Autologous T-Cells Expressing a Second Generation CAR for Treatment of T-Cell Malignancies Expressing CD5 Antigen
| Status: | Recruiting |
|---|---|
| Conditions: | Lymphoma, Lymphoma |
| Therapuetic Areas: | Oncology |
| Healthy: | No |
| Age Range: | Any - 75 |
| Updated: | 3/17/2019 |
| Start Date: | November 1, 2017 |
| End Date: | June 1, 2036 |
| Contact: | Rayne Rouce, MD |
| Email: | rhrouce@txch.org |
| Phone: | 832-824-4716 |
Phase 1 Therapy of Manufactured Autologous T-Cells Expressing a Second Generation Chimeric Antigen Receptor (CAR) for Treatment of T-Cell Malignancies Expressing CD5 Antigen
Patients eligible for this study have a type of blood cancer called T-cell leukemia or
lymphoma (lymph gland cancer).
The body has different ways of fighting infection and disease. No one way seems perfect for
fighting cancers. This research study combines two different ways of fighting disease,
antibodies and T cells, hoping that they will work together. Antibodies are types of proteins
that protect the body from bacterial and other diseases. T cells, also called T lymphocytes,
are special infection-fighting blood cells that can kill other cells including tumor cells.
Both antibodies and T cells have been used to treat patients with cancers; they have shown
promise, but have not been strong enough to cure most patients.
T lymphocytes can kill tumor cells but there normally are not enough of them to kill all the
tumor cells. Some researchers have taken T cells from a person's blood, grown more of them in
the laboratory and then given them back to the person. The antibody used in this study is
called anti-CD5. It first came from mice that have developed immunity to human leukemia. This
antibody sticks to T-cell leukemia or lymphoma cells because of a substance on the outside of
these cells called CD5. CD5 antibodies have been used to treat people with T-cell leukemia
and lymphoma. For this study, anti-CD5 has been changed so that instead of floating free in
the blood it is now joined to the T cells. When an antibody is joined to a T cell in this way
it is called a chimeric receptor.
In the laboratory, the investigators have also found that T cells work better if proteins
that stimulate T cells are also added, such as one called CD28. Adding the CD28 makes the
cells grow better and last longer in the body, thus giving the cells a better chance of
killing the leukemia or lymphoma cells.
In this study investigators are going to attach the CD5 chimeric receptor with CD28 added to
it to the patient's T cells. The investigators will then test how long the cells last. These
CD5 chimeric receptor T cells with CD28 are investigational products not approved by the Food
and Drug Administration .
lymphoma (lymph gland cancer).
The body has different ways of fighting infection and disease. No one way seems perfect for
fighting cancers. This research study combines two different ways of fighting disease,
antibodies and T cells, hoping that they will work together. Antibodies are types of proteins
that protect the body from bacterial and other diseases. T cells, also called T lymphocytes,
are special infection-fighting blood cells that can kill other cells including tumor cells.
Both antibodies and T cells have been used to treat patients with cancers; they have shown
promise, but have not been strong enough to cure most patients.
T lymphocytes can kill tumor cells but there normally are not enough of them to kill all the
tumor cells. Some researchers have taken T cells from a person's blood, grown more of them in
the laboratory and then given them back to the person. The antibody used in this study is
called anti-CD5. It first came from mice that have developed immunity to human leukemia. This
antibody sticks to T-cell leukemia or lymphoma cells because of a substance on the outside of
these cells called CD5. CD5 antibodies have been used to treat people with T-cell leukemia
and lymphoma. For this study, anti-CD5 has been changed so that instead of floating free in
the blood it is now joined to the T cells. When an antibody is joined to a T cell in this way
it is called a chimeric receptor.
In the laboratory, the investigators have also found that T cells work better if proteins
that stimulate T cells are also added, such as one called CD28. Adding the CD28 makes the
cells grow better and last longer in the body, thus giving the cells a better chance of
killing the leukemia or lymphoma cells.
In this study investigators are going to attach the CD5 chimeric receptor with CD28 added to
it to the patient's T cells. The investigators will then test how long the cells last. These
CD5 chimeric receptor T cells with CD28 are investigational products not approved by the Food
and Drug Administration .
