Advances Reported in Phase I/II Trials of Radioimmunotherapy for Breast Cancer

PRINCETON, NJ--New approaches in radioimmunotherapy for patientswith advanced breast cancer have had promising preliminary results,according to research presented at the Fifth Conference on Radioimmunodetectionand Radioimmunotherapy of Cancer.

Treatment with alpha-interferon to increase expression of targetantigen on tumor surfaces has been moderately well-tolerated andresulted in a few clinical responses, according to the preliminaryresults of a phase II clinical trial described by James L. Murray,MD, of the University of Texas M.D. Anderson Cancer Center. Otherspeakers at the meeting described separate phase I dose-escalationtrials of iodine 131-labeled and yttrium 90-labeled antibodieswith autologous stem cell support.

The trial at M.D. Anderson was based on the observations thatthe TAG-72 antigen is expressed by breast cancer cells and that,in animal models, treatment with interferon led to improved targetingof TAG-72-directed radioimmunotherapy and an enhanced therapeuticresponse. A phase I study at Memorial Sloan-Kettering Cancer Centerhad previously shown that treatment with 131I-labeled CC49 (ananti-TAG-72 murine monoclonal antibody) resulted in favorableantibody targeting and limited toxicity in patients with breastcancer.

The primary aim of the present trial was to determine whetherinterferon could enhance targeting, biodistribution, and efficacyof radioimmunotherapy in patients with recurrent breast cancer.Fifteen patients were treated. All had skin or soft-tissue diseasethat was biopsied serially to measure tumor antigen up-regulation.

After the initial skin or lymph node biopsy was obtained, patientswere randomized, with one group beginning daily alpha-interferontreatment. After 3 days, patients received a tracer dose of 131I-labeledCC49. Tumor biopsies were obtained 2 days later and analyzed immunohistochemicallyfor antigen up-regulation.

Following dosimetry studies, all patients then received treatmentwith the antibody in amounts calculated to deliver less than 200cGy to the bone marrow, resulting in doses of 60 to 75 mCi/m².The seven patients initially randomized to receive interferoncontinued to receive it for a total of 14 days. The second groupbegan 14 days' treatment with interferon simultaneously with theradiolabeled antibody.

The serial immunohistochemistry studies showed a mean increasein tumor TAG-72 expression of 46% in patients pretreated withinterferon-alpha, compared with minimal up-regulation in the controlgroup. The calculated radiation dose to red marrow was increasedby 15% to 20% in patients receiving interferon, compared withcontrols. Pretreatment also resulted in somewhat longer bloodretention time of the radioantibody.

There were two partial, one minor, and several mixed responsesin the group as a whole, Dr. Murray said.

Moderate hematologic toxicity was fairly common, especially atthe higher initial radioantibody dose of 75 mCi/m2, he continued.It is possible that interferon increased the toxicity of treatmentby increasing marrow radiation exposure. Eleven of the 15 patientsdeveloped human anti-mouse antibody (HAMA) responses.

BrE-3 Antibody

Other investigators described dose escalation trials with radiolabeledantibodies to two different tumor antigens.

BrE-3 antibody binds to an antigen of human milk fat globulin.The antigen is reportedly found on 80% of breast cancers, butin the present study, it was identified in breast tumor specimensfrom all of 41 consecutive candidates for the study's bone marrowtransplantation protocol.

This finding suggests that "the antigen is highly represented,at least in younger patients with breast cancer, who representmost of our patients," said Roy B. Jones, MD, of the Universityof Colorado Health Sciences Center, Denver.

Most of the nine patients who entered this ongoing phase I clinicaltrial had undergone previous chemotherapy and bone marrow transplantationand had progressed while in treatment.

Patients received high-dose 90Y-labeled BrE-3, followed in 14days by autologous stem cell support and granulocyte colony-stimulatingfactor (G-CSF, Neupogen). After treatment, four patients developedthrombocytopenia requiring platelet transfusion.

Of eight evaluable patients, four have had at least a partialresponse, and the nonevaluable patient had a reduction in bonepain. Responses were seen in lymph node, bone, brain, and bonemarrow disease. The duration of these responses has been brief,lasting only 2 to 3 months. However, given the response rate tochemotherapy of 20% in this patient group, the present resultsare "encouraging," and further dose escalation is continuing,Dr. Jones said.

A dose escalation study of a radioiodinated chimeric L6 antibodywas described by Carol M. Richman, MD, of the University of California,Davis, School of Medicine. L6 targets an antigen present on tumorcells from about half of patients with breast cancer; it is immunologicallyactive, capable of inducing antibody-dependent and cell-mediatedcytotoxicity.

A previous phase I trial showed that the antibody has antitumoreffects but also causes HAMA formation and has dose-limiting hematologictoxicity. The present study evaluated the use of cyclo-sporine(Sandimmune) and peripheral blood stem cell transfusions to preventthese adverse effects.

In this study, patients receive G-CSF before peripheral stem cellharvest and are treated with cyclosporine prior to antibody administrationand continuing for a total of 14 days. The initial radiation doseadministered in this dose-escalation trial is 150 mCi/m²,2.5 times the maximum tolerated dose established in the previousphase I trial.

Patients receive three treatments at 8-week intervals, with onethird of the harvested stem cells transfused after each treatment.The study design calls for three to five patients to be treatedin each dose-escalation phase.

So far, three patients have received a total of six treatmentswith the 150 mCi/m² dose, Dr. Richman said. Peripheral stemcell support appears to permit repeated high-dose therapy withmanageable hematologic toxicity. Dose-limiting nonhematologictoxicity was not observed despite total lung doses of up to 3,100cGy in the patient who received three treatments.

The first two treated patients developed HAMA and could not completethree courses of therapy. In the third patient, who was the firstto receive cyclo-sporine for all three treatments, HAMA did notdevelop, and a clinical response was observed.