Work

Immune consolidation after stem cell transplant for CD20+ nonhodgkin’s lymphoma using multiple infusions of autologous activated t cells (ATC) with anti-cd3 x anti-cd20 bispecific antibody (CD20Bi) to improve graft-vs-lymphoma effects

Year: 2006

Type: article

Abstract: Relapse after autologous stem cell transplant (SCT) for high risk in remission, refractory or relapsed non-Hodgkin’s lymphoma (NHL) patients remain unacceptably high. In order to augment the anti-lymphoma effect and decrease relapsed rates, we combine the cytotoxicity mediated by anti-CD3 activated autologous T cells (ATC) armed with a anti-CD3 x anti-CD20 bispecific antibody (CD20Bi) that redirects ATC to kill CD20+ targets with SCT after high dose chemotherapy (HDC). Arming with CD20Bi converts each T cell into a cytotoxic T lymphocyte directed at CD20+ targets. Our phase I trial tests whether multiple infusions of armed ATC given after HDC consisting of cyclophosphamide, thiotepa, and carboplatin (CTC) as a preparative regimen followed by SCT are safe. Furthermore, we will evaluate whether such infusions will provide an anti-lymphoma effect to improve overall survival and disease free survival after SCT for NHL. Beginning day +4, the patients receive immune consolidation consisting of 3 infusions of CD20Bi-armed ATC per week for 3 weeks and then 1 infusion per week for 6 additional weeks. Dose levels for the phase I trial are 5, 10, 15, and 20 × 109 cells/infusion with total armed ATC doses equaling 75, 150, 225, and 300 × 109 CD20Bi-armed ATC. Patients receive daily subcutaneous IL-2 (300,000 IU/m2/day) beginning within 24 hours of the first infusion and ending on the day of the last infusion. One patient has completed the first dose level. The first patient was a 58 year old man with relapsed diffuse, large B-cell lymphoma. He was primed with G-CSF, leukapheresed for CD34 enriched PBSC and lymphocytes. His CD34+ enriched PBSC were cryopreserved and his T cells were expanded with anti-CD3 activation and IL-2. The infused armed ATC product was 96% CD3, 44% CD4, 53% CD8, 81% CD4+CD45/RO+, and 93% CD8+CD45/RO+. He received a SCT after CTC and completed all 15 infusions at the first dose-level (total of 75 × 109) without any side-effects. He is 90 days after SCT and his restaging is pending. The cytotoxicicity mediated by the patient’s ex vivo expanded, armed ATC against the B9C cell line was considerably higher than unarmed ATC. These early results suggest that large numbers of armed autologous ATC can be infused after HDC and SCT without major side effects. This strategy used in combination with HDC and SCT may provide an unique opportunity to increase the GVL effect without increasing toxicities after SCT for hematologic malignancies.

Source: Transplantation and Cellular Therapy

DOI: 10.1016/j.bbmt.2005.11.365