Adoptive Immunotherapy with Autologous CD25-Depleted and CD3/CD28-Costimulated T-Cells (ACTC) Enhances Numeric and Functional Lymphocyte Recovery after Cyclophosphamide - Fludarabine Chemotherapy in Patients with Low-Grade Follicular Lymphoma.

Fludarabine-based chemotherapy combinations are highly effective in patients (pts) with low-grade follicular lymphoma (FL), but cause severe and long-lasting immunosuppression due to depletion of normal CD4 T-cells. Aside from increasing the risk of serious infections, this toxicity may limit the ability of the immune system to eliminate minimal residual disease. Adoptive immunotherapy using autologous CD25-depleted, CD3/CD28-costimulated T-cells expanded ex vivo (ACTC) may enhance immune reconstitution and improve disease control. We initiated a phase I study in pts with purine analog-naive relapsed/refractory FL (grades 1 and 2). After leukapheresis, pts receive 4 cycles of fludarabine (25 mg/m²) days 1 – 3 and cyclophosphamide (250 mg/m²) days 1 – 3. Four weeks after last chemotherapy, responding patients (CR, CRu, PR) receive escalating doses of ACTC prepared from autologous T-cells collected prior to chemotherapy. Thirteen pts have been enrolled to date. Median age is 49 y (range: 32 – 68). Median number of prior therapies is 2 (range: 1 – 3). Two pts were withdrawn from the study due to hematologic toxicity related to chemotherapy, one patient was withdrawn for progressive disease during chemotherapy, and one patient has not completed first response assessment after ACTC infusion. For 9 assessable pts completing chemotherapy and ACTC infusion, 7 pts achieved a CR and 2 pts achieved a PR; 5 pts received 1 – 5 x 10⁹ and 4 patients received 5 – 10 x 10⁹ CD3+ ACTC. There have been no adverse events related to T-cell infusions. Median follow-up after ACTC infusion is 20 months (range: 2 – 42 months). CD4 counts increased in all patients by 1 month after T-cell infusion, with a median increase of 3.8 fold (n = 8; range: 1.5 – 71). For patients at dose level 1, the median increase was 2.2 fold (n = 4; range: 1.5 – 21); at dose level 2, it was 4.2 fold (n = 4; range: 3.8 – 71). CD8 counts also increased, with a median increase of 8.1 fold (range: 1.0 – 30). All 9 pts receiving ACTC were anergic to candida antigen by delayed type hypersensitivity (DTH) skin testing before chemotherapy; 5 pts developed a positive DTH response to candida antigen 60 days after ACTC infusion. From the start of therapy for patients receiving T-cells, median follow-up is 24 months (range: 6 – 47) with median progression-free survival of 18 months, which is significantly longer than the time to progression from last therapy (median 11 months) (p = 0.01, log-rank test). Thus, ACTC results in more rapid CD4+ lymphocyte recovery in pts after cyclophosphamide-fludarabine chemotherapy compared to historical controls and results in reconstitution of recall immunity. These encouraging clinical responses provide the rationale for clinical trials to test ACTC as a way to enhance cellular immunity to tumor-specific antigens after chemotherapy.