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

PHILADELPHIA-The successof anti-CD20 therapy with rituximab(Rituxan) in non-Hodgkin's lymphoma(NHL) has generated interest inthe development of other novel targetedtherapies for single-agent andcombination therapy in patients withNHL. Several novel agents, includingantibodies and oncolytic viruses, inpreclinical or clinical developmenthave the potential to improve the opportunitiesfor targeted therapies inNHL.One potential agent is IDEC-114.[1] A primatized human immunoglobulinG1 anti-CD80 antibody,IDEC-114 inhibits the binding of theB7-1 ligand on antigen-presentingcells to the CD28 receptor on T cells,thus blocking the secondary signalnecessary for T-cell activation. IDEC-114 was initially targeted as a potentialtherapy for psoriasis, but clinical developmentwas halted after disappointingphase II studies. Now, however,IDEC-114 is in clinical developmentfor the treatment of relapsed NHL.Myron Czuczman, MD, of RoswellPark Cancer Institute in Buffalo, NewYork, presented data on a phase I/IIdose-ranging study to determine thepharmacokinetics and safety of IDEC-114 in relapsed or refractory follicularNHL (ASH abstract 610).[1] Eight ofthe nine patients (three men and sixwomen) enrolled in the phase I portionof the study had stage III/IV disease.Three dose cohorts (125, 250, or375 mg/m2) had three patients each,and IDEC-114 was administered onceweekly by intravenous infusion for 4weeks.

All patients completed the fourdoseregimen, and IDEC-114 was safeand well tolerated, with no dose-limitingtoxicities observed. All adverseevents were mild to moderate in severity.Pharmacokinetic parameterswere dose-dependent (see Table 1)[1]and within predictable levels.The phase II portion of the studyrevealed a reduction in tumor burden,with one partial response at the375-mg/m² dose level. Although verypreliminary, this study suggests thatIDEC-114 may be beneficial as monotherapyin the treatment of NHL. Inaddition, studies are ongoing withIDEC-114 and rituximab combinationtherapy.Cytotoxic T Lymphocytes
In preclinical studies, JinjuanWang, MD, and colleagues at FredHutchinson Cancer Research Centerin Seattle and City of Hope in Duarte,California, have investigated the useof cytotoxic T lymphocytes (CTLs)for the treatment of follicular lymphoma(ASH abstract 755).[2] Theinvestigators tested CD8+ CTLs expressinga CD20-specific, single-chainFvFc:zeta, chimeric T-cell-receptorgene.[3] The preclinical studies demonstratedthat CD8+ CTLs can be producedafter exposure to human CD20+lymphoma cell lines and that theseCTLs can specifically lyse CD20+ targetcells. These results suggested thatcellular immunotherapy with CD20-specific CTLs is feasible. A phase Iclinical trial for relapsed follicularlymphoma is planned.[2]Viruses Investigated
Due to their ability to specificallytarget and lyse cells, several viruses,including adenoviruses and herpes viruses,have been investigated in cancertreatment.[4] Oncolytic virusescan be genetically engineered to selectivelyinfect and/or replicate in cancercells. Attenuated measles virus(MV), for example, may have therapeuticpotential.Adele Fielding, MD, and colleaguesat the Mayo Clinic in Rochester, Minnesota,tested whether they could engineerthe entry of measles virusthrough a target antigen (ie, CD20)clinically relevant to NHL (ASH abstract756).[5] Studies in cell linesdemonstrated selective entry of measles virus into cells designed to expressCD20.This is the first report demonstratingthat entry of a replicating oncolyticvirus can be facilitated through interactionbetween an NHL-relevantsingle-chain antibody and its targetantigen. Recently, this group of investigatorspublished the in vitro datareviewed above, along with in vivoresults in immunodeficient mice containinga B-cell lymphoma xenograft.[6] A phase I clinical studyhas been approved.[7]

References:

1.

Czuczman MS, Witzig TE,Younes A, et al: IDEC-114, an anti-CD80 monoclonal antibody for relapsedor refractory, follicular NHL:phase I/II study of safety, efficacy, andpharmacokinetics (abstract 610).Blood 100:163a, 2002.

2.

Wang J, Press OW, LindgrenCG, et al: Generation and characterizationof CD20-specific CD8+ cytotoxicT lymphocytes (CTL) geneticallymodified by introduction of anscFvFc: zeta chimeric T cell receptorgene: Preclinical studies prior to aphase I trial of cellular immunotherapyof follicular lymphoma (abstract755). Blood 100:201a, 2002.

3.

Jensen M, Tan G, Forman S, etal: CD20 is a molecular target forscFvFc:zeta receptor redirected T cells:Implications for cellular immunotherapyof CD20+ malignancy. BiolBlood Marrow Transplant 4:75-83,1998.

4.

Mullen JT, Tanabe KK. Viraloncolysis. Oncologist 7:106-119, 2002.

5.

Fielding A, Bucheit A, Kumar S,et al: Replicating attenuated measlesvirus can be engineered to enter cellsthrough the CD20 antigen (abstract756). Blood 100:201a, 2002.

6.

Bucheit AD, Kumar S, GroteDM, et al: An oncolytic measles virusengineered to enter cells through theCD20 antigen. Mol Ther 7:62-72, 2003.

7.

Grote D, Russell SJ, Cornu TI, etal: Live attenuated measles virus inducesregression of human lymphomaxenografts in immunodeficientmice. Blood 97:3746-3754, 2001.