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Targeted Therapeutics Demonstrate Potential to Improve Treatment of Non-Hodgkin’s Lymphoma

Targeted Therapeutics Demonstrate Potential to Improve Treatment of Non-Hodgkin’s Lymphoma

PHILADELPHIA-The success of anti-CD20 therapy with rituximab (Rituxan) in non-Hodgkin's lymphoma (NHL) has generated interest in the development of other novel targeted therapies for single-agent and combination therapy in patients with NHL. Several novel agents, including antibodies and oncolytic viruses, in preclinical or clinical development have the potential to improve the opportunities for targeted therapies in NHL. One potential agent is IDEC- 114.[1] A primatized human immunoglobulin G1 anti-CD80 antibody, IDEC-114 inhibits the binding of the B7-1 ligand on antigen-presenting cells to the CD28 receptor on T cells, thus blocking the secondary signal necessary for T-cell activation. IDEC- 114 was initially targeted as a potential therapy for psoriasis, but clinical development was halted after disappointing phase II studies. Now, however, IDEC-114 is in clinical development for the treatment of relapsed NHL. Myron Czuczman, MD, of Roswell Park Cancer Institute in Buffalo, New York, presented data on a phase I/II dose-ranging study to determine the pharmacokinetics and safety of IDEC- 114 in relapsed or refractory follicular NHL (ASH abstract 610).[1] Eight of the nine patients (three men and six women) enrolled in the phase I portion of the study had stage III/IV disease. Three dose cohorts (125, 250, or 375 mg/m2) had three patients each, and IDEC-114 was administered once weekly by intravenous infusion for 4 weeks. All patients completed the fourdose regimen, and IDEC-114 was safe and well tolerated, with no dose-limiting toxicities observed. All adverse events were mild to moderate in severity. Pharmacokinetic parameters were dose-dependent (see Table 1)[1] and within predictable levels. The phase II portion of the study revealed a reduction in tumor burden, with one partial response at the 375-mg/m2 dose level. Although very preliminary, this study suggests that IDEC-114 may be beneficial as monotherapy in the treatment of NHL. In addition, studies are ongoing with IDEC-114 and rituximab combination therapy. Cytotoxic T Lymphocytes
In preclinical studies, Jinjuan Wang, MD, and colleagues at Fred Hutchinson Cancer Research Center in Seattle and City of Hope in Duarte, California, have investigated the use of cytotoxic T lymphocytes (CTLs) for the treatment of follicular lymphoma (ASH abstract 755).[2] The investigators tested CD8+ CTLs expressing a CD20-specific, single-chain FvFc:zeta, chimeric T-cell-receptor gene.[3] The preclinical studies demonstrated that CD8+ CTLs can be produced after exposure to human CD20+ lymphoma cell lines and that these CTLs can specifically lyse CD20+ target cells. These results suggested that cellular immunotherapy with CD20- specific CTLs is feasible. A phase I clinical trial for relapsed follicular lymphoma is planned.[2] Viruses Investigated
Due to their ability to specifically target and lyse cells, several viruses, including adenoviruses and herpes viruses, have been investigated in cancer treatment.[4] Oncolytic viruses can be genetically engineered to selectively infect and/or replicate in cancer cells. Attenuated measles virus (MV), for example, may have therapeutic potential. Adele Fielding, MD, and colleagues at the Mayo Clinic in Rochester, Minnesota, tested whether they could engineer the entry of measles virus through a target antigen (ie, CD20) clinically relevant to NHL (ASH abstract 756).[5] Studies in cell lines demonstrated selective entry of mea sles virus into cells designed to express CD20. This is the first report demonstrating that entry of a replicating oncolytic virus can be facilitated through interaction between an NHL-relevant single-chain antibody and its target antigen. Recently, this group of investigators published the in vitro data reviewed above, along with in vivo results in immunodeficient mice containing a B-cell lymphoma xenograft.[ 6] A phase I clinical study has been approved.[7]

References

1. Czuczman MS, Witzig TE, Younes A, et al: IDEC-114, an anti- CD80 monoclonal antibody for relapsed or refractory, follicular NHL: phase I/II study of safety, efficacy, and pharmacokinetics (abstract 610). Blood 100:163a, 2002.
2. Wang J, Press OW, Lindgren CG, et al: Generation and characterization of CD20-specific CD8+ cytotoxic T lymphocytes (CTL) genetically modified by introduction of an scFvFc: zeta chimeric T cell receptor gene: Preclinical studies prior to a phase I trial of cellular immunotherapy of follicular lymphoma (abstract 755). Blood 100:201a, 2002.
3. Jensen M, Tan G, Forman S, et al: CD20 is a molecular target for scFvFc:zeta receptor redirected T cells: Implications for cellular immunotherapy of CD20+ malignancy. Biol Blood Marrow Transplant 4:75-83, 1998.
4. Mullen JT, Tanabe KK. Viral oncolysis. Oncologist 7:106-119, 2002.
5. Fielding A, Bucheit A, Kumar S, et al: Replicating attenuated measles virus can be engineered to enter cells through the CD20 antigen (abstract 756). Blood 100:201a, 2002.
6. Bucheit AD, Kumar S, Grote DM, et al: An oncolytic measles virus engineered to enter cells through the CD20 antigen. Mol Ther 7:62-72, 2003.
7. Grote D, Russell SJ, Cornu TI, et al: Live attenuated measles virus induces regression of human lymphoma xenografts in immunodeficient mice. Blood 97:3746-3754, 2001.
 
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