Cancer Immune Therapy Edited by G. Stuhler and P. Walden ...

362 17 Immunotoxins and Recombinant Immunotoxins in Cancer Therapy
tion, growth factor fusion proteins have been made that target the IL-2, IL-4, IL-6
and granulocyte macrophage colony stimulating factor (GM-CSF) receptors.
The most potent immunotoxin produced against leukemia cells is anti-Tac(Fv)±PE38
(LMB-2); this targets CD25, which is over-expressed on many T cell leukemias [11,
80]. LMB-2 is very active against leukemia cell lines in vitro and has very good activity
in animal models [121]. It also selectively kills cells in vitro obtained from patients
with adult T cell leukemia without harming hematopoietic stem cells [95, 96]. Phase
I clinical trials with LMB-2 are showing promising results [108, 109]. The immunotoxin
was administered to 35 patients for a total of 59 treatment cycles. One hairy
cell leukemia (HCL) patient achieved a complete remission, which is ongoing at 20
months. Seven partial responses were observed in cutaneous T cell lymphoma, HCL,
chronic lymphocytic leukemia, Hodgkin's disease and adult T cell leukemia. Responding
patients had a 2±5 log reduction of circulating malignant cells, improvement
in skin lesions, and regression of lymphomatous mass and splenomegally. All
four patients with HCL responded to the treatment (one with complete responses
and three had 98±99.8% reductions in malignant circulating cells). A phase II trial is
planned in patients with CD25 + hematologic malignancies and phase I trials are
planned for the prevention of GvHD in patients undergoing high-risk allotransplantation
[124].
The conventional immunotoxin RFT5±SMPT±dgA has also been developed to target
CD25 and has resulted in several responses in Hodgkin's disease, one of which
lasted over 2 years [125, 126]. It is already undergoing testing for the prevention of
GvHD in patients undergoing allotransplantation and has recently been shown ex
vivo to remove alloreactive donor T cells while preserving antileukemia and antiviral
T cell responses [127].
A new agent, RFB4(dsFv)±PE38 (BL22), is a dsFv±immunotoxin directed at the
CD22 differentiation antigen present on most B cell leukemias [90]. It has high cytotoxic
activity on cultured tumor cells as well as in animal models and preclinical tests
have been completed. This recombinant immunotoxin recently entered clinical trials
in patients with leukemias [128]. Initial phase I trials in 16 chemotherapy-resistant
HCL patients resulted in 11 complete responses and two partial responses, including
two partial responses in patients ineligible for LMB-2 because of CD25 ± HCL cells.
Responses to BL22 were associated with at least a 99.5% reduction in circulating
HCL cells [128]. BL22 also induced responses in chronic lymphocytic leukemia.
These recent results demonstrate that recombinant Fv±immunotoxins containing
truncated PE are particularly effective in patients with chemotherapy-refractory HCL
and other hematological malignancies. Other targets for the development of B cell
leukemia-specific recombinant immunotoxins include the CD19 and CD20 differentiation
antigens in B cell tumors, and CD30 in Hodgkin's lymphoma.
The B cell lymphoma markers CD22 and CD19 were also targeted using conventional
first-generation immunotoxins with dgA ± IgG±RFB4±dgA (targeting CD22)
and IgG±HD37±dgA (targeting CD19) [129±135]. Leukemias and lymphomas were
also targeted with recombinant fusions of IL-2 with truncated DT [136±139].