Relapse rates after high dose chemotherapy (HDC) autologous peripheral blood stem cell transplant (PBSCT) for high risk refractory or relapsed non-Hodgkin’s lymphoma (NHL) patients remain unacceptably high. In order to augment the anti-lymphoma effect and decrease relapsed rates, our strategy combines 1) the cytotoxicity mediated by anti-CD3 activated autologous T cells (ATC) armed with a bispecific antibody (BiAb) that redirects ATC to kill CD20 + lymphoma cells and circumvents rituximab resistance (

Exp Hemat 33:452, 2005
) and 2) autologous PBSCT after high dose chemotherapy. Arming ATC with anti-CD3 x anti-CD20 (CD20Bi) converts each ATC into a CD20-specific cytotoxic T cell. Our phase I trial tests whether multiple infusions of armed ATC armed given after HDC followed by PBSCT are safe and whether such infusions will provide an anti-lymphoma effect to improve overall survival and disease free survival after PBSCT. On 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. The dose levels are 5, 10, 15, and 20 x 109 cells/infusion with total armed ATC doses equaling 75, 150, 225, and 300 x 109 CD20Bi-armed ATC. Subcutaneous IL-2 (300,000 IU/m2/day) will be given daily beginning d+4 and ending after the last dose of armed ATC. The dose of CD34+/kg ranged from 1.04 to 3.4 x 106. T cells in the leukopheresis product were activated with anti-CD3 and expanded in low dose IL-2, harvested, armed with CD20Bi, and cryopreserved for infusions after PBSCT. The ATC harvest ranged from 119–140 billion with >94% viability with 96–99% CD3+, 33–67% CD4+, 32–53% CD8+, and <6.5% CD4+CD25+ and CD8+CD25+ cells. All three patients received all of their infusions. Three patients completed the first dose level (total of 70 x 109 CD20Bi armed ATC) without any dose limiting toxicities. All of the patients are alive 780, 650, and 521 days after PBSCT. Two are free of disease and one was transplanted with persistent disease went into remission after PBSCT and relapsed 8 months after PBSCT. He is now in remission following chemotherapy and a MUD PBSCT. The cytotoxicity mediated by the patients’ ex vivo expanded, armed ATC against the B9C cell line was significantly higher than unarmed ATC. CTL activity directed at B cell targets was detected by 3 weeks after PBSCT. These results suggest that large numbers of armed autologous ATC can be infused after PBSCT without major side effects related to the armed targeted ATC. This strategy may provide a unique opportunity to increase the GVL effect without increasing toxicities after autologous PBSCT for CD20+ lymphomas.

Topics:
antibodies, bispecific, cd20 antigens, lymphoma, lymphoma, non-hodgkin, peripheral blood stem cells, tissue transplants, t-lymphocytes, transplantation, chemotherapy regimen, cytotoxicity

Author notes

Disclosure: Ownership Interests: Lawrence Lum is founder of Transtarget. Research Funding: Study is funded by Leukemia & Lymphoma Society. Membership Information: Lawrence Lum on speaker’s bureau for Berlex. Off Label Use: IL-2 and GM-CSF use.

2007, The American Society of Hematology
2007
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