Evaluation of Recovery From Drug-Induced Lymphopenia Using Cytomegalovirus-specific T-cell Adoptive Transfer
| Status: | Completed |
|---|---|
| Conditions: | Brain Cancer, Hematology |
| Therapuetic Areas: | Hematology, Oncology |
| Healthy: | No |
| Age Range: | 18 - Any |
| Updated: | 2/1/2018 |
| Start Date: | September 2008 |
| End Date: | April 2015 |
The purpose of this research study is to learn if your own immune cells can be activated and
multiplied in order to help your body fight off the tumor cells in your brain. The safety of
this procedure will also be studied. This procedure, called CMV-autologous lymphocyte
transfer or CMV-ALT is investigational which means that it is not approved by the US Food and
Drug Administration (FDA) and is still being tested in research studies. Autologous
lymphocyte transfer or ALT means that you will receive your own immune cells back (and not
from another donor) as a treatment after they have been activated and grown to large numbers
in a clinical lab.
It is believed that the body's immune (protection) system can attack tumor cells and kill
them. Immune cells called T-lymphocytes (T-cells) can recognize special proteins on the
surface of tumors as a signal to attack and fight the cancer. In most patients with advanced
cancer, the immune system does not adequately destroy the tumor because the white blood cells
or T-cells are not stimulated enough.
Before your T-cells can become active against tumor cells, they require strong stimulation.
There are special "stimulator" cells in the body called Dendritic Cells (DCs) that can take
up proteins released from cancer cells and present pieces of these proteins to T lymphocytes
to create this strong stimulation. Dendritic cells taken from your blood will be "pulsed" or
loaded with genetic material called RNA (ribonucleic acid), which stimulates the DC to change
the RNA into a protein called pp65. This protein is produced by a common virus called
Cytomegalovirus (CMV) that 70-80% of us have been exposed to in our lifetime. Recently, we
have found that this virus is present in many malignant brain tumors. Brain tumors are very
aggressive and, for reasons we do not yet understand, are difficult for the body to attack.
The CMV virus is a target in the tumor that, if attacked by your immune systems cells, may
prevent your tumor from growing. We have found that we can grow immune cells to very large
numbers from the blood of people who have evidence of prior exposure to this virus. You will
therefore be tested to determine if you have pre-existing antibodies to this virus in order
to participate in this study.
We will use your DCs to activate and grow immune cells from your blood to large numbers in a
clinical laboratory. These CMV-specific immune cells, called CMV-ALT, will be returned to
your body when they have become activated. It is hoped that these cells will seek out and
kill tumor cells that express the CMV viral protein and not attack normal cells. The transfer
of immune cells that stimulates your immune system is called adoptive immunotherapy. We will
evaluate two doses of immune cells in this study (Dose 1 and Dose 2). Depending on when you
are enrolled in this study you will receive either Dose 1 or 2. The first six patients
enrolled on this study will receive Dose 1 (the lower dose) and the next six patients will
receive Dose 2 (the higher dose). We do not know at this time if either dose is more
effective or safer to administer which is why we are testing both doses. Dose 2 will be a
larger number of immune cells if the treatment is found to be safe in the first six patients
treated during this study.
In this study we will also see, in some randomly selected patients, if giving an injection of
the DC pulsed with pp65 RNA into the skin improves the function of the CMV-ALT treatment or
not. You will receive three injections under the skin of either some of the same DC that were
used to stimulate your immune cells in the clinical laboratory or three injections of saline
(salt solution) under the skin starting with the infusion of the CMV-ALT. It is unknown if a
DC injection will be beneficial to the immune cells or not so the responses will be compared
in patients who receive DC versus saline injection with their CMV-ALT. After these three
injections, blood will be collected to compare the responses between patients that received
saline to those that received DC injections.
multiplied in order to help your body fight off the tumor cells in your brain. The safety of
this procedure will also be studied. This procedure, called CMV-autologous lymphocyte
transfer or CMV-ALT is investigational which means that it is not approved by the US Food and
Drug Administration (FDA) and is still being tested in research studies. Autologous
lymphocyte transfer or ALT means that you will receive your own immune cells back (and not
from another donor) as a treatment after they have been activated and grown to large numbers
in a clinical lab.
It is believed that the body's immune (protection) system can attack tumor cells and kill
them. Immune cells called T-lymphocytes (T-cells) can recognize special proteins on the
surface of tumors as a signal to attack and fight the cancer. In most patients with advanced
cancer, the immune system does not adequately destroy the tumor because the white blood cells
or T-cells are not stimulated enough.
Before your T-cells can become active against tumor cells, they require strong stimulation.
There are special "stimulator" cells in the body called Dendritic Cells (DCs) that can take
up proteins released from cancer cells and present pieces of these proteins to T lymphocytes
to create this strong stimulation. Dendritic cells taken from your blood will be "pulsed" or
loaded with genetic material called RNA (ribonucleic acid), which stimulates the DC to change
the RNA into a protein called pp65. This protein is produced by a common virus called
Cytomegalovirus (CMV) that 70-80% of us have been exposed to in our lifetime. Recently, we
have found that this virus is present in many malignant brain tumors. Brain tumors are very
aggressive and, for reasons we do not yet understand, are difficult for the body to attack.