To make the T cells the investigators will take the patient's blood and stimulate it with
growth factors to make the T cells grow. To get the CD5 antibody and CD28 to attach to the
surface of the T cell, investigators insert the antibody gene into the T cell. This is done
with a virus called a retrovirus that has been made for this study and will carry the
antibody gene into the T cell. This virus also helps investigators find the T cells in the
patient's blood after they are injected. Because the patient will have received cells with a
new gene in them the patient will be followed for a total of 15 years to see if there are any
long term side effects of gene transfer.
When the patient is enrolled on this study, they will be assigned a dose of CD5 chimeric
receptor-T cells. Several studies suggest that the infused T cells need room to be able to
proliferate (grow) and accomplish their functions and that this may not happen if there are
too many other T cells in circulation . Because of that, the patient will receive two
chemotherapy medications prior to receiving the CD5 chimeric receptor-T cells.
One medication is called cyclophosphamide and the other fludarabine. The patient will receive
3 daily doses of each drug, ending at least one day before the patient receives the chimeric
receptor-T cells. These drugs will decrease the numbers of the patient's own T cells before
the CD5 chimeric receptor T cells are infused and also will help decrease the number of other
cells that may interfere with the chimeric receptor-T cells working well. Although we do not
expect any effect on the patient's tumor with the doses that the patient will receive, these
drugs are part of many regimens that are used to treat leukemia or lymphoma.
The patient will be given an injection of cells into the vein through an IV at the assigned
dose. The injection will take from 1 to 10 minutes. Before the patient receives the
injection, they may be given a dose of Benadryl and Tylenol. The treatment will be given by
the Center for Cell and Gene Therapy at Texas Children 's Hospital or Houston Methodist
Hospital.
The patient will be followed in the clinic after the injection for up to 3 hours, and the
patient will have to remain locally for at least 3 weeks after the infusion. If the patient
experiences any side effects, they may have to be hospitalized for evaluation and management.
If after a 6-8 week evaluation period after the infusion, the patient has achieved a complete
response (measured by bone marrow or radiology scans), the patient's primary oncology doctors
may decide the patient should proceed to bone marrow transplant, at which time the patient
will be removed from the treatment portion of the study.
Before being treated, the patient will receive a series of standard medical tests:
Physical exam and History; Blood tests to measure blood cells, kidney and liver function;
Pregnancy test for female patients who are of child bearing potential; Measurements of the
patient's tumor by scans and/or bone marrow studies
The patient will also receive standard medical tests during treatment and after:
Physical exams and History; Blood tests to measure blood cells, kidney and liver function;
Measurements of the patient's tumor by scans and/or bone marrow studies 6-8 weeks after the
infusion and then per standard of care.
To learn more about the way the CD5 chimeric receptor-T cells are working and how long they
last in the body, extra blood will be drawn. The total amount on any day is about 10
teaspoons (50 mL) or no more than 3 mL per 2.2 pounds body weight in children. This volume is
considered safe but may be decreased if the patient is anemic. This blood may be drawn from a
central line if the patient has one. Blood will be taken before the chemotherapy drugs,
several hours after the T cell infusion, at 1 week, 2 weeks, 3 weeks (optional), 4 weeks, 6
weeks and 8 weeks (optional) after the infusion, at 3 months, 6 months, 9 months, at 1 year,
every 6 months for 4 years, then yearly for a total of 15 years. We will also test blood to
check for signs of viral infection at the following time points: within 1 to 2 weeks prior to
chemotherapy drugs, prior to T cell infusion, then at weeks 1, 2, 3, 4, 6, 8 for all
patients, and months 3, 6, 9, 12 for patients who do not proceed to bone marrow transplant.
The total blood drawn during participation in this study will not exceed 280 teaspoons.
growth factors to make the T cells grow. To get the CD5 antibody and CD28 to attach to the
surface of the T cell, investigators insert the antibody gene into the T cell. This is done
with a virus called a retrovirus that has been made for this study and will carry the
antibody gene into the T cell. This virus also helps investigators find the T cells in the
patient's blood after they are injected. Because the patient will have received cells with a
new gene in them the patient will be followed for a total of 15 years to see if there are any
long term side effects of gene transfer.
When the patient is enrolled on this study, they will be assigned a dose of CD5 chimeric
receptor-T cells. Several studies suggest that the infused T cells need room to be able to
proliferate (grow) and accomplish their functions and that this may not happen if there are
too many other T cells in circulation . Because of that, the patient will receive two
chemotherapy medications prior to receiving the CD5 chimeric receptor-T cells.
