Fusion Toxins

A number of strategies have been developed to target cytotoxic proteins to tumor cells, including conjugated immunotoxins, single-chain antibody-immuno-toxin conjugates, and fusion toxins. Table 68.1 summarizes in vitro and in vivo data using immunotoxins in lymphoid malignancies. The major limitation of immunotoxins, in which the toxin moiety is conjugated to a monoclonal antibody, is their ability to be internalized by the cell and translocate efficiently into the cytoplasm where they can inhibit protein synthesis. Because of their large size, conjugated immunotox-ins may not be efficiently translocated into the cell and may, by nature of their epitopes, be immunogenic. Both ricin A-chain and pseudomonas exotoxin-based immunoconjugates have been developed and have demonstrated limited efficacy and significant toxicity in patients with Hodgkin's disease and NHL.7-11

Denileukin diftitox is a genetically engineered fusion protein combining the enzymatically active domains of diphtheria toxin and the full-length sequence of interleukin-2 (IL-2), and targets tumor cells expressing the intermediate- and high-affinity IL-2 receptors (IL-2R).12 Denileukin diftitox has been approved for the therapy of refractory CTCL based on

Table 68.1 Immunotoxins in lymphoma

Immunotoxin

Activity in vitro or in clinical trials

Reference

Rituximab/saporin-S6

Induced apoptosis in B-cell NHL cells in vitro, synergistic with fludarabine in vitro

Polito et al.

anti-CD19 (HD37-dgRTA) + anti-CD22 (RFB4-dgRTA)

In vitro study of combination immunotoxins demonstrated 100% survival in acute lymphocytic leukemia xenograft

Herrera et al.

anti-CD22 (RFB4-dgRTA)

Phase I study in B-cell NHL; 15 patients with refractory disease, 38% PR

Vitetta, 1991.

Ki-4.dgA anti-CD30 immunotoxin

Phase I study of 17 pts with refractory CD30+ lymphoma: 1 CR, 1 PR

Schnell et al.

anti-B4-bR

Phase II study in 16 CD19+ refractory B-cell NHL patients, no durable responses

Multani et al.

G28-5 sFv-PE40

In vitro activity in B-cell NHL, targets CD40

Francisco et al.

BL22 (RFB4(dsFv)-PE38)

In vitro efficacy, targets CD22

Barth et al.

anti-Tac(Fv)-PE38 (LMB-2)

Phase I trial in 35 patients with CD25+ lymphoma: 7 PR (1 HD, 1 CLL, 3 hairy cell , 1 CTCL, 1 ATL)

Kreitman et al.

CLL, chronic lymphocytic leukemia, CTCL, cutaneous T-cell lymphoma; NHL, non-Hedgkin's lymphoma.

CLL, chronic lymphocytic leukemia, CTCL, cutaneous T-cell lymphoma; NHL, non-Hedgkin's lymphoma.

an overall response rate of 30% in heavily pretreated patients.1314 Toxicities include hypersensitivity related to the infusion of protein and a low-grade vascular leak syndrome seen in 23% of patients manifested by low albumin, peripheral edema, and/or hypotension. Recent studies using steroid premedication and hydration have significantly reduced the incidence and severity of these events in patients with CTCL.15

Previous studies have demonstrated IL-2R expression on a variety of B-cell non-Hodgkin's lymphomas, including both low- and intermediate-grade lym-phomas.1617 In a phase I study of escalating doses of denileukin diftitox ranging from 3 to 31 ^g/kg/day X 5 days for a 21-day cycle, the expression of IL-2R was determined by immunohistochemistry as an entry criteria. Of 66 B-cell NHL patients screened, 29 expressed a component of the IL-2R (p55 or CD25, or p75 or CD122).16 The overall response rate in 23 heavily pretreated NHL patients was 17%, including 2 of 9 patients with intermediate-grade NHL who had partial responses. On the basis of these data, a phase II study was initiated at MD Anderson Cancer Center to evaluate the efficacy of denileukin diftitox in relapsed/refractory B NHL.1819 All low- and intermediate-grade B-cell NHL patients were eligible, and IL-2R expression was determined based on expression of CD25 on tumor cells. Denileukin diftitox was administered at 18 ^g/kg/day for 5 days every 3 weeks, for up to eight cycles. Corticosteroid premedication prior to each drug infusion was given in an attempt to reduce the incidence and severity of acute hypersensitivity. Most patients had undergone multiple prior treatments, including autologous stem cell transplants, and many had compromised bone marrow reserve. Of 29 patients treated, there were three (CR) complete response (one follicular mixed B-cell lymphoma, one B-cell DLCL, one mantle cell lymphoma), and four (PR) partial response (one SLL, three B-cell DLCL) for an overall response rate of 24%. Another study exploring the activity of denileukin diftitox in B-cellNHL was conducted by the Eastern Cooperative Oncology Group to explore the activity in IL-2R expressing and nonexpressing low-grade B-cell NHL. Studies are underway to further explore the activity of denileukin diftitox in combination with rituximab in low- and intermediate-grade refractory B-cell NHL and B-CLL.

0 0

Post a comment