National Cancer Institute Tests TCR-Transduced T-Cell Therapy for Solid Tumors in Phase 2 Trial
The treatment under study involves isolating neoantigen-reactive TCRs from patients’ tumor-infiltrating lymphocytes and incorporation into gamma retroviral vectors of the TCR α and β chains.
The National Cancer Institute (NCI) is currently evaluating T-cell receptors (TCR)-transduced T-cell therapy for the treatment of various kinds of solid tumors in a phase 2 clinical trial (NCT03412877).1 For this installment of Clinical Trials in Progress, CGTLive® has decided to take a closer look at this ongoing study.
Specifically, the treatment under study involves isolating neoantigen-reactive TCRs from patients’ tumor-infiltrating lymphocytes and incorporation into gamma retroviral vectors of the TCR α and β chains.2 These are then used to transduce peripheral blood lymphocytes that are then readministered to patients after lymphodepleting chemotherapy.
The trial, which was launched on September 6, 2018, is evaluating the treatment in 2 arms: one that uses a treatment regimen that does not include the use of pembrolizumab (arm 1) and one that uses a treatment regimen including the use of pembrolizumab.1 The trial is a single-center study taking place at the National Institutes of Health Clinical Center in Bethesda, Maryland. Steven A Rosenberg, MD, of the NCI, is serving as the study’s principal investigator. According to the clinicaltrials.gov page for the study, which was most recently updated on April 6, 2025, the trial is actively recruiting participants. It is expected to enroll 270 patients in total, and has an estimated primary completion date of March 23, 2027, and an estimated completion date of April 23, 2028.
The trial’s primary end point is response rate as measured by the percentage of patients who are administered pembrolizumab during their treatment regimen and have a clinical response to treatment in the form of objective tumor regression. The response rate will be measured at 6 weeks and 12 weeks after cell infusion, then every 3 months 3 times, then every 6 months for 2 years, and then at the discretion of principal investigator. The trial’s secondary end point is safety and tolerance as measured by standard Common Terminology Criteria for Adverse Events 5.0. The time frame for this end point is 6 weeks after dosing of the cell product or 30 days after the last dose of pembrolizumab.
Eligible participants must be between 18 and 72 years of age with a documented diagnosis of metastatic, measurable solid cancer that falls within one of 5 defined cohorts: gastrointestinal and genitourinary cancers; breast, ovarian, and other solid tumors; non–small cell lung cancer (NSCLC); endocrine tumors, including neuroendocrine tumors; and multiple myeloma with measurable solid tumors. Patients with multiple myeloma are eligible only if they meet specific criteria for measurable disease following plasmacytoma resection. All participants must have disease that is refractory to standard systemic therapy appropriate to their cancer type. In particular, patients with colorectal cancer must have received oxaliplatin or irinotecan, those with breast or ovarian cancer must be refractory to first-line and refractory to or declined second-line therapy, and patients with NSCLC must have previously received at least 1 platinum-based chemotherapy and 1FDA-approved targeted agent, if indicated. Participants with neuroendocrine tumors must be refractory to first-line therapy and refractory to or declined second-line options if any were indicated.
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Up to 3 asymptomatic brain metastases measuring less than 1 cm are permitted, provided any treated lesions are stable for at least 1 month post-stereotactic radiosurgery. ECOG performance status of 0 or 1 is required. Participants must have completed any prior systemic therapy and recovered from related toxicities (grade ≤1), although minor surgeries and limited field radiotherapy are allowed within 4 weeks of enrollment. Specific hematologic and biochemical parameters must be met, including absolute neutrophil count > 1000/mm³, WBC ≥ 2500/mm³, platelets ≥ 80,000/mm³, hemoglobin > 8.0 g/dL, ALT/AST ≤ 5× ULN, serum creatinine ≤ 1.6 mg/dL, and total bilirubin ≤ 2.0 mg/dL (or ≤ 3.0 mg/dL in participants with Gilbert’s Syndrome). HIV seronegativity is required; seronegativity for hepatitis B antigen and hepatitis C antibody is also necessary. If a patient tests positive for hepatitis C antibody, they must be tested for antigen by reverse transcription polymerase chain reaction and be HCV RNA negative.
Participants of childbearing potential must agree to pregnancy testing prior to treatment and to use effective contraception during the study and for 12 months following chemotherapy. Those able to father a child must use birth control for 4 months posttreatment. Written informed consent and a durable power of attorney are required, and participants must also be co-enrolled on Cell Harvest and Preparation for Surgery Branch Adoptive Cell Therapy Protocols (protocol 03-C-0277).
Participants will be excluded if they are pregnant, breastfeeding, or receiving systemic steroid therapy. Additional exclusion criteria include active systemic infections requiring treatment, significant coagulation disorders, or serious uncontrolled illnesses. Patients with untreated or nonpalliable major bronchial obstruction or bleeding (NSCLC cohort), primary immunodeficiency, or a history of major autoimmune diseases are ineligible. Prior grade 3 or 4 immune-related adverse events (irAEs) involving major organs following antiPD-1/PD-L1 therapy will exclude participation in the pembrolizumab arm but may still be eligible for the arm without pembrolizumab. Patients with a history of severe allergic reactions to cyclophosphamide, fludarabine, or aldesleukin are excluded, as are those receiving other investigational agents. Additional exclusions apply based on cardiac and pulmonary history, including coronary revascularization, LVEF ≤ 45%, or FEV₁ ≤ 50% predicted for those with relevant clinical indications. The principal investigator may determine that certain patients with significant clinical history are not suitable for high-dose aldesleukin; low-dose aldesleukin may be considered in the NSCLC.
Notably interim results from the trial were reported in Nature Medicine in July 2024.2 The data specifically pertained to patients with metastatic gastrointestinal cancers.
“In a phase 2 single-arm study, we treated 7 patients with metastatic, mismatch repair-proficient colorectal cancers who had progressive disease following multiple previous therapies...” Maria Parkhurst, PhD, an associate scientist at NCI, and colleagues wrote in the paper’s abstract.2 “The primary end point of the study was the objective response rate as measured using RECIST 1.1, and the secondary end points were safety and tolerability. There was no prespecified interim analysis defined in this study. Three patients had objective clinical responses by RECIST criteria including regressions of metastases to the liver, lungs and lymph nodes lasting 4 to 7 months... TCR-transduced cells were detected in the peripheral blood of five patients, including the 3 responders, at levels ≥10% of CD3+ cells 1 month post-ACT. In 1 patient who responded to therapy, ~20% of CD3+ peripheral blood lymphocytes expressed transduced TCRs more than 2 years after treatment. This study provides early results suggesting that ACT with T cells genetically modified to express personalized neoantigen-reactive TCRs can be tolerated and can mediate tumor regression in patients with metastatic colorectal cancers.”