One medication is called cyclophosphamide and the other fludarabine. The patient will receive
3 daily doses of each drug, ending at least one day before the patient receives the chimeric
receptor-T cells. These drugs will decrease the numbers of the patient's own T cells before
the CD5 chimeric receptor T cells are infused and also will help decrease the number of other
cells that may interfere with the chimeric receptor-T cells working well. Although we do not
expect any effect on the patient's tumor with the doses that the patient will receive, these
drugs are part of many regimens that are used to treat leukemia or lymphoma.
The patient will be given an injection of cells into the vein through an IV at the assigned
dose. The injection will take from 1 to 10 minutes. Before the patient receives the
injection, they may be given a dose of Benadryl and Tylenol. The treatment will be given by
the Center for Cell and Gene Therapy at Texas Children 's Hospital or Houston Methodist
Hospital.
The patient will be followed in the clinic after the injection for up to 3 hours, and the
patient will have to remain locally for at least 3 weeks after the infusion. If the patient
experiences any side effects, they may have to be hospitalized for evaluation and management.
If after a 6-8 week evaluation period after the infusion, the patient has achieved a complete
response (measured by bone marrow or radiology scans), the patient's primary oncology doctors
may decide the patient should proceed to bone marrow transplant, at which time the patient
will be removed from the treatment portion of the study.
Before being treated, the patient will receive a series of standard medical tests:
Physical exam and History; Blood tests to measure blood cells, kidney and liver function;
Pregnancy test for female patients who are of child bearing potential; Measurements of the
patient's tumor by scans and/or bone marrow studies
The patient will also receive standard medical tests during treatment and after:
Physical exams and History; Blood tests to measure blood cells, kidney and liver function;
Measurements of the patient's tumor by scans and/or bone marrow studies 6-8 weeks after the
infusion and then per standard of care.
To learn more about the way the CD5 chimeric receptor-T cells are working and how long they
last in the body, extra blood will be drawn. The total amount on any day is about 10
teaspoons (50 mL) or no more than 3 mL per 2.2 pounds body weight in children. This volume is
considered safe but may be decreased if the patient is anemic. This blood may be drawn from a
central line if the patient has one. Blood will be taken before the chemotherapy drugs,
several hours after the T cell infusion, at 1 week, 2 weeks, 3 weeks (optional), 4 weeks, 6
weeks and 8 weeks (optional) after the infusion, at 3 months, 6 months, 9 months, at 1 year,
every 6 months for 4 years, then yearly for a total of 15 years. We will also test blood to
check for signs of viral infection at the following time points: within 1 to 2 weeks prior to
chemotherapy drugs, prior to T cell infusion, then at weeks 1, 2, 3, 4, 6, 8 for all
patients, and months 3, 6, 9, 12 for patients who do not proceed to bone marrow transplant.
The total blood drawn during participation in this study will not exceed 280 teaspoons.
Procurement Inclusion Criteria
Referred patients will initially be consented for procurement of blood for generation of
the transduced ATL. Eligibility criteria at this stage include:
1. Diagnosis of recurrent T-cell acute lymphoblastic leukemia (T-ALL), T-cell acute
lymphoblastic lymphoma (T-LLy), or T-non-Hodgkin lymphoma (T-NHL, including
Angioimmunoblastic T-cell lymphoma (AITL), Enteropathy-associated T-cell lymphoma
(EATL), Monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL), Peripheral
T-cell lymphoma (PTCL) NOS, Anaplastic large cell lymphoma (ALCL), Adult T-cell
leukemia/lymphoma, T cell prolymphocytic leukemia with symptomatic disease, Extranodal
NK/T cell lymphoma, Mycosis fungoides/ Sezary Syndrome Stage IIB or higher)
AND Suitable for allogeneic HSCT with confirmation of an identified eligible allo-HSCT
donor by a FACT accredited transplant center
AND with confirmation that the center plans to proceed with transplant if CD5.CAR
treatment induces a complete remission.
2. CD5-positive tumor (result can be pending at this time). > 50% CD5 + blasts by flow
cytometry or immunohistochemistry (tissue) assessed by a CLIA certified Flow
Cytometry/Pathology laboratory.
3. Age less than or equal to 75 years old. NOTE: The first six (6) patients treated on
the study will be adults (>18 yrs of age). Six adolescents (age 12-18) will be treated
before children (>3 yrs of age) are eligible.
