T-cell receptors for cytokines: targets for immunotherapy of leukemia/lymphoma

Abstract

Background: Cytokine receptors are exceptionally valuable targets for immunotherapy. For example, the high affinity IL-2 receptor is expressed by abnormal T cells in patients with certain lymphoid malignancies or autoimmune disorders and in individuals rejecting allografts whereas it is not expressed by normal resting cells.

Design: To exploit this difference in receptor expression in normal resting cells and leukemic cells we have introduced different forms of IL-2 receptor directed therapy including an unmodified murine antibody to the alpha subunit of the IL-2 receptor (anti-Tac), humanized anti-Tac as well as this antibody armed with truncated Pseudomonas exotoxin or alpha- and beta-emitting radionuclides (e.g., 211At and 90Y). In particular, unmodified murine anti-Tac was used in the therapy of HTLV-I-associated adult T-cell leukemia (ATL).

Results: Six of nineteen patients treated with this antibody underwent a partial (four) or complete (two) remission. In a subsequent clinical trial involving anti-Tac armed with 90Y over 50% of the patients with ATL treated underwent a partial or complete remission.

Conclusions: New agents under development include humanized antibodies directed toward shared cytokine receptors such as IL-2/15R beta used by both IL-2 and IL-15 as well as to a shared signal transduction element Jak3 utilized by the T-cell stimulatory cytokines IL-2, IL-4, IL-7, IL-9 and IL-15. Thus our emerging understanding of cytokine receptors and their signaling pathways taken in conjunction with the ability to produce humanized antibodies armed with radionuclides or toxins are providing novel perspectives for the treatment of leukemia and lymphoma.