Fully human monoclonal antibodies and targeted radionuclide therapy

To the editor:

I would like to applaud Dr Hagenbeek for performing the first human trial using a fully human monoclonal antibody (mAb), ofatumumab, which targets the CD20 antigen.¹  A response rate of 20% to 63% is reported and questionably one patient developed HAGA (human antiglobulin antibody). In comparison to rituximab (chimeric), the potential benefit of using a fully human mAb is a favorable toxicity profile and improved efficacy when multiple administrations are delivered. But, are these the only potential benefits?

Multiple administrations of murine or chimeric antibodies result in high rates of seroconversion to HAGA when used in targeted radionuclide therapy (TRT).²  Considering that radionuclides are more cytotoxic than common chemotherapy agents³  and that response rates are significantly increased when anti-CD20 antibodies are radiolabeled,^4,5  it should be compelling to initiate trials using TRT, with ofatumumab being “center stage.” The linear quadratic formula can quantitate cell kill when using TRT. If a dose rate of 10 to 15 cGy/h, an effective half-life of 4 days, half-time repair of 1.5 hours, α/β equals 10, and an absorbed tumor dose of 15 to 20 Gy are delivered by a single instillation, then a 2 to 3 log cell kill should result. This scenario would sterilize 60% of clinically undetectable cell aggregates (10³ cells), 30% of millimeter size tumors (10⁶ cells), or 20% of clinically apparent disease (10⁹ cells).⁶  Remarkably, responses of 60% to 80% are reported after single instillations TRT when treating NHL. If the current phase 1 and 2 trials using TRT as adjuvant therapy with chemotherapy are favorable, then the prototypical lymphoma model of TRT will be that of a single administration in the adjuvant setting. This is definitely a step in the right direction and certainly may be the maximum amount of radionuclide that can be tolerated in a combined modality setting by patients heavily pretreated with chemotherapy. Recognizing that tumor growth is governed by Gompertzian kinetics, multiple cycles of dose-dense chemotherapy are used. Given subclinical tumor volumes of 10³ to 10⁵ cells, at least 3 to 4 cycles of chemotherapy are prescribed to exercise multilog cell kill. What then, would be a reasonable fractionated schedule of TRT?

The current treatment regimens of TRT for NHL use single administrations resulting in dose rates of 1 to 10 cGy/h and absorbed tumor doses in the range of 10 to 15 Gy.⁷  The typical administered activity ranges from 50 to 200 mCi for Bexxar and 20 to 30 mCi for Zevalin. This results in a total body (marrow) equivalent dose of 75 cGy and 47 to 69 cGy, respectively.⁸  Extrapolating from ¹³¹I therapy for thyroid cancer, cumulative activities of at least 1000 mCi may be given as long as dose limiting bone marrow (BM) is monitored and 3 Gy or less for BM or 30 Gy or less for lung is not reasonably breached.⁹  By all accounts, there does appear to be the potential for dose escalation and the safe delivery of multiple fractions of TRT. This is particularly sanguine when viewed in the context of our current ability to use fully human antibodies, pretargeting, and bone marrow support. Thus, it is not unreasonable to consider 3 to 6 cycles of “dose-dense” TRT, a treatment that could theoretically deliver at least 60 to 100 Gy tumor dose and eradicate clinically detectable tumors (10⁹ cells). The ability to deliver multiple fractions of TRT now exists with the advent of fully human mAb's. It is time to apply the principles of dose-dense chemotherapy delivery to TRT and investigate the feasibility and efficacy of multiple fractions (cycles) of these very promising agents.