The article by Meredith and LoBuglio represents a thorough description of the clinical strategies that have been attempted with radioimmunoconjugates. The authors appropriately point to the extraordinary promise of these agents in the treatment of hematologic malignancies. They also acknowledge the disappointments that have been encountered in the systemic therapy of solid tumors, while noting that there may be some reason for optimism regarding locoregional administration of radioimmunoconjugates.
Following a description of the dose-limiting toxicities that have been achieved or predicted, the authors briefly describe the range of modifications and adaptations that are under study to improve the potential for therapeutic efficacy. However, some additional points can be addressed.
With regard to the use of radioimmunoconjugates in lymphoma, there is sound encouragement for pursuing iodine-131-labeled anti-CD20 antibodies. Whether low- or high-dose strategies are used, clear clinical efficacy of these antibodies has been noted in both phase I and phase II trials. However, anti-CD20 antibodies may have immunotherapeutic potential independent of the attached radionuclide, and most of these trials (eg, with the B1 antibody) have included loading doses of unlabeled antibody.
It is apparent from studies with other anti-CD20 antibodies (which recognize an alternative epitope) that immunotherapy can be efficacious in treating lymphoma. An improved understanding of the relative roles of the respective therapeutic components is certainly worthy of further investigation and would help optimize this therapy.
With regard to Hodgkin's disease, the authors point to encouraging clinical studies of ytrrium-90-labeled polyclonal antiferritin conducted by Vriesendorp et al. It is important to note that all of the work with single- agent ytrrium-90 polyclonal antiferritin in Hodgkin's disease has been conducted in the phase I setting. Phase II trials (including confirmatory trials) are needed to clarify the therapeutic potential of this radioimmunoconjugate.
Studies of radioimmunotherapy for acute myelogenous leukemia at Memorial Sloan-Kettering Cancer Center and the Fred Hutchinson Cancer Center are also extremely promising. The authors appropriately point out that the dose-limiting toxicity of myelosuppression is of less importance in this setting because of the availability of allogeneic hematopoietic stem-cell rescue techniques. However, it is also important to note that proposed treatment strategies using humanized M195 conjugated to bismuth-212 or bismuth-213 (alpha-particle emitters with high linear energy transfer) theoretically can cause single cell death, and thus, may avoid bystander radiotoxicity to normal bone marrow progenitors. This approach would circumvent the need for allogeneic hematopoietic stem-cell transplantation and its associated toxicities.
Meredith and LoBuglio have done a careful job in outlining the status of radioimmunotherapy for solid tumors. However, their comments about the antitumor effects observed with monoclonal antibody (MoAb) CC49 may be too generous. The majority of objective responses seen with iodine-131-MoAb CC49 treatment have occurred in trials that involve multimodality therapy; thus, the contribution of the radiolabeled antibody is unclear and needs further study.
This is also true of studies of radiolabeled polyclonal antiferritin therapy for primary liver cancer. A randomized trial conducted by the Radiation Therapy Oncology Group could not confirm a benefit of the addition of the radiolabeled antibody on objective response or survival.
The authors' optimism for the future of radioimmunotherapy using locoregional routes of delivery (particularly intraperitoneal routes) seems to be justified. The outlook for intralesional and intra-arterial treatments for central nervous system tumors is unclear, however. The clinical trials to date that have reported promising results have compared contemporary data from selected patients with historical controls. Much work needs to be done.
Future Research Targets
After almost 15 years of earnest and enthusiastic investigation, the therapeutic role of radioimmunotherapy is about to be defined in the treatment of lymphoma and, possibly, leukemia. Moreover, investigators now have a clear vision of the impediments to the successful use of this therapy in a broad range of clinical settings.
In describing future areas of research needs, Meredith and LoBuglio appropriately focus on two targets: (1) the nature of the radiolabeled antibody and (2) factors that influence the ability of the radioimmunoconjugate to reach and accumulate in target sites. Available technology has clearly allowed us to test and evaluate high-affinity antibodies using very stable chelates. New engineered antibodies with low immunogenic potential are poised to enter clinical trials. However, the success of systemic radioimmunotherapy, at least for solid tumors, will undoubtedly lie in manipulating the host and/or tumor to improve the access of radioimmunoconjugates to the tumor target.