A person s tumor is studied for mutations. When cells are found that can attack the mutation
in a person s tumor, the genes from those cells are studied to find the parts that make the
attack possible. White blood cells are then taken from the person s body, and the gene
transfer occurs in a laboratory. A type of virus is used to transfer the genes that make
those white blood cells able to attack the mutation in the tumor. The gene transfer therapy
is the return of those white blood cells back to the person.
To see if gene transfer therapy of white blood cells can shrink tumors.
People with certain metastatic cancer for which standard treatments have not worked.
Participants may complete screening under another protocol. Screening includes:
Getting tumor cells from a previous procedure
Blood, urine, heart, and lung tests
The study has 8 stages:
Screening tests repeated over 1-2 weeks. Participants will have leukapheresis: Blood is
removed by a needle in one arm. A machine removes white blood cells. The rest of the
blood is returned by a needle in the other arm.
Care at home over approximately 12 weeks.
Stopping therapy for 4-6 weeks while their cells are changed in a lab.
Hospital stay approximately 3-4 weeks for treatment. An IV catheter will be placed in
the chest to administer drugs.
Patients on Arm 2 of the study will receive the first dose of pembrolizumab while in the
hospital. Three additional doses will be given after the cell infusion 3 weeks apart.
Receiving changed cells by catheter. Then getting a drug over 1-5 days to help the cells
Recover in the hospital for 1-2 weeks. Participants will get drugs and have blood and
Participants will take an antibiotic and maybe an antiviral for at least 6 months after
treatment. They will have repeat screening tests at visits every few months for the
first year, every 6 months for the second year, then as determined.
The administration of autologous tumor-infiltrating lymphocytes (TIL) can mediate
complete, durable regressions in 20-25% of participants with metastatic melanoma. Recent
studies have shown that these TIL predominantly recognize unique mutated neoantigens
expressed by the cancer not shared by other melanomas.
Administration of bulk autologous TIL to participants with a variety of other solid
cancers, including cancers of the gastrointestinal tract and genitourinary tract, have
little if any therapeutic impact.
Recent studies in the National Cancer Institute Surgery Branch, (NCI-SB), have shown
that TIL from non-melanoma solid cancers can also contain T-cells reactive against
non-shared unique mutated or oncoviral neoantigens expressed in the cancer. The
frequency of these T-cells is very low (often < 0.1%) and it is thus difficult to
isolate and grow mutation reactive T-cells to levels required for effective therapy.
In a single patient with chemo-refractory metastatic cholangiocarcinoma we were able to
grow a relatively pure population of neoantigen reactive TIL and administration of these
cells mediated a near-complete regression of all metastatic disease now lasting 2.5
We have developed approaches to identify these rare neoantigen reactive T-cells from
common non-melanoma cancers, to isolate their T-cell receptors (TCR), and to genetically
engineer autologous peripheral blood lymphocytes (PBL) to express these TCRs with high
efficiency. The neoantigen TCR gene-modified cells can recognize and destroy the
autologous cancer in vitro.
In addition to reactivity to neoantigens derived from nonsynonymous mutations, T-cells
can recognize human papilloma virus (HPV) epitopes in participants with HPV- induced
cancers. The TCR from these reactive cells can be isolated and retrovirally-transduced
into autologous PBL with high efficiency.
With these techniques, we have isolated a number of TCRs selectively recognizing shared
mutated oncogenes (e.g., KRAS, TP53) or shared oncoviral proteins (e.g. HPV) in the
context of several major histocompatibility complexes (MHC-I and MHC-II).
This clinical protocol will treat participants with refractory solid cancers using the
adoptive transfer of autologous PBL transduced with genes encoding TCRs that recognize
unique mutated or oncoviral neoantigens expressed by the cancer.