4. Hgb greater than or equal to 7.0 (can be transfused)
5. Life expectancy greater than 12 weeks
6. If pheresis required to collect blood:
- Creatinine <1.5 × upper limit normal
- AST <1.5 × upper limit normal
- PT and APTT <1.5 × upper limit normal
7. Informed consent explained to, understood by and signed by patient/guardian.
Patient/guardian given copy of informed consent.
Procurement Exclusion Criteria:
1. Active infection requiring antibiotics.
2. Active infection with HIV or HTLV.
3. Clinically significant viral infection or uncontrolled viral reactivation of EBV, CMV,
Adv, BK-virus, or HHV-6.
4. Cardiac criteria: Atrial fibrillation/flutter; Myocardial infarction within the last
12 months; Prolonged QT syndrome or secondary prolonged QT, per investigator
discretion. Cardiac echocardiography with LVSF less than or equal to 30% or LVEF less
than or equal to 50% or clinically significant pericardial effusion; Cardiac
dysfunction NYHA III or IV (Confirmation of absence of these conditions within 12
months of treatment).
5. History of other cancer (except non-melanoma skin cancer or in situ breast cancer or
cervix cancer) unless the tumor was successfully treated with curative intent at least
2 years before trial entry.
Treatment Inclusion Criteria:
1. Diagnosis of recurrent T-cell acute lymphoblastic leukemia (T-ALL), T-cell acute
lymphoblastic lymphoma (T-LLy), or T-non-Hodgkin lymphoma (T-NHL, including
Angioimmunoblastic T-cell lymphoma (AITL), Enteropathy-associated T-cell lymphoma
(EATL), Monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL), Peripheral
T-cell lymphoma (PTCL) NOS, Anaplastic large cell lymphoma (ALCL), Adult T-cell
leukemia/lymphoma, T cell prolymphocytic leukemia with symptomatic disease, Extranodal
NK/T cell lymphoma, Mycosis fungoides/ Sezary Syndrome Stage IIB or higher)
AND suitable for allogeneic HSCT with confirmation of an identified eligible allo-HSCT
donor by a FACT accredited transplant center
AND with confirmation that the center plans to proceed with transplant if CD5.CAR
treatment induces a complete remission.
2. CD5-positive tumor: >50% CD5+ blasts by flow cytometry or immunohistochemistry
(tissue) assessed in a CLIA certified Flow Cytometry/Pathology laboratory.
3. Age less than or equal to 75 years old. NOTE: The first six (6) patients treated on
the study will be adults (>18 yrs of age). Six adolescents (age 12-18) will be treated
before children (>3 yrs of age) are eligible.
4. Bilirubin less than 3 times the upper limit of normal.
5. AST less than 5 times the upper limit of normal.
6. Estimated GFR > 60 mL/min.
7. Pulse oximetry of > 90% on room air
8. Karnofsky or Lansky score of greater than or equal to 60%.
9. Recovered from acute toxic effects of prior chemotherapy at least one week before
entering this study.
10. Available autologous activated peripheral blood T cell products with greater than or
equal to 20% expression of CD5.CAR.28 zeta and <0.5% gene-modified malignant T blasts
by flow cytometry.
11. Life expectancy of greater than 12 weeks.
12. 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.
13. Informed consent explained to, understood by, and signed by patient/guardian.
Patient/guardian given copy of informed consent.
Treatment Exclusion Criteria:
1. Currently receiving any investigational agents or having received any tumor vaccines
within the previous 6 weeks.
2. History of hypersensitivity reactions to murine protein-containing products.
3. Pregnant or lactating.
4. Tumor in a location where enlargement could cause airway obstruction.
5. Active infection with HIV or HTLV.
6. Clinically significant viral infection or uncontrolled viral reactivation of EBV, CMV,
Adv, BK-virus, or HHV-6.
7. Cardiac criteria: Prolonged QT syndrome; Atrial fibrillation/flutter; Myocardial
infarction within the last 12 months; Cardiac echocardiography with LVSF less than or
equal to 30% or LVEF less than or equal to 50%; Cardiac dysfunction NYHA III or IV;
Cardiac echocardiography with clinically significant pericardial effusion.
8. CNS abnormalities: Presence of CNS-3 disease defined as detectable cerebrospinal blast
cells in a sample of CSF with greater than or equal to 5 WBCs per mm3; History or
presence of any CNS disorder such as a seizure disorder, cerebrovascular
ischemia/hemorrhage, dementia, cerebellar disease, or any autoimmune disease with CNS
involvement.
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