The New Golden Era for Radioimmunotherapy - numerous solid tumors including ovarian cancer

open access/Medscape

Background: Radioimmunotherapy (RIT) has been approved for the treatment of B-cell non-Hodgkin lymphomas in the United States for more than a decade. However, the history of the development of RIT agents for advanced-stage solid malignancies dates back much further, and recent advances have renewed interest in this approach for solid tumors.

Methods: This paper reviews available evidence for the preclinical and clinical development of RIT agents for solid tumors.

Ovarian Cancer (section)

"Approximately 22,280 cases of ovarian cancer (OC) were diagnosed in the United States in 2012, with an estimated 15,500 deaths caused by the disease.^[15,16] Approximately 24 RIT constructs have been evaluated in preclinical and/or clinical studies. Intraperitoneal administration of RIT for advanced OC was first described more than 25 years ago.^[89]
Human milk fat globule (HMFG) 1 is a murine monoclonal antibody directed against MUC-1. A phase I/II clinical trial of intraperitoneal ⁹⁰Y-HMFG1 suggested an extended PFS following CR to surgery and chemotherapy with RIT.^[90] The follow-up randomized controlled trial of intraperitoneal ⁹⁰Y-HMFG1 showed no clinical benefit in adding an RIT agent compared with standard care following a complete clinical remission after chemotherapy and surgery.^[91] However, the study did show a decrease in intraperitoneal relapse rates.^[92]
Placental-like alkaline phosphatase (PLAP) is a surface membrane enzyme expressed in the majority of ovarian tumors.^[93,94] Hu2PLAP is a human IgG monoclonal antibody directed against PLAP and has been used clinically for the radioimmunodetection of ovarian tumors, labeled with ¹¹¹In and ¹²³I. Both labeled agents were shown to localize to PLAP-positive ovarian tumors with no significant toxicity, and 2 of the 30 patients in the study exhibited immunogenicity.^[95] No therapeutic studies using Hu2PLAP have been reported to date.
Trastuzumab is a humanized IgG monoclonal antibody directed against the extracellular domain of the oncoprotein human epidermal growth factor receptor 2 (HER-2)/neu, commonly overexpressed in breast, ovarian, and gastrointestinal tumors.^[96] This antibody has been labeled with several radionuclides for preclinical and clinical studies, including ⁹⁰Y,^{[97] 177}Lu,^{[98 188]}Re,^[99] astatine-211 (²¹¹At),^[100,101] lead-212 (²¹²Pb),^[102] actinium-225 (²²⁵Ac),^[103] and thorium-227 (²²⁷Th).^[104] There is an ongoing phase I study of intraperitoneal ²¹²Pb-trastuzumab for patients with advanced OC with positive pelvic washings or peritoneal studding.^[105]
Pertuzumab is a human monoclonal antibody directed against the HER-2 dimerization domain. Labeled with ¹⁷⁷Lu, this agent has been evaluated in a murine xenograft model. Mice treated with ¹⁷⁷Lupertuzumab exhibited a delayed tumor progression without evidence of significant toxicity.^[106]
As with previously described solid tumors, TAG- 72 is frequently expressed on the surface of ovarian tumors. CC49, labeled with ⁹⁰Y or ¹⁷⁷Lu, has been evaluated in a number of OC clinical studies. Meredith et al^[107] reported the results of a phase I study in 12 patients with advanced OC, intraperitoneally delivering ¹⁷⁷Lu-CC49. No MTD was reached up to 30 mCi/m², and RIT was well tolerated, with only mild myelosuppression. Only 1 of 8 patients with gross disease showed an objective response, but 3 of the 4 patients with occult disease remained without evidence of progression after 18 months. The same group reported on a phase I/II study of intraperitoneal ¹⁷⁷Lu-CC49 in 27 chemotherapy-refractory patients.^[108] As with the prior study, only 1 patient with gross disease responded, but 80% of those with occult disease remained disease-free for up to 3 years; the MTD was determined to be 45 mCi/m². A phase I study of ⁹⁰Y-CC49 was published by Alvarez et al^[109] in which 20 patients with OC and intra-abdominal disease were treated with immunotherapy, paclitaxel, and escalated doses of ⁹⁰Y-CC49. The MTD in this combined modality setting was 24.2 mCi/m². Patients with nonmeasurable disease had durable responses, while 2 patients with measurable disease exhibited PRs to therapy.
