Project summary/abstract This is a phase I, 3+3 dose escalation, first in man, clinical trial to study CD4 Redirected Chimeric Antigen Receptor T Cell Therapy (CD4CAR) for CD4 Positive T cell heavily pretreated or refractory patients with CD4+ T cell malignancies. The investigational agent to be studied are autologous CD4CAR T-cells engineered to express an anti-CD4scFV domain derived from the monoclonal antibody (mAb) Ibalizumab (Hu5A8 or TNX-355) paired with an intracellular tyrosine-based activation motif from the T-cell receptor (TCR) and two costimulatory domains, CD28 and 4BB via lentiviral transduction in a good manufacturing practice (GMP) clean facility. We plan to enroll up to 30 patients in order to treat ̴15 subjects (accounting for screen and manufacturing failures) with CD4CAR. Eligible subjects are patients with relapsed or refractory CD4 positive T cell lymphoma and leukemia to second line standard therapy. The primary objective of the clinical trial is to test the feasibility to manufacture and the safety of CD4CAR cells in this patient population. Subjects will be screened and entered into the study if eligible. Subjects will then be conditioned with cytoreductive chemotherapy using cyclophosphamide and fludarbine for lymphodepletion. After meeting release criteria CD4CAR autologous cells will be administered over a short infusion time. Patients will be hospitalized for the period of infusion and till expected serious side effects are resolved. Major side effects include cytokine release syndrome and neurotoxicity, accelerated CAR proliferation, and generation of replication capable lentivirus. As well as infections related to CD4-deplete host. Strict prophylaxis and monitoring for early treatment for all of those will be implemented. Study subjects will be monitored closely during and after discharge from hospital with physical exams, lab work, CAR T persistence testing and end organ toxicity. Description of objective responses will be recorded. This is a high risk study with long follow up (up to 15 years).