

    TREATMENT

    1. Currently receiving any investigational agents or have received any tumor vaccines or
    T cell antibodies within previous 4 weeks.

    2. Severe intercurrent infection.

    3. Pregnancy or lactation.

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: N/A

    Eligible Gender: Both

    Primary Outcome Measures

    Number of Patients with DLT

    Secondary Outcome Measures

    Number of HPVST cells in Blood

    Number of HPVST cells in Blood

    Number of Patients with Tumor Response

    Number of HPVSTs in the blood that have been transduced with a dominant-negative receptor for TGF

    Number of HPVSTs in the blood that have been transduced with a dominant-negative receptor for TGF

    Trial Keywords

    recurrent cancer

    refractory cancer

    virus specific T-cells

    gene therapy

    HPV