OC125 is a murine F(ab')^[2] monoclonal antibody fragment directed against CA-125, an OC tumor marker. Three clinical studies have been published using this antibody for intraperitoneal administration.^[110–112] In the first study, ⁹⁰Y-OC125 was infused into 5 participants going for a second-look surgery.^[110] Intraoperative scintigraphy was performed to localize tumor foci for additional resection. In addition, the investigators performed normal organ dosimetric measurements that showed most of the infused dose remaining within the intraperitoneal space and approximately a 6:1 concentration of tumor to normal tissue. Mahé et al^[111] reported the results of a phase II trial of ¹³¹I-OC125 in patients with OC and minimal residual disease following surgery and chemotherapy. Participants received 120 mCi of RIT given intraperitoneally approximately 1 week following surgery. Three patients exhibited SD, while 3 progressed; all 6 patients demonstrated HAMAs following RIT, and the primary adverse events were hematologic. A phase I study by Muto et al^[112] examined escalating intraperitoneal doses of ¹³¹I-OC125 in women with refractory OC, with doses ranging from 18 to 144 mCi in a single dose. The MTD was reported to be 100 mCi, with unacceptable hematologic and gastrointestinal toxicity above this dose. The authors concluded that intraperitoneal RIT with ¹³¹I-OC125 was safe and feasible in this patient population.
MOv18 is a murine or chimeric monoclonal antibody directed against a folate-binding protein present on the surface of nearly all ovarian carcinomas.^[113,114] Although the antibodies specifically target the folatebinding protein, significant heterogeneity was found between patients and even between tumor foci within patients following RIT, perhaps owing to differences in folate-binding protein in the tumors.^[115] The same group examined differences between intravenous and intraperitoneal administration of the ¹³¹I-labeled antibody and found no targeting benefits to intraperitoneal delivery but possibly less hematologic toxicity.^[116]
Another intriguing potential target for RIT in OC is the cell-surface sodium-dependent phosphate transport protein 2b, recognized by the murine IgG MX35.^[117,118] A Swedish group^[119] has performed extensive preclinical studies on intraperitoneal delivery of the alpha-emitter-labeled antibody, ²¹¹At-MX35 F(ab').^[2] Nude mice inoculated intraperitoneally with OC xenografts were treated with either the targeted agent ²¹¹At-MX35 F(ab')^[2] or the nonspecific ²¹¹At-rituximab F(ab').^[2] The alpha-labeled MX35 was significantly more effective at tumor kill, with a relatively higher mean absorbed dose (> 22 Gy) than is typically seen with beta-emitter–labeled antibodies. In a murine dose-escalation study,^[120] absorbed doses of up to 400 Gy were intraperitoneally given, with posttherapy tumor- free fractions up to 61% with ²¹¹At-MX35 F(ab').^[2] An experiment that treated mice with one infusion vs repeated weekly infusions showed a significant improvement in tumor-free status with repeat therapy.^[121] In the one published clinical trial of this agent, 9 women with recurrent OC who were in complete remission following salvage systemic therapy were enrolled into a phase I study of intraperitoneal ²¹¹At- MX35 F(ab').^[2,122] No toxicity was observed, and only 6% of the infused dose was measurable in the serum, so the authors concluded that intraperitoneal therapy with ²¹¹At-MX35 F(ab')^[2] was both feasible and safe for patients with recurrent OC.
Several other potential targets for RIT in OC have been described, but with little or no clinical experience.^[123–131] RIT for OC appears to be a potentially promising option, particularly in patients who have been optimally debulked following surgery and chemotherapy but who still are at high risk for microscopic intraperitoneal disease. Alpha-emitting radionuclides hold particular promise in nonbulky disease, given the higher linear energy transfer and shorter path length compared with beta particles. Therefore, the accrual of ongoing clinical trials of these novel agents should be encouraged."