--Determine the rate of objective response (using RECIST v1.1 criteria) of participants with
solid cancers who receive pembrolizumab plus autologous PBL (Arm 2) that have been transduced
with genes encoding T-cell receptors that recognize mutated or oncoviral neoantigens in the
-Participants must be/have:
Age greater than or equal to 18 years and less than or equal to 70 years
Metastatic solid cancer with at least one lesion that can be measured, that falls into
one of five cohorts: (1) gastrointestinal and genitourinary cancers; (2) breast,
ovarian, and other solid cancers; (3) non-small cell lung cancer (NSCLC); and, (4)
endocrine tumors including neuroendocrine tumors and, (5) multiple myeloma with solid
Evaluable solid cancer that has recurred following standard chemotherapy or standard
Normal basic laboratory values.
No allergies or hypersensitivity to high-dose aldesleukin administration
No concurrent major medical illnesses or any form of immunodeficiency.
Participants will have already undergone resection or biopsy to obtain tumor for
generation of autologous TIL cultures. This will have been conducted under the NCI-SB
cell harvest protocol 03-C-0277 (Cell Harvest and Preparation for Surgery Branch
Adoptive Cell Therapy Protocols).
Exomic sequencing, and often RNA-Seq will be performed to identify the mutations
expressed in the patient s cancer. Multiple autologous TIL cultures will be grown and
tested for reactivity against mutations from the autologous tumor using assays we have
developed that involve the exposure of autologous antigen-presenting cells to long
peptides containing the mutation or tandem mini-genes encoding the mutation.
T-cell cultures with reactivity against mutations will be identified and the individual
T- cell receptors that recognize the mutation will be synthesized and used to create a
retrovirus for transduction of the TCR into the patient s autologous PBL.
Participants that present with tumors expressing oncoviral neoantigens will be treated
with autologous PBLs retrovirally transduced with TCR(s) targeting the oncoviral
Participants that present with tumors expressing mutated shared oncogenes (e.g., KRAS,
TP53) or oncoviral proteins (e.g., HPV) that also express the appropriate restriction
element may be treated with autologous PBLs retrovirally transduced with TCR(s)
previously isolated in the Surgery Branch targeting the shared mutated antigen. These
participants will be administered a cell infusion product of TCRs targeting mutated
shared oncogenes (e.g., KRAS, TP53) or oncoviral proteins (e.g., HPV). Their cell
infusion product will not include PBL transduced with unique (i.e., non-shared) TCR(s).
Participants will be enrolled into one of five cohorts: (1) metastatic gastrointestinal
and genitourinary cancers; (2) metastatic breast, ovarian, and other solid cancers; (3)
metastatic non-small cell lung cancer (NSCLC); (4) metastatic endocrine tumors including
neuroendocrine tumors and, (5) multiple myeloma with solid masses (plasmacytomas).
Autologous PBL transduced with TCR(s) targeting neoantigens (mutated shared oncogenes
e.g., TP53, KRAS, individual non-synonymous mutations , or oncoviral proteins) will then
be expanded to large numbers using our standard rapid expansion protocol.
Participants enrolled on Arm 1 and Arm 2 will receive a non-myeloablative,
lymphodepleting preparative regimen consisting of cyclophosphamide and fludarabine
followed by the infusion of autologous transduced PBL and high-dose aldesleukin. At the
discretion of the Principal Investigator (PI), participants enrolled in Cohort 3 (NSCLC)
may receive low-dose aldesleukin.
Participants enrolled on Arm 2 will receive pembrolizumab prior to cell administration
and three additional doses every three weeks following the cell infusion. Participants
who have experienced major organ toxicity due to previous treatment with pembrolizumab
(or equivalent PD-1/PD-L1 blockade) will be enrolled on Arm 1.
Clinical and immunologic response will be evaluated about 4-6 weeks after cell infusion
and periodically thereafter.
It is anticipated that approximately one participant per month may enroll on the trial
for each of the four histologic cohorts for Arm 2. There will be a limit of 15
participants per cohort enrolled on Arm 1 (75 participants for Arm 1), and accrual of up
to 4 x 50 = 200 total evaluable participants on Arm 2. It is expected that once full
manufacturing capability is reached, the accrual may be completed in approximately 4-5
years. In order to allow for a small number of inevaluable participants, the accrual
ceiling will be set to 285.
If you are confirmed eligible after full screening, you will be required to understand and sign the informed consent if you decide to enroll in the study. Once enrolled you may be asked to make scheduled visits over a period of time.
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