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.
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
- ORG STUDY ID:
H-36021 HESTIA
- NCT ID:
NCT02379520
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
Interventions
| Drug | Synonyms | Arms |
|---|
| Cytoxan | cyclophosphamide | Group B |
| Fludarabine | Fludara | Group B |
| Nivolumab | Opdivo | Group B |
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.
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.
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 390 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 1 to 10 minutes.
Initially, one dose of T cells will be given (which is considered day 0).
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).
If treatment with HPVST cells alone proves safe, additional group of patients (Group B) will
receive HPVST cells with nivolumab in lymphodepleted environment. One dose of the drug
nivolumab is given one day before the HPVST cells are infused and then every 2 weeks for a
total of four doses of nivolumab. Lymphodepletion will be given daily starting day -4 prior
to administration of HPVSTs.
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 |
|---|
| Group A | Experimental | HPV Specific T Cells | |
| Group B | Experimental | HPV Specific T Cells plus lymphodepletion (Cytoxan and Fludarabine) and nivolumab | - Cytoxan
- Fludarabine
- Nivolumab
|
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 explained to, understood by and signed by patient/guardian.
Patient/guardian given copy of 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 ≥ 7.0 g/dL
7. Pulse oximetry of > 90% on room air.
8. GFR > 30 mL/min calculated by the Cockcroft-Gault, MDRD study, or CKD-EPI creatinine
equations, or equivalent
9. Informed consent explained to, understood by and signed by patient/guardian.
Patient/guardian given copy of informed consent
10. Sexually active patients must be willing to utilize one of the more effective birth
control methods during the study and for 6 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.
| Maximum Eligible Age: | N/A |
| Minimum Eligible Age: | 18 Years |
| Eligible Gender: | All |
| Healthy Volunteers: | No |
Primary Outcome Measures
| Measure: | Number of patients with dose limiting toxicity (DLT) |
| Time Frame: | 6 weeks |
| Safety Issue: | |
| Description: | DLT will be defined as any toxicity that is irreversible or life threatening, defined as the following, considered to be possibly, probably, or definitely related to the HPVST injection.
Non-hematologic DLT is any grade 3 or grade 4 non-hematologic toxicity.
Hematologic DLT is defined as any grade 4 hematologic toxicity. |
Secondary Outcome Measures
| Measure: | Overall response rate |
| Time Frame: | 6 weeks |
| Safety Issue: | |
| Description: | To measure anti-tumor effects of HPV-specific T lymphocytes |
Details
| Phase: | Phase 1 |
| Primary Purpose: | Interventional |
| Overall Status: | Recruiting |
| Lead Sponsor: | Baylor College of Medicine |
Trial Keywords
- recurrent cancer
- refractory cancer
- virus specific T-cells
- gene therapy
- HPV
Last Updated
January 6, 2021
