In Vivo Persistence of Adoptively-Transferred TIL Cultured With Akti in People With Metastatic Melanoma
Status: | Suspended |
---|---|
Conditions: | Skin Cancer |
Therapuetic Areas: | Oncology |
Healthy: | No |
Age Range: | 18 - 70 |
Updated: | 5/14/2016 |
Start Date: | June 2015 |
End Date: | November 2019 |
A Phase I Trial for the Evaluation of the In Vivo Persistence of Adoptively-transferred Tumor-Infiltrating Lymphocytes Cultured With a Pharmacologic Inhibitor of AKT in Patients With Metastatic Melanoma
Background:
- One cancer therapy involves taking white blood cells from a person, changing them in a
lab, and then giving the cells back to the person. These cells are called tumor infiltrating
lymphocytes (TIL). Researchers want to grow some of the TIL cells with the drug Akti to see
if they live longer than those grown without it.
Objectives:
- To see if TIL cells grown with Akti live longer than those grown without it.
Eligibility:
- Adults 18 70 with metastatic melanoma
Design:
- Participants will:
- Be screened with tests including scans, x-rays, heart and lung tests, blood and urine
tests, and a < TAB> possible colonoscopy.
- Have tumor surgery or biopsy.
- Have a large catheter inserted into a vein in the upper chest.
- Receive leukapheresis for 4 5 hours. Blood is removed through a needle in an arm. White
blood cells < TAB> are removed. The rest of the blood is returned by needle in the
other arm.
- The cells will be changed in a laboratory.
- Participants will check into the hospital and:
- For 5 days, get 1 2 chemotherapy drugs by catheter.
- For 1 3 days, get the changed cells by catheter.
- For several days, get 2 drugs to stimulate cells, one by injection, the other by
catheter.
- For 7 12 days, recover in the hospital.
- After treatment, participants will:
- Take an antibiotic and antiviral for at least 6 months.
- Return to NIH for several 2-day visits for a few years. At each visit, participants
will have lab tests, imaging studies, and a physical exam. At some visits, they may
have leukapheresis or blood tests.
- One cancer therapy involves taking white blood cells from a person, changing them in a
lab, and then giving the cells back to the person. These cells are called tumor infiltrating
lymphocytes (TIL). Researchers want to grow some of the TIL cells with the drug Akti to see
if they live longer than those grown without it.
Objectives:
- To see if TIL cells grown with Akti live longer than those grown without it.
Eligibility:
- Adults 18 70 with metastatic melanoma
Design:
- Participants will:
- Be screened with tests including scans, x-rays, heart and lung tests, blood and urine
tests, and a < TAB> possible colonoscopy.
- Have tumor surgery or biopsy.
- Have a large catheter inserted into a vein in the upper chest.
- Receive leukapheresis for 4 5 hours. Blood is removed through a needle in an arm. White
blood cells < TAB> are removed. The rest of the blood is returned by needle in the
other arm.
- The cells will be changed in a laboratory.
- Participants will check into the hospital and:
- For 5 days, get 1 2 chemotherapy drugs by catheter.
- For 1 3 days, get the changed cells by catheter.
- For several days, get 2 drugs to stimulate cells, one by injection, the other by
catheter.
- For 7 12 days, recover in the hospital.
- After treatment, participants will:
- Take an antibiotic and antiviral for at least 6 months.
- Return to NIH for several 2-day visits for a few years. At each visit, participants
will have lab tests, imaging studies, and a physical exam. At some visits, they may
have leukapheresis or blood tests.
Background:
- Adoptive cellular immunotherapy (ACT) using autologous tumor-infiltrating lymphocytes
(TIL) can mediate regression of bulky metastatic melanoma when administered with
high-dose aldesleukin (IL-2) following a non-myeloablative lymphodepleting chemotherapy
preparative regimen consisting of cyclophosphamide and fludarabine.
- Regression of tumor in mouse models and humans strongly correlates with anti-tumor T
cells that exhibit features of immunologic memory and have a capacity to persist for
long periods after adoptive-transfer into tumor-bearing hosts.
- In our preclinical work with TIL, we have identified a pharmacologic inhibitor of AKT
that promotes features of immunologic memory in TIL (as evidenced by transcriptomic,
proteomic, metabolomic, and functional assays described in the Background section).
Consistently, AKT inhibition of human TIL significantly enhances persistence after
adoptive-transfer into an immunodeficient mouse model.
- We therefore aim to evaluate whether pharmacologic inhibition of AKT in TIL may enhance
persistence after adoptive-transfer into patients with advanced melanoma.
