A Phase II Study Using the Administration of Autologous T-Cells Genetically Engineered to Express T-Cell Receptors Reactive Against Neoantigens in Patients With Metastatic Cancer

  • End date
    Mar 23, 2028
  • participants needed
  • sponsor
    National Cancer Institute (NCI)
Updated on 25 October 2022
platelet count
systemic therapy
karnofsky performance status
squamous cell carcinoma
cytotoxic chemotherapy
white blood cells
tumor cells
brain metastases
chemotherapy regimen
gene therapy
cancer chemotherapy
recurrent disease
recurrent glioblastoma
cytotoxic agents
platinum-based chemotherapy
cancer of the ovary
lung carcinoma



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
  • Medical history
  • Physical exam
  • Scans
  • Blood, urine, heart, and lung tests

The study has 8 stages:

  1. 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.
  2. Care at home over approximately 12 weeks.
  3. Stopping therapy for 4-6 weeks while their cells are changed in a lab.
  4. Hospital stay approximately 3-4 weeks for treatment. An IV catheter will be placed in the chest to administer drugs.
  5. 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.
  6. Receiving changed cells by catheter. Then getting a drug over 1-5 days to help the cells live longer.
  7. Recover in the hospital for 1-2 weeks. Participants will get drugs and have blood and urine tests.
  8. 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 years.
  • 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.

-Primary objective:

--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 autologous cancer


-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 masses (plasmacytomas).
  • Evaluable solid cancer that has recurred following standard chemotherapy or standard systemic therapy
  • 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 neoantigen.
  • 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.

Condition Endocrine Tumors, Non-Small Cell Lung Cancer, Ovarian Cancer, Breast Cancer, Gastrointestinal/Genitourinary Cancers, Neuroendocrine Tumors, Multiple Myeloma
Treatment aldesleukin, cyclophosphamide, Fludarabine, Individual Patient TCR-Transduced PBL, Pembrolizumab (KEYTRUDA )
Clinical Study IdentifierNCT03412877
SponsorNational Cancer Institute (NCI)
Last Modified on25 October 2022


Yes No Not Sure

Inclusion Criteria

Metastatic, solid cancer 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); (4) endocrine tumors including neuroendocrine tumors and, (5) multiple myeloma that includes measurable solid tumors (plasmacytomas). Participants with multiple myeloma are potentially eligible only if they have measurable multiple myeloma as defined in Section 16.7 after plasmacytoma resection
Note: NSCLC includes but is not limited to squamous cell carcinoma, adenosquamous
carcinoma, or adenocarcinomas
Confirmation of diagnosis of cancer by the NCI Laboratory of Pathology
Participants with metastatic colorectal cancer must have received oxaliplatin or
Refractory to approved standard systemic therapy. Specifically
Participants with breast and ovarian cancer must be refractory to both first- and
second- line treatments
Participants with NSCLC must have received at least one platinum-based
chemotherapy regimen and at least one FDA-approved targeted treatment (when
Age greater than or equal to 18 years and less than or equal to 70 years
Participants with endocrine tumors including neuroendocrine tumors must be refractory
asymptomatic are eligible. Lesions that have been treated with stereotactic
to first-line therapy (e.g., lanreotide, octreotide) and must be refractory or have
radiosurgery must be clinically stable for one month after treatment for the
refused second-line treatments such as everolimus, sunitinib, or 177 Lu-Dotatate, if
participant to be eligible. Participants with surgically resected brain metastases are
Participants with multiple myeloma must have received at least four prior lines of
therapy that included at least one exposure to an immunomodulatory drug such as
Clinical performance status of ECOG 0 or 1
lenalidomide, a proteosome inhibitor, an anti-CD38 antibody treatment, and an
Participants of both genders must be willing to practice birth control from the time
autologous stem cell transplant
of enrollment on this study and for four months after treatment
Participants with three (3) or fewer brain metastases that are < 1 cm in diameter and
ANC > 1000/mm^3 without the support of filgrastim
Women of child-bearing potential must be willing to undergo a pregnancy test prior to
the start of treatment because of the potentially dangerous effects of the treatment
on the fetus
Hemoglobin > 8.0 g/dl. Subjects may be transfused to reach this cut-off
Seronegative for HIV antibody. (The experimental treatment being evaluated in
Serum ALT/AST less than or equal to 5.0 x ULN
this protocol depends on an intact immune system. Participants who are HIV
Serum creatinine less than or equal to 1.6 mg/dl
seropositive may have decreased immune-competence and thus be 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 participant must be tested for the
presence of antigen by RT-PCR and be HCV RNA negative
WBC greater than or equal to 2500/mm^3
Platelet count greater than or equal to 80,000/mm^3
Willing to sign a durable power of attorney
Subjects must be co-enrolled on protocol 03-C-0277
Total bilirubin less than or equal to 2.0 mg/dl, except in participants with
Gilbert's Syndrome, who must have a total bilirubin less than or equal to 3.0
Participants must have completed any prior systemic therapy at the time of enrollment
Note: Participants may have undergone minor surgical procedures or limited field
radiotherapy within the four weeks prior to enrollment, as long as related major organ
For Cohort 3: More than two weeks must have elapsed since any prior palliation for
major bronchial occlusion or bleeding at the time the patient receives the preparative
regimen, and patient s toxicities must have recovered to a grade 1 or less
Ability of subject to understand and the willingness to sign a written informed
consent document
toxicities have recovered to grade 1 or less. In addition, participants with multiple
myeloma may receive bridging therapy during the time between study enrollment and start of
study therapy. This may be necessary due to the long time needed for cell production on
this study. After bridging therapy and within 14 days of protocol treatment start
participants with multiple myeloma must still have measurable multiple myeloma

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
Concurrent systemic steroid therapy
Active systemic infections requiring anti-infective treatment, coagulation disorders
or any other active or uncompensated major medical illnesses
For Cohort 3: Any major bronchial occlusion or bleeding not amenable to palliation
History of coronary revascularization or ischemic symptoms
Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency Disease
and AIDS)
For Arm 2: Grade 3 or 4 major organ irAEs following treatment with anti-PD-1/PD-L1
including but not limited to myocarditis and pneumonitis
Note: Participants with grade 3 or 4 major organ irAEs may be enrolled on Arm 1 if all
other eligibility criteria are met
Concurrent opportunistic infections (The experimental treatment being evaluated in
this protocol depends on an intact immune system. Participants who have decreased
immune-competence may be less responsive to the experimental treatment and more
susceptible to its toxicities.)
History of severe immediate hypersensitivity reaction to cyclophosphamide
fludarabine, or aldesleukin
History of major organ autoimmune disease
For Cohorts 1, 2, or 4: Clinically significant participant history which in the
judgment of the Principal Investigator (PI) would compromise the participants ability
to tolerate high-dose aldesleukin
Note: At the discretion of the PI, participants enrolled in Cohort 3 may receive low-dose
For select participants with a clinical history prompting cardiac evaluation: last
known LVEF less than or equal to 45%
For select participants with a clinical history prompting pulmonary evaluation: known
FEV1 less than or equal to 50% predicted
Participants who are receiving any other investigational agents
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