A Phase I Study of Autologous T Cells Transduced With Retroviral Vectors Expressing TCRs for Participant-specific Neoantigens in Patients With Acute Myeloid Leukemia, Myelodysplastic Syndrome, and Other Hematologic Malignancies
National Cancer Institute (NCI)
Summary
Background: Blood cancers (such as leukemias) can be hard to treat, especially if they have mutations in the TP53 or RAS genes. These mutations can cause the cancer cells to create substances called neoepitopes. Researchers want to test a method of treating blood cancers by altering a person s T cells (a type of immune cell) to target neoepitopes. Objective: To test the use of neoepitope-specific T cells in people with blood cancers Eligibility: People aged 18 to 75 years with any of 9 blood cancers. Design: Participants will have a bone marrow biopsy: A sample of soft tissue will be removed from inside a pelvic bone. This is needed to confirm their diagnosis and the TP53 and RAS mutations in their cancer cells. They will also have a skin biopsy to look for these mutations in other tissue. Participants will undergo apheresis: Blood will be taken from their body through a vein. The blood will pass through a machine that separates out the T cells. The remaining blood will be returned to the body through a different vein. The T cells will be grown to become neoepitope-specific T cells. Participants receive drugs for 3 days to prepare their body for the treatment. The modified T cells will be given through a tube inserted into a vein. Participants will need to remain in the clinic at least 7 days after treatment. Participants will have 8 follow-up visits in the first year after treatment. They will have 6 more visits over the next 4 years. Long-term follow-up will go on for 10 more years.
Description
Background: * Many difficult-to-treat hematologic malignancies carry mutations in the tumor suppressor gene TP53 or the oncogenes NRAS and KRAS (shortened to RAS). * Missense mutations in TP53 and RAS result in immunogenic peptides (neoepitopes) that can be presented by human leukocyte antigens (HLA) to initiate an immune response. * The NCI Surgery Branch has previously identified T-cell receptors (TCRs) that selectively recognize p53 or Ras neoepitopes. * We propose to evaluate 3 TCRs targeting p53 neoepitopes and 4 TCRs targeting Ras neoepitopes in participants with hematologic malignancie…
Eligibility
- Age range
- 18–120 years
- Sex
- All
- Healthy volunteers
- No
* INCLUSION CRITERIA: Malignancy diagnosis requirements: -Eligible diagnoses include AML (acute myeloid leukemia), MDS (myelodysplastic syndrome), CMML(chronic myelomonocytic leukemia), CML (chronic myeloid leukemia), and T-ALL (T-acute lymphoblastic leukemia/lymphoma) meeting standard diagnostic criteria as described in the 5th edition World Health Organization Classification of Hematologic Tumors and/or the International Consensus Classification of Myeloid Neoplasms and Acute Leukemias. Multiple myeloma participants meeting International Working Group diagnostic criteria are eligible. Thes…
Interventions
- Drugaldesleukin
Aldesleukin 600,000 IU/kg IV (based on total body weight) over 15 minutes approximately every 8 hours beginning within 24 hours of cell infusion and continuing for up to 4 days (maximum 10 doses).
- Drugcyclophosphamide
300 mg/m\^2 IV infusion over 30 minutes. Daily x 3 doses on days -5, -4, -3.
- Drugfludarabine phosphate
30 mg/m\^2 IV infusion over 30 minutes administered immediately following cyclophosphamide on day -5, -4, -3. Participants with renal dysfunction receive a lower dose of fludarabine.
- BiologicalIndividual Patient TCR-Transduced PBL
Up to 1.5x10\^11 total cells for non-transplant subjects. 1x10\^10 total cells for post-alloHSCT subjects.
- DeviceTruSight Oncology (TSO) 500
TSO500 sequencing panel performed in the NCI Laboratory of Pathology to detect TP53 or RAS mutations
Location
- National Institutes of Health Clinical CenterBethesda, Maryland