Objectives:
- Primary objective:
- To determine whether ACT using TIL cultured in a pharmacologic inhibitor of AKT
(during ex vivo expansion) results in enhanced in vivo persistence of TIL after
adoptive transfer into autologous patients with advanced melanoma.
- Secondary objectives:
- Determine the toxicity profile of this treatment regimen.
- Determine whether ACT using a combination of AKTi-treated and conventional TIL can
mediate tumor regression by RECIST (Response Evaluation Criteria in Solid Tumors)
guidelines in patients with advanced melanoma.
Eligibility:
- Age greater than or equal to 18 and less than or equal to 70 years
- Evaluable metastatic melanoma
- Metastatic melanoma lesion suitable for surgical resection for the preparation of TIL
- No contraindications to high-dose aldesleukin administration
- No concurrent major medical illnesses or any form of immunodeficiency
Design:
- Patients with metastatic melanoma will undergo ACT in conventional manner, with the
exception that half of tumor fragments from which TIL are isolated will be cultured in
the presence of a pharmacologic AKT inhibitor. Prior to infusion of TIL, the AKT
inhibitor (hereafter AKTi) will be washed from the therapeutic TIL product and will not
be systemically administered. Each patient will receive a 1:1 mixture of conventional
TIL and AKTi-treated TIL. To evaluate persistence of AKTi-treated and conventional TIL
after adoptive co-transfer, we will perform high-throughput deep sequencing of the TCR
V-beta CDR3 region of TIL from the infusion-bag and from peripheral blood when
sufficient lymphocyte reconstitution (> 200 lymphocytes/microliter) has occurred and
approximately 4-6 weeks after infusion.
- Up to 20 patients may be enrolled over 20-24 months.
- Adoptive cellular immunotherapy (ACT) using autologous tumor-infiltrating lymphocytes
(TIL) can mediate regression of bulky metastatic melanoma when administered with
high-dose aldesleukin (IL-2) following a non-myeloablative lymphodepleting chemotherapy
preparative regimen consisting of cyclophosphamide and fludarabine.
- Regression of tumor in mouse models and humans strongly correlates with anti-tumor T
cells that exhibit features of immunologic memory and have a capacity to persist for
long periods after adoptive-transfer into tumor-bearing hosts.
- In our preclinical work with TIL, we have identified a pharmacologic inhibitor of AKT
that promotes features of immunologic memory in TIL (as evidenced by transcriptomic,
proteomic, metabolomic, and functional assays described in the Background section).
Consistently, AKT inhibition of human TIL significantly enhances persistence after
adoptive-transfer into an immunodeficient mouse model.
- We therefore aim to evaluate whether pharmacologic inhibition of AKT in TIL may enhance
persistence after adoptive-transfer into patients with advanced melanoma.
Objectives:
- Primary objective:
- To determine whether ACT using TIL cultured in a pharmacologic inhibitor of AKT
(during ex vivo expansion) results in enhanced in vivo persistence of TIL after
adoptive transfer into autologous patients with advanced melanoma.
- Secondary objectives:
- Determine the toxicity profile of this treatment regimen.
- Determine whether ACT using a combination of AKTi-treated and conventional TIL can
mediate tumor regression by RECIST (Response Evaluation Criteria in Solid Tumors)
guidelines in patients with advanced melanoma.
Eligibility:
- Age greater than or equal to 18 and less than or equal to 70 years
- Evaluable metastatic melanoma
- Metastatic melanoma lesion suitable for surgical resection for the preparation of TIL
- No contraindications to high-dose aldesleukin administration
- No concurrent major medical illnesses or any form of immunodeficiency
Design:
- Patients with metastatic melanoma will undergo ACT in conventional manner, with the
exception that half of tumor fragments from which TIL are isolated will be cultured in
the presence of a pharmacologic AKT inhibitor. Prior to infusion of TIL, the AKT
inhibitor (hereafter AKTi) will be washed from the therapeutic TIL product and will not
be systemically administered. Each patient will receive a 1:1 mixture of conventional
TIL and AKTi-treated TIL. To evaluate persistence of AKTi-treated and conventional TIL
after adoptive co-transfer, we will perform high-throughput deep sequencing of the TCR
V-beta CDR3 region of TIL from the infusion-bag and from peripheral blood when
sufficient lymphocyte reconstitution (> 200 lymphocytes/microliter) has occurred and
approximately 4-6 weeks after infusion.
- Up to 20 patients may be enrolled over 20-24 months.
