Clinical Trials Logo

Clinical Trial Summary

Background: 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. Objective: To learn if a person s white blood cells modified with T-cell receptors can cause solid tumors to shrink. Eligibility: People ages 18-70 who have cancer of the gastrointestinal tract, genitourinary tract, ovary, breast, or lung that has spread, or who have glioblastoma. Design: Participants will be screened and have their cells prepared for treatment in another protocol. 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 Chest X-ray Physical exam 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.


Clinical Trial Description

Background: - 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. Objective: -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 Beauty system. Eligibility: Patients who are age greater than or equal to 18 years and less than or equal to 70 years must have: - 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 Design: - 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 lymphodepleting regimen. - 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 10 doses). - 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. ;


Study Design


Related Conditions & MeSH terms


NCT number NCT04102436
Study type Interventional
Source National Institutes of Health Clinical Center (CC)
Contact
Status Suspended
Phase Phase 2
Start date September 7, 2021
Completion date December 31, 2029

See also
  Status Clinical Trial Phase
Recruiting NCT04681911 - Inetetamab Combined With Pyrotinib and Chemotherapy in the Treatment of HER2 Positive Metastatic Breast Cancer Phase 2
Recruiting NCT04574609 - Evaluation of the Impact of the Use of Hypnotherapy Performed by a Virtual Reality Toolalong the Care Pathway of Patients Undergoing Breast Cancer Treatment. N/A
Recruiting NCT04890327 - Web-based Family History Tool N/A
Terminated NCT04066790 - Pyrotinib or Trastuzumab Plus Nab-paclitaxel as Neoadjuvant Therapy in HER2-positive Breast Cancer Phase 2
Completed NCT03591848 - Pilot Study of a Web-based Decision Aid for Young Women With Breast Cancer, During the Proposal for Preservation of Fertility N/A
Recruiting NCT03954197 - Evaluation of Priming Before in Vitro Maturation for Fertility Preservation in Breast Cancer Patients N/A
Terminated NCT02202746 - A Study to Assess the Safety and Efficacy of the VEGFR-FGFR-PDGFR Inhibitor, Lucitanib, Given to Patients With Metastatic Breast Cancer Phase 2
Active, not recruiting NCT01472094 - Clinical and Biological Predictors of Chemotherapy Toxicity in Older Adults
Recruiting NCT04631835 - Phase I Study of the HS-10352 in Patients With Advanced Breast Cancer Phase 1
Enrolling by invitation NCT04307407 - Exercise in Breast Cancer Survivors N/A
Recruiting NCT03544762 - Correlation of 16α-[18F]Fluoro-17β-estradiol PET Imaging With ESR1 Mutation Phase 3
Active, not recruiting NCT02482389 - Study of Preoperative Boost Radiotherapy N/A
Enrolling by invitation NCT00068003 - Harvesting Cells for Experimental Cancer Treatments
Completed NCT00226967 - Stress, Diurnal Cortisol, and Breast Cancer Survival
Active, not recruiting NCT00341939 - Retrospective Analysis of a Drug-Metabolizing Genotype in Cancer Patients and Correlation With Pharmacokinetic and Pharmacodynamics Data
Not yet recruiting NCT05048095 - Artificial Intelligence in Breast Cancer Screening in Region Östergötland Linkoping
Recruiting NCT04190381 - A Study to Evaluate the Safety and Clinical Outcome of Using FR-Mask in Breast Cancer Patients With Radiation-irritated Skin After Radiotherapy N/A
Active, not recruiting NCT04088955 - A Digimed Oncology PharmacoTherapy Registry
Recruiting NCT03667716 - COM701 (an Inhibitor of PVRIG) in Subjects With Advanced Solid Tumors. Phase 1
Suspended NCT03412877 - Administration of Autologous T-Cells Genetically Engineered to Express T-Cell Receptors Reactive Against Neoantigens in People With Metastatic Cancer Phase 2