Strategies For Future Studies

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Early lack of success in solid tumor RIT, combined with the encouraging results in RIT of lymphoma, has provided impetus for the development of a plethora of treatment approaches for solid tumors. Constructs linked to radionuclides with varying radiobiologic characteristics, patient-specific therapy, fractionated therapy and pretargeting are some methods currently being investigated. A new generation of clinical trials are either being initiated or in planning stages to try to maximize therapeutic efficacy of RIT for solid tumors. These trials share some similar characteristics:

1. Advances in radiochemistry: Auger and alpha emitters have been labeled without loss of immunoreactivity to a variety of antigen-binding constructs. Positron emitters like 64Cu, 86Y, and 124I are now available for PET-based dosimetry. These will permit the calculation of tumor and critical organ radiation-absorbed doses and optimize

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accurate dose delivery. Although I, Re, Re, and Lu are ideal radionuclides for external single-photon imaging, surrogate gamma emitters must be used to evaluate the distribution and clearance of pure beta emitters. 111In has been considered to be an appropriate surrogate for 90Y. Their half-lives are almost identical, and both are readily incorporated into the same metal-chelating agents. A recent study using PET imaging to compare 86Y and 111In as surrogates for 90Y showed that, although 111In and 86Y have similar biodistribution, 86Y remained in organs, such as bone for a longer period of time (97). 86Y is a more suitable surrogate for 90Y, and the short T1/2 of

86Y may not be a limitation, given the inherent sensitivity of PET. This feature has been used to obtain extremely accurate dosimetry in bone-seeking radiopharmaceuticals (97) and with radiolabeled peptides (98).

2. Genetic engineering: Putatively nonimmunogenic antibody constructs, pretargeting strategies, affinity-enhancement systems, and other methods will lead to enhanced tumor uptake and/or improved tumor-to-nontumor ratios, leading to an increase in tumor radiation dose. Pretargeting studies, first described by Goodwin et al. several decades ago (99), demonstrate the great potential of this strategy, realized only now by appropriate genetic engineering. Genetic modification of antigen-binding constructs has included exploration of their production not only in bacterial systems, but also in yeast and mammalian cells. Univalent sFv proteins may be more stable when grown in yeast or mammalian cells. Bivalent diabodies have the advantage of improved affinity, but are retained to a great degree in the kidney (100), thus raising the specter of unacceptable nephrotoxicity. It may be possible to retain bivalency and minimize renal accumulation by adding other moieties, notably the CH3 domain (101), or adding cytotoxic agents, such as tumor necrosis factor (TNF) dimers (102).

3. Understanding radiobiology: Utilizing radionuclides with physical characteristics tailored to the individual disease condition, bulky tumors, minimal residual disease, and adjuvant therapy, will improve our ability to treat tumors appropriately. Successful systemic-targeted radiotherapy depends not only on careful selection of appropriate antigen targets and antibody constructs, but also on the choice of radio-nuclides appropriate for the extent and type of disease. Alpha emitters will be more suitable for microscopic disease, energetic beta emitters for bulky disease, low-energy beta emitters in a system that permits adequate distribution of radioactivity throughout tumor will limit the side effects to normal tissue. Toxicity is always the prime concern of therapy. The physical and biologic characteristics of radionuclides will need to be combined with the pharmacodynamic properties of the antigen-binding constructs for combination therapies. Sequential therapies with different nuclides based on tumor burden and other characteristics will be critical in multinuclide therapy selection. Combination RIT will likely be as important to successful therapy as combination chemotherapy has been.

4. Combination multimodality therapy: Using chemotherapy or external beam radiotherapy in conjunction with RIT, earlier in the treatment of solid tumors, may maximize the promise of RIT. Complementary modalities have great potential. Chemotherapeutic agents, such as paclitaxel and gemcitabine, may not only have independent cytotoxi-city, but also act as radiosensitizers, and enhance the efficacy of RIT (though it is as yet unclear whether normal tissue toxicity will be similarly enhanced). We are investigating the potential of small molecule inhibitors that can cause downstream metabolic effects that will change tumor uptake of and the susceptibility of tumor cells to, RIT. Agents, such as tirapazamine, which affect the hypoxic fraction of tumors may also enhance RIT efficacy. Agents that cause changes in the permeability and vascularity of tumors will permit radioimmuno-conjugate access to tumor regions that may otherwise not be reached. The use of antiangiogenic agents, in particular, is of great interest as it appears clear that these agents may decrease the tumor uptake of radioimmunoconjugate (if RIT is instituted after antiangiogenic therapy), and conversely decrease egress of radioimmunoconjugate if the antiangiogenic agent is administered at an as yet undetermined time after RIT. These exciting studies are currently being designed in preclinical models and will soon be applied in the clinic.

5. Administration schedule: The use of fractionated multidose RIT instead of single larger dose RIT may result in a slower rate of tumor cell repopulation. Theoretical models have compared the effects of large single-dose administration and rapid fractionation (103). Although a large single dose may have a large rate of cell killing, fractionated therapy may offer the advantages of lower toxicity and prolonged tumor response. In addition, similar to the rationale behind multimodality therapy, preceding doses may cause architectural changes in the tumor that may allow subsequent doses to target previously inaccessible regions. However, studies with fractionated and single large-dose RIT have shown no advantage in safety or total tumor radiation-absorbed dose. We are currently analyzing the data to determine whether changes in intratumoral distribution of radioactivity (86) occur with fractionated RIT. Nevertheless, RIT dose fractionation may have promise when combined in a multimodality therapeutic strategy.

These and other as yet undetermined strategies will lead to a new era of tailored RIT for solid tumors that is safe and effective. The success of RIT for hemato-logic cancers has led to an expectation that RIT will find its niche in solid tumor cancer therapy, both in the adjuvant situation and in bulky disease. Combination RIT, either given in sequence or simultaneously, will soon be a crucial player in the era of molecular therapeutics, as cancer therapy must target both isolated cancer cells and bulky tumors. It is heartening that the FDA has been very receptive to the idea of multimodality therapy with RIT and biologic/chemotherapeutic agents.

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