The CMV virus is a target in the tumor that, if attacked by your immune systems cells, may
prevent your tumor from growing. We have found that we can grow immune cells to very large
numbers from the blood of people who have evidence of prior exposure to this virus. You will
therefore be tested to determine if you have pre-existing antibodies to this virus in order
to participate in this study.
We will use your DCs to activate and grow immune cells from your blood to large numbers in a
clinical laboratory. These CMV-specific immune cells, called CMV-ALT, will be returned to
your body when they have become activated. It is hoped that these cells will seek out and
kill tumor cells that express the CMV viral protein and not attack normal cells. The transfer
of immune cells that stimulates your immune system is called adoptive immunotherapy. We will
evaluate two doses of immune cells in this study (Dose 1 and Dose 2). Depending on when you
are enrolled in this study you will receive either Dose 1 or 2. The first six patients
enrolled on this study will receive Dose 1 (the lower dose) and the next six patients will
receive Dose 2 (the higher dose). We do not know at this time if either dose is more
effective or safer to administer which is why we are testing both doses. Dose 2 will be a
larger number of immune cells if the treatment is found to be safe in the first six patients
treated during this study.
In this study we will also see, in some randomly selected patients, if giving an injection of
the DC pulsed with pp65 RNA into the skin improves the function of the CMV-ALT treatment or
not. You will receive three injections under the skin of either some of the same DC that were
used to stimulate your immune cells in the clinical laboratory or three injections of saline
(salt solution) under the skin starting with the infusion of the CMV-ALT. It is unknown if a
DC injection will be beneficial to the immune cells or not so the responses will be compared
in patients who receive DC versus saline injection with their CMV-ALT. After these three
injections, blood will be collected to compare the responses between patients that received
saline to those that received DC injections.
Six CMV seropositive patients with newly-diagnosed GBM will be randomized to receive CMV-ALT
(3 x 107/Kg) with or without vaccine with CMV-DCs (2 x 107). All patients will undergo a
leukapheresis after resection for harvest of PBLs for CMV-ALT and CMV-DC generation. Patients
will then receive RT and concurrent TMZ at a standard targeted dose of 75 mg/m2/d. Patients
with histologically or clinically-proven progressive disease during radiation, dependent on
steroid supplements above physiologic levels at time of vaccination, and are unable to
tolerate TMZ will be replaced. If sufficient CMV-specific T-cells can't be expanded or ALT
doesn't meet release criteria, the patient will be replaced and their cells may be used to
offer them another DC vaccination study, such as ATTAC Pro00003877. Remaining patients will
then receive the initial cycle of TMZ at a standard targeted dose of 200mg/m2/d for 5 days 3
+ 1 weeks after completing RT and will be randomized to receive CMV-DCs or saline
simultaneous with CMV-ALT as vaccine #1. While the standard targeted dose of 200mg/m2/d for 5
days TMZ treatment is recommended, TMZ regimen may be adjusted at the discretion of the
treating neuro-oncologist. Patients with MRI changes consistent with pseudoprogression who
continue on TMZ will receive CMV-ALT with vaccinations as scheduled. Peripheral blood will be
drawn at 0 hours, 24 hours, 48 hours, 72 hours, and 1 week post vaccine #1 for T-cell
kinetics. DCs or saline will be given intradermally and divided equally to both inguinal
regions. Vaccines #2 and #3 will occur at 2 week intervals. All patients will then undergo
leukapheresis again for immunologic monitoring with specific assessment of baseline
antigen-specific cellular and humoral immune responses.
If the initial dose of CMV-ALT is safe and the combination of CMV-DCs is safe and does not
produce an inferior CMV pp65-specific immune response, a 3rd cohort of patients will be
enrolled and receive a higher dose of CMV-ALT (3 x 108/Kg) along with vaccine with CMV-DCs (2
x 107). If the combination is unsafe or inferior only the CMV-ALT will be given. If CMV-ALT
(3 x 108/Kg) is safe a 4th cohort of 3 patients will be enrolled and receive the same
treatment as the 3rd cohort except the T-cells will be labeled with 111In and cultured ex
vivo with 13C-glucose and their proliferation, persistence, and migration followed by
peripheral blood sampling, Single Photon Emission Computed Tomography (SPECT ), and MRI.
After the initial 3 vaccines, patients will then receive subsequent TMZ cycles every 4 weeks
for at least 6 cycles and up to 12 cycles after RT. TMZ will be given on days 1-5 of a 28 day
cycle. Patients will then be imaged bimonthly and followed until death. This study will be
halted if any 2 patients in any cohort of 3 experience a drug-related Grade IV or
irreversible Grade III toxicity.
