Once cancer metastasizes to the central nervous system, CSF is a natural conduit for further dissemination to the leptomeninges and other parts of the brain. Antibody-based therapy delivered through the CSF has potential for tumor control. GD2 is an adhesion molecule abundant on NB. It is also widely expressed among melanoma, small cell lung cancer, bone or soft tissue sarcoma, retinoblastoma and brain tumor [25
], with limited expression in normal tissues, except neurons, skin cells and pain fibers. This antigen is genetically stable, rarely down-regulated, and not easily released from the cell membrane. Scintigraphy studies using radiolabeled MoAb confirms excellent tumor targeting [25
]. At least two antibody families have been tested clinically, i.e. murine antibody 3F8 [26
] and chimeric 14.18 [27
]. Intra-Ommaya 131
I-3F8 was successfully tested in delivering RIT through the CSF [11
], and a single-compartment pharmacokinetic model was developed to study CSF RIT [16
]. Ch14.18 consists of the variable region of murine MoAb 14.18 and the constant regions of human IgG1-K [28
]. In a recent randomized phase III trial, the combination of intravenous ch14.18 with GM-CSF and IL-2 improved survival among high risk NB patients in remission undergoing stem cell transplant (ClinicalTrials.gov NCT00026312) [29
In this report, the two-compartment model showed convincing fit to the actual CSF clearance data in a cohort of 25 patients receiving IO 131I-3F8. This was especially evident for the initial radioactivity values after each injection, with a much better data fitting than the corresponding values predicted by the one-compartment model. This discrepancy was due to the assumption in the one-compartment model that antibodies distributed evenly through the entire CSF space (ventricles and subarachnoid space) immediately after infusion. In contrast, the two-compartment model took into account the flow of antibodies would be delayed in the ventricular reservoir before entering into the subarachnoid space.
The one-compartment model predicted that the optimal half life of the isotope for RIT to be 64 hours, and half life beyond 64 hours did not significantly improve therapeutic ratio [16
]. However, other parameters such as immunoreactivity and specific activity and antigen density must also be considered. Furthermore, the biological effect of radiation from different isotopes varies depending on the type of radioactive particles emitted and their respective energy levels (see footnote) [30
]. Simulations of the combined effects of these isotope-dependent parameters suggest that only immunoreactivity has a significant effect on the therapeutic endpoints for isotopes with half-lives longer than 64 hours.
Analysis on the effect of immunoreactivity on the therapeutic ratio showed a linear relationship at low antibody dosage, with less obvious improvements when the dose was higher. This suggests that lower antibody dosage was necessary to achieve the benefit from higher immunoreactivity. This prediction is now being explored using 8H9, which has ≥90% immunoreactivity at a specific activity of 50 mCi/mg of 131I (ClinicalTrials.gov NCT00089245).
Antigen density should dictate the antibody dose required to optimize intrathecal RIT. When tumor (and antigen) density is low, a smaller antibody dose should be adequate to eliminate the tumor cells while minimizing the collateral damage to the bystander cells. Analysis using the two-compartment model showed that decreasing dosage only slightly improved the therapeutic ratio at high antigen density. Furthermore, this increase in therapeutic ratio was accompanied by a reduction in the AUC[CIAR]. When there was less antigen, lowering the antibody dose did not provide any significant benefit to therapeutic ratio, although AUC[CIAR] was greatly reduced. The implications are: (1) lowering antibody dose to adjust for the diminishing number of tumor cells is not beneficial, and (2) lowering the dosage alone has no overall benefit, since improvements in therapeutic ratio is negated by the reduction in AUC[CIAR].
An optimal schedule for IO RIT is emerging from these optimization studies. A continuous infusion of the 2 mg dose over a short period of time (<24 hours) only slightly improved the therapeutic endpoints over bolus injections. However, if the same dose was given over a slightly longer period of time from 24 hours up to 72 hours, both therapeutic endpoints could improve. Beyond 72 hours, the AUC[CIAR
] did not improve further although therapeutic ratio continued to rise. Alternatively, splitting the 2 mg dose into smaller injections could yield similar results, e.g., two 1 mg doses or four 0.5 mg doses. Here, the optimal time interval between successive doses appeared to be 24 hours, regardless of the number of doses or the quantity of antibodies in each dose. These findings were consistent with the predictions using the one-compartment model [16
Both the one-compartment model and the two-compartment model established antibody affinity as the major factor in maximizing therapeutic endpoints. Based on the two-compartment model, antibody affinities corresponding to KD values of 2 × 10−10 M or better, were necessary if a single bolus was used, irrespective of antibody dose between 0.2 mg and 2 mg. Compared to the KD of 4 × 10−9 M for 3F8, this required a 50 fold improvement in antibody affinity. Alternatively, if four 1.4 mg doses of antibodies with the current 3F8 affinity was given 24 hours apart, the same therapeutic goal could be achieved.
In conclusion, as antibodies gained increasing acceptance in cancer therapy, their well-known physicochemical properties, ease of genetic engineering and facile production will provide opportunities for RIT to a variety of human cancers metastatic to the LM and CNS, as long as there is no obstruction to CSF flow. As new novel radioisotopes and their microdosimetry become available, further improvement in the pharmacokinetic modeling of CNS RIT modality should refine this emerging therapy to fit the clinical context.