A Phase II Study Using the Administration of Autologous T-Cells Engineered Using the Sleeping Beauty Transposon/Transposase System to Express T-Cell Receptors Reactive Against Mutated Neoantigens in Patients With Metastatic Cancer
A person s white blood cells can be modified in a lab to recognize certain changes in their
tumor. Many of these cells are collected from the person, modified, then given back to the
person. This may help treat some cancers.
To learn if a person s white blood cells modified with T-cell receptors can cause solid
tumors to shrink.
People ages 18-70 who have cancer of the gastrointestinal tract, genitourinary tract, ovary,
breast, or lung that has spread, or who have glioblastoma.
Participants will be screened and have their cells prepared for treatment in another
Participants will be hospitalized one week before treatment. They will stay approximately 3 -
4 weeks after treatment.
Participants will get the modified white blood cells and chemotherapy through an IV catheter,
which is a small plastic tube inserted in a vein.
Participants will take drugs by mouth to prevent infection. They will receive filgrastim as a
shot or injection under the skin.
Participants will have tests before, during, and after treatment:
Heart, blood, and urine tests
Scans: They will lie in a machine that takes pictures of the body.
Possible apheresis: The participant s blood is removed through a needle in an arm. The blood
goes through a machine that removes the white blood cells. The rest of the blood is returned
through a needle in the other arm.
Participants will have visits about 6 and 12 weeks after treatment. If they are responding to
treatment, they will then have visits every 3-6 months for 3 years. Then they will join
another study and be followed about 12 more years.
The administration of autologous tumor infiltrating lymphocytes (TIL) can mediate
complete, durable regressions in 20-25% of patients 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 patients 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 Surgery Branch, NCI, have shown that TIL from non-melanoma solid
cancers can also contain T-cells reactive against non-shared unique mutated 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 several patients with chemo-refractory metastatic epithelial cancers, we were able to
grow an enriched population of neoantigen reactive TIL and administration of these cells
mediated several partial regressions of metastatic disease and one complete regression
of all metastatic breast cancer now lasting more than 3 years.
We have now 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) using the Sleeping Beauty system
to express these TCRs with high efficiency. The neoantigen TCR gene- modified cells can
recognize and destroy the autologous cancer in vitro.
We are now proposing a clinical protocol to treat patients with refractory solid cancers
using the adoptive transfer of autologous PBL transposed with genes encoding TCRs that
recognize unique mutated neoantigens expressed by the cancer.
-To determine the rate of objective response (using RECIST v1.1 criteria) of patients with
solid cancers who receive autologous PBL that have been genetically modified with genes
encoding TCRs that recognize mutated neoantigens in the autologous cancer using the Sleeping
Patients who are age greater than or equal to 18 years and less than or equal to 70 years
Measurable solid cancer with at least one lesion that is resectable for TIL generation
with minimal morbidity plus at least one other lesion that can be measured that falls
into one of four cohorts: (1) gastrointestinal and genitourinary, (2) breast and
ovarian, (3) non- small cell lung cancer (NSCLC), and (4) glioblastoma. Metastatic
disease is required for Cohorts 1-3 but not for Cohort 4.
Evaluable solid cancer that has recurred following standard chemotherapy or standard
erapy OR therapy has been declined
Adequate organ function
No allergies or hypersensitivity to cyclophosphamide, fludarabine, or aldesleukin.
No concurrent major medical illnesses or any form of immunodeficiency
Patients will undergo resection or biopsy to obtain tumor for generation of autologous
TIL cultures. Patients will be entered into four cohorts that include (1)
gastrointestinal and genitourinary tract cancers, (2) breast and ovarian cancers, (3)
non-small cell lung cancer (NSCLC), and (4) glioblastomas. Exome 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
TCRs that recognize the mutation will be synthesized and used to transfect the TCR into
patient s autologous PBL using the Sleeping Beauty system.
Transposed autologous PBL will then be expanded to large numbers using our standard
rapid expansion protocol and administered to the patient following a non-myeloablative
All patients will receive a non-myeloablative lymphodepleting preparative regimen of
cyclophosphamide and fludarabine. Patients will then receive the infusion of autologous
transposed PBL and begin high-dose aldesleukin (720,000 IU/kg IV every 8 hours for up to
Clinical and immunologic response will be evaluated approximately 4-6 weeks after cell
infusion and periodically thereafter.
It is anticipated that approximately one patient per month will enroll into the trial
for each of the four histologic groups. Thus, accrual of up to 4 x 50=200 total
evaluable patients may be completed in approximately 2-4 years. In order to allow for a
small number of inevaluable patients the accrual ceiling will be set to 210.
Endocrine/Neuroendocrine, Non-Small Cell Lung Cancer, Breast Cancer, Gastrointestinal/Genitourinary Cancers, Ovarian Cancer
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.
Every year hundreds of thousands of volunteers step forward to participate in research. Sign up as a volunteer and receive email notifications when clinical trials are posted in the medical category of interest to you.