Combined Modality Radioimmunotherapy with Taxol and ⁹⁰Y-LYM-1 for Raji Lymphoma Xenografts

Abstract

Despite effective therapies for non-Hodgkin's lymphoma (NHL), the majority of patients are not cured. Radioimmunotherapy (RIT) has shown good results in preclinical and clinical trials even in patients that are non-responsive to standard chemotherapy. To make RIT more effective, agents such as paclitaxel (Taxol), that can enhance radiation effects, are being tested. Nude mice bearing human Burkitt's lymphoma (Raji) xenografts were treated with: 1) 150 or 200 microCi (5.5 or 7.3 MBq) of 90Y-2IT-BAD-Lym-1 alone, 2) 600 micrograms of Taxol alone, 3) 150 or 200 microCi of 90Y-2IT-BAD-Lym-1 plus 600 micrograms of Taxol given 24 hours after RIT, or 4) no treatment. Tumor size, survival, mouse weight and blood counts were monitored to assess efficacy and toxicity. Survival for mice treated in this 84 day trial was: 71% for 90Y-2IT-BAD-Lym-1 (200 microCi) plus Taxol, 29% for Taxol alone, 6% for 90Y-2IT-BAD-Lym-1 (200 microCi) alone and 14% in the untreated group. Average tumor volume in the 90Y-2IT-BAD-Lym-1 (200 microCi) plus Taxol group was reduced by 89 and 99% compared to the RIT alone and Taxol alone groups, respectively. Mice treated with 150 microCi had less toxicity than those treated with 200 microCi of 90Y-2IT-BAD-Lym-1, however, the higher radiation dose, and Taxol, were required for improved survival. Mouse weights and myelotoxicity in the combined modality (RIT plus Taxol) groups were similar to those receiving the same dose of RIT alone. In the Raji tumored nude mouse model, addition of Taxol to 90Y-2IT-BAD-Lym-1, in doses clinically achievable in humans, provided therapeutic synergy without increased or excessive toxicity.

Combined 90Yttrium‐DOTA‐labeled PAM4 antibody radioimmunotherapy and gemcitabine radiosensitization for the treatment of a human pancreatic cancer xenograft

“…In contrast, we, and