SBIR-STTR Award

This study will determine the feasibility of using autologous activated T cells for the treatment of B-CLL. Xcyte s technology uses para-magnetic beads covalently coated with anti-CD3 and anti-CD28 anti-bodies, which makes the bead a potent polyclonal activator of T cells. Cells generated this way have been used at the University of Chicago to treat relapsed/chemorefractory B Cell-NHL patients. This trial represents the first successful use of an ex-vivo costimulatory autologous T cell immunotherapeutic approach for patients with this malignancy. B-CLL patients present special difficulties for this therapy, including high leukemic burden in the blood, associated with T cell immunosuppression and hypo- gammaglobulinemia. The proposed study is designed to address using Xcyte s technology in a clinical trial for B-CLL patients who have failed primary therapy. The study will assess the ability of coordinated CD3xCD28 activation to expand T cells from the peripheral blood of B-CLL patients to therapeutically relevant numbers, and to correct T cell defects which prevent them from responding to autologous leukemia cells. Successful demonstration of these aims will justify the initiation of a phase I clinical trial in B-CLL conducted jointly by Xcyte Therapies and collaborators at the Oregon Health Sciences University. PROPOSED COMMERCIAL APPLICATION Xcyte Therapies has built a GMP manufacturing facility to generate activated T cells for clinical trials. A pivotal trial for 3x28 activated T cells will begin in 2000. About 20,000 NHL patients will be eligible for this therapy in the USA, and another 20,000 patients with other malignancies, such as B-CLL will also be eligible. The therapy may have applications to breast, lung and prostate cancer as well.

Thesaurus Terms:
B lymphocyte, T lymphocyte, autologous transplantation, cell transplantation, chronic lymphocytic leukemia, leukocyte activation /transformation, neoplasm /cancer immunotherapy CD28 molecule, CD3 molecule, hybrid antibody, immunomodulator, surface antigen, surface coating clinical research, human subject, immunomagnetic separation

Xcyte Therapies has developed a process ("Xcellerate") for the ex vivo activation and expansion of T cells using magnetic beads coated with antibodies to CD3 and CD28. Xcellerated T Cells from patients with CLL demonstrate an enhanced T cell repertoire, and the ability to induce the apoptosis of autologous tumor cells. Xcyte Therapies now plans to test this process as a therapy for patients with CLL. A dose escalation trial will be performed. The Specific Aims of this proposal are to: 1. Optimize large-scale bioreactor production of Xcellerated T Cells for CLL patients. Xcyte has developed a large-scale production process that will be able to achieve the cell doses required for the first two patient cohorts in the proposed clinical trial. Xcyte is now developing a bioreactor process to achieve the higher cell yields, which will be required to treat the third cohort of patients in the clinical trial. Xcyte will optimize and validate this process specifically for CLL. 2. Determine the safety & feasibility of infusinq Xcellerated T Cells in CLL patients in a dose escalation trial. Each patient will receive a single dose of Xcellerated T Cells. The cell dose will be escalated in cohorts of three patients each to determine the maximum tolerated dose (up to a maximum of 1 x 1011). The Xcellerated T Cell doses for each cohort will be: 1 x 1010, 3 x 1010, and 1 x 1011. Patients will be monitored carefully for toxicity. We will assess the influence of patient disease and prior treatment factors on final product characteristics. 3. Characterize immune reconstitution in patients treated with Xcellerated T Cells. We will assess changes in lymphocyte subsets by flow cytometry, immunoglobulin levels, and T cell repertoire by spectratyping. 4. Assess anti-tumor activity in CLL patients treated with Xcellerated T Cells. Patients will be monitored for clinical responses, changes in lymph node area, leukemic cell counts, expression of immunologic effector molecules on B cells, plasma cytokine levels, and anti-tumor T cell reactivity by ELISPOT. Xcyte Therapies has designed the clinical trial in collaboration with Dr. Thomas Kipps from the University of California, San Diego. He will serve as the principal clinical investigator for the trial. If the Xcellerate therapy can be determined to be safe, to improve the immune repertoire of patients, and to demonstrate evidence of anti-tumor activity, Xcyte will conduct subsequent trials to demonstrate its clinical benefit in CLL patients. Subsequent trials will also examine immune reconstitution following therapy with agents such as fludarabine and Campath

Thesaurus Terms:
T lymphocyte, autologous transplantation, bioreactor, cell growth regulation, chronic lymphocytic leukemia, human therapy evaluation, immunomagnetic separation, leukapheresis, leukocyte activation /transformation, method development antibody formation, cell population study, cell sorting, clinical trial phase I, clinical trial phase II, cytokine, dosage clinical research, cryopreservation, enzyme linked immunosorbent assay, flow cytometry, human subject, statistics /biometry