Halperin7e_CH29

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C H A P T E R 2 9  Radioimmunotherapy and Unsealed Radionuclide Therapy

FIGURE 29.5.  Bispecific pretargeting proce- dure. The bsMAb is injected, and over several days, it will localize in the tumor and clear from the blood. The bsMAb shown in this example is based on the dock-and-lock method for pre- paring recombinant bsMAb that has two bind- ing arms for the tumor and one for the hapten. Once the molar concentration of the bsMAb is low enough, the radiolabeled hapten–peptide is given. The hapten–peptide has two haptens for more stable binding within the tumor, perhaps by cross-linking two adjacent bsMAb through a process known as the affinity enhancement sys- tem (AES). The peptide portion usually contains four to five D-amino acids with a single chelator bound to one of the amino acids that is used to capture the radionuclide. (From Sharkey RM, Goldenberg DM. Pretargeted radioimmunother- apy. In: Speer TW, ed. Targeted radionuclide therapy . Philadelphia: Lippincott Williams & Wilkins, 2011:194. With permission.)

Section II

its respective indications and there are other competing drugs that are not radioactive and don’t require close coordination with medical departments such as medical oncology, radiation oncology, and nuclear medicine.Table 29.5 lists FDA-approved and current phase III RIT drugs. Progress has been less san- guine for solid tumor malignancies, and phase III trials are lacking. 39,40 For the sake of clarity and brevity, this section will focus on clinically relevant phase II/III trials and U.S. FDA (or its international equivalent)-approved RIT therapeutics. Hematologic Trials and Approved Therapeutic Agents The National Comprehensive Cancer Network (NCCN) guide- lines have recommended RIT for the following follicular lym- phoma clinical situations: (1) first-line therapy for the elderly or infirm (Category 2B), (2) first-line consolidation (Category 2B), and (3) second-line (relapse/refractory) and subsequent therapy (Category 1). Initially, the NCCN guidelines rendered a Category 1 designation for first-line consolidation but down- graded this to Category 2B because of concerns about toxicity, although there is not a uniform consensus. 41 Zevalin contin- ues to show very promising results for follicular lymphoma first-line monotherapy, diffuse large B-cell lymphoma and mantle cell lymphoma consolidation and second-line therapy, and transplantation studies. To date, however, none of these approaches have reached clinical phase III status. Zevalin has the only U.S. FDA approval for first-line consolidation and second-line therapy. Currently, there is only one U.S. FDA-approved RIT agent in the United States: 90 Y ibritumomab tiuxetan (Zevalin; 2002). 131 I tositumomab (Bexxar; 2003) was removed from the mar- ket in 2013 by GSK. The demise of Bexxar was not because of lack of efficacy or toxicity, but because of unforeseen mar- ket pressure and financial decisions (http://www.xconomy. com/national/2013/08/26/why-good-drugs-sometimes-fail-in- the-market-the-bexxar-story/). Both will be briefly discussed as they represent common RIT paradigms. Zevalin has U.S. FDA approval for relapsed or refractory follicular NHL and as a frontline adjuvant agent for follicular NHL achieving a complete response (CR) or partial response (PR) to induc- tion chemotherapy. Bexxar had U.S. FDA approval for the relapse or refractory setting as well as transformed NHL. Both are murine IgG mAbs that target the CD20 surface antigen on follicular NHL. 42 90 Y ibritumomab tiuxetan utilizes 90 Y, a

delivery of a large, macromolecule-targeting construct (pro- longed circulation time) from the delivery of a much smaller cytotoxic radioconjugate (more rapid circulation time). Two main approaches have been employed: a bispecific monoclo- nal antibody (bsmAb) system and a streptavidin–biotin sys- tem. In the bsmAb system (Fig. 29.5), a portion of the antibody has affinity for the tumor (antitumor), and another portion has affinity for the radionuclide carrier ligand or hapten–pep- tide (antihapten). Initially (step 1), a large “saturation” dose of the unlabeled bsmAb is administered, and the antibody local- izes in the tumor over several days. Occasionally, a clearing step is used to facilitate the clearance of the bsmAb from the circulation. Subsequently (step 2), a radionuclide conjugated to a hapten–peptide is administered that has high affinity for the antihapten portion of the bsmAb. This step results in a rapid distribution of the radionuclide in the tumor owing to the high affinity of the hapten–peptide for the bsmAb. Because the hapten–peptide has a small molecular weight, it will clear rapidly from the body and result in a low–bone marrow expo- sure to radiation. In the streptavidin–biotin system, strepta- vidin is conjugated to the initial pretargeting macromolecule, and biotin is conjugated to the radionuclide. Streptavidin and biotin have a very high affinity for each other (10 15 M − 1 ).When either system is used, the tumor/blood ratios of the target- ing agent are significantly increased, but there may be some advantages to the bsmAB system. 37,38 CONJUGATED THERAPY The current state of RIT continues to improve. The basic premise has been the delivery of targeted cytotoxic radio- therapy that is low dose, LDR, sparsely ionizing and delivered in a single fraction. Initially, this reality seemed to be a natu- ral “fit” for hematologic malignancies that were sensitive to most types of radiation. However, for RIT to ultimately impact significantly upon the world of oncology, it is clear that cur- rent approaches need to be modified so that it can be applied to carcinomas. Zevalin and Bexxar were FDA-approved in 2002 and 2003, respectively, as RIT drugs to treat relapse follicular NHL for an end point of progression-free survival. Subsequently, Zevalin received an approved frontline indica- tion (FIT trial). Bexxar was withdrawn from production by GlaxoSmithKline (GSK) in 2013. Currently, Zevalin is greatly underutilized because it has not shown a survival benefit for