- INCLUSION CRITERIA
- Measurable metastatic melanoma with at least one lesion that is resectable for TIL
generation, plus one other lesion that can be measured.
- Confirmation of diagnosis of metastatic melanoma by the Laboratory of Pathology of
NCI.
- Patients with 3 or fewer brain metastases that are less than 1 cm in diameter and
asymptomatic are eligible. Lesions that have been treated with stereotactic
radiosurgery must be clinically stable for 1 month after treatment for the patient to
be eligible. Patients with surgically resected brain metastases are eligible.
- Prior therapy with at least one first line standard therapy including check point
inhibitors such as pembrolizumab, nivolumab, or ipilimumab.
- Note: Six weeks must have elapsed from the time of any of these prior antibody
therapies that could affect an anti-cancer immune response, at the time the
patient receives the preparative regimen to allow antibody levels to decline.
- Note: Patients who have previously received ipilimumab and have documented GI
toxicity must have a normal colonoscopy with normal colonic biopsies.
- Greater than or equal to 18 years of age and less than or equal to 70 years of age.
- Willing to sign a durable power of attorney.
- Able to understand and sign the Informed Consent Document
- Clinical performance status of ECOG 0 or 1.
- Life expectancy of greater than three months.
- Patients of both genders must be willing to practice birth control from the time of
enrollment on this study and for up to four months after treatment.
- Serology:
- Seronegative for HIV antibody. (The experimental treatment being evaluated in
this protocol depends on an intact immune system. Patients who are HIV
seropositive can have decreased immune-competence and thus are less responsive
to the experimental treatment and more susceptible to its toxicities.)
- Seronegative for hepatitis B antigen, and seronegative for hepatitis C antibody.
If hepatitis C antibody test is positive, then patient must be tested for the
presence of antigen by RT-PCR and be HCV RNA negative.
- Women of child-bearing potential must have a negative pregnancy test because of the
potentially dangerous effects of the treatment on the fetus.
- Hematology:
- Absolute neutrophil count greater than 1000/mm^3 without the support of
filgrastim
- WBC greater than or equal to 3000/mm^3
- Platelet count greater than or equal to 100,000/mm^3
- Hemoglobin > 8.0 g/dl
- Chemistry:
- Serum ALT/AST less than or equal to 2.5 times the upper limit of normal
- Serum Creatinine less than or equal to 1.6 mg/dl
- Total bilirubin less than or equal to 1.5 mg/dl, except in patients with Gilbert
s Syndrome who must have a total bilirubin less than 3.0 mg/dl.
- More than four weeks must have elapsed since any prior systemic therapy at the time
the patient receives the preparative regimen, and patients toxicities must have
recovered to a grade 1 or less (except for toxicities such as alopecia or vitiligo).
Patients must have progressive disease after prior treatment.
- Note: Patients may have undergone minor surgical procedures within the past 3
weeks, as long as all toxicities have recovered to grade 1 or less.
- Six weeks must have elapsed from the time of any antibody therapy that could affect
an anti cancer immune response, including anti-CTLA4 antibody therapy, at the time
the patient receives the preparative regimen to allow antibody levels to decline.
- Note: Patients who have previously received ipilimumab and have documented GI
toxicity must have a colonoscopy with normal colonic biopsies.
EXCLUSION CRITERIA
- Women of child-bearing potential who are pregnant or breastfeeding because of the
potentially dangerous effects of the treatment on the fetus or infant.
- Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency
Disease).
- Concurrent opportunistic infections (The experimental treatment being evaluated in
this protocol depends on an intact immune system. Patients who have decreased immune
competence may be less responsive to the experimental treatment and more susceptible
to its toxicities).
- Active systemic infections (for e.g.: requiring anti-infective treatment),
coagulation disorders or other active major medical illnesses of the cardiovascular,
respiratory or immune system, as evidenced by a positive stress thallium or
comparable test, myocardial infarction, cardiac arrhythmias, obstructive or
restrictive pulmonary disease.
- Concurrent systemic steroid therapy.
- History of severe immediate hypersensitivity reaction to cyclophosphamide or
fludarabine.
- History of coronary revascularization or ischemic symptoms.
- Documented LVEF of less than or equal to 45%, testing is required in patients with:
- Age greater than or equal to 60 years old
- Clinically significant atrial and or ventricular arrhythmias including but not
limited to: atrial fibrillation, ventricular tachycardia, second or third degree
heart block.
We found this trial at
1
site
9000 Rockville Pike
Bethesda, Maryland 20892
Bethesda, Maryland 20892
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