Azacitidine and Abatacept in Relapsed or Refractory T-Cell Lymphoma

Background: * Relapsed or refractory T-cell lymphoma is typically incurable with a median survival of less than 1 year. Angioimmunoblastic T-cell lymphoma (AITL) is the most commonly defined subtype of T-cell lymphoma and has a similarly poor prognosis. * We have developed the first AITL cell lines that maintain immunophenotypic fidelity with AITL and used these cell lines to identify novel therapies for patients with AITL. * We found that CD28 blockade with the Food and Drug Administration (FDA)-approved rheumatologic agent abatacept, which blocks CD28 signaling, impaired the proliferation of AITL cell lines, and that injection of abatacept into patient-derived xenograft (PDX) models of AITL significantly prolonged their survival. Based on this we conclude that targeting CD28 with abatacept in AITL is a promising, novel therapeutic approach that warrants clinical testing in people with relapsed/refractory (R/R) T-cell lymphoma. * Abatacept can be combined with the deoxyribonucleic acid (DNA) methyltransferase inhibitor azacitidine, which has been shown to be preferentially active in patients with a TET2 mutation, the most common genetic abnormality in patients with AITL. We confirmed that azacitidine indeed inhibits AITL cell lines synergistically with abatacept. Objectives: * Arm 1: To estimate the maximum tolerated dose (MTD) of the combination of azacitidine and abatacept in relapsed or refractory T-cell lymphoma. * Arm 2: To estimate the complete response rate (CRR) of the combination of azacitidine and abatacept. Eligibility: * Participants \>= 18 years with relapsed or refractory T-cell lymphoma after initial systemic treatment. * Adequate organ and marrow function. * Eastern Cooperative Oncology Group (ECOG) performance status \<= 2. Design: * This is a non-randomized, open-label, single-site phase I trial evaluating the combination of azacitidine and abatacept. * Treatment will be delivered in cycles consistent of 28 days. * During Cycle 0 abatacept will be administered intravenously on Days 1 and 15. * During Cycles 1-6 abatacept administered on Day 1 will be combined with subcutaneous azacitidine delivered on Days 1-5 or Days 1-7. * After Cycle 6 participants will be evaluated and participants who have a response will get additional 6 cycles of the monotherapy with azacitidine.