As part of standard care for these patients, upon tumor progression, participants may undergo
stereotactic biopsy or resection. As this is not a research procedure consent will be
obtained separately. However, if tissue is obtained, it will be used to confirm tumor
progression histologically and to assess immunologic cell infiltration and pp65 antigen
escape at the tumor site. Patients consenting to biopsy or resection will also be offered
intratumoral vaccination with CMVpp65 LAMP-loaded, 111In-labeled DCs at the time of surgery
to determine if they migrate to cervical lymph nodes.
(3 x 107/Kg) with or without vaccine with CMV-DCs (2 x 107). All patients will undergo a
leukapheresis after resection for harvest of PBLs for CMV-ALT and CMV-DC generation. Patients
will then receive RT and concurrent TMZ at a standard targeted dose of 75 mg/m2/d. Patients
with histologically or clinically-proven progressive disease during radiation, dependent on
steroid supplements above physiologic levels at time of vaccination, and are unable to
tolerate TMZ will be replaced. If sufficient CMV-specific T-cells can't be expanded or ALT
doesn't meet release criteria, the patient will be replaced and their cells may be used to
offer them another DC vaccination study, such as ATTAC Pro00003877. Remaining patients will
then receive the initial cycle of TMZ at a standard targeted dose of 200mg/m2/d for 5 days 3
+ 1 weeks after completing RT and will be randomized to receive CMV-DCs or saline
simultaneous with CMV-ALT as vaccine #1. While the standard targeted dose of 200mg/m2/d for 5
days TMZ treatment is recommended, TMZ regimen may be adjusted at the discretion of the
treating neuro-oncologist. Patients with MRI changes consistent with pseudoprogression who
continue on TMZ will receive CMV-ALT with vaccinations as scheduled. Peripheral blood will be
drawn at 0 hours, 24 hours, 48 hours, 72 hours, and 1 week post vaccine #1 for T-cell
kinetics. DCs or saline will be given intradermally and divided equally to both inguinal
regions. Vaccines #2 and #3 will occur at 2 week intervals. All patients will then undergo
leukapheresis again for immunologic monitoring with specific assessment of baseline
antigen-specific cellular and humoral immune responses.
If the initial dose of CMV-ALT is safe and the combination of CMV-DCs is safe and does not
produce an inferior CMV pp65-specific immune response, a 3rd cohort of patients will be
enrolled and receive a higher dose of CMV-ALT (3 x 108/Kg) along with vaccine with CMV-DCs (2
x 107). If the combination is unsafe or inferior only the CMV-ALT will be given. If CMV-ALT
(3 x 108/Kg) is safe a 4th cohort of 3 patients will be enrolled and receive the same
treatment as the 3rd cohort except the T-cells will be labeled with 111In and cultured ex
vivo with 13C-glucose and their proliferation, persistence, and migration followed by
peripheral blood sampling, Single Photon Emission Computed Tomography (SPECT ), and MRI.
After the initial 3 vaccines, patients will then receive subsequent TMZ cycles every 4 weeks
for at least 6 cycles and up to 12 cycles after RT. TMZ will be given on days 1-5 of a 28 day
cycle. Patients will then be imaged bimonthly and followed until death. This study will be
halted if any 2 patients in any cohort of 3 experience a drug-related Grade IV or
irreversible Grade III toxicity.
As part of standard care for these patients, upon tumor progression, participants may undergo
stereotactic biopsy or resection. As this is not a research procedure consent will be
obtained separately. However, if tissue is obtained, it will be used to confirm tumor
progression histologically and to assess immunologic cell infiltration and pp65 antigen
escape at the tumor site. Patients consenting to biopsy or resection will also be offered
intratumoral vaccination with CMVpp65 LAMP-loaded, 111In-labeled DCs at the time of surgery
to determine if they migrate to cervical lymph nodes.
Inclusion Criteria:
- Age >18 years of age.
- GBM (WHO Grade IV) with definitive resection <4 weeks prior to leukapheresis with
residual radiographic contrast enhancement on post-resection CT or MRI of <1 cm in
maximal diameter in any axial plane.
- Karnofsky Performance Status (KPS ) of > 80% and a Curran Group status of I-IV.
Exclusion Criteria:
- Radiographic or cytologic evidence of leptomeningeal or multicentric disease at any
time prior to vaccination.
- Prior conventional anti-tumor therapy other than steroids, RT, or TMZ.
- Pregnant or need to breast feed during the study period (Negative b-HCG test
required).
- Requirement for continuous corticosteroids above physiologic levels at time of first
vaccination.
- Active infection requiring treatment or an unexplained febrile (> 101.5o F) illness.
- Known immunosuppressive disease or human immunodeficiency virus infection.
- Patients with unstable or severe intercurrent medical conditions such as severe heart
or lung disease.
- Allergic or unable to tolerate TMZ for reasons other than lymphopenia.
- Patients with previous inguinal lymph node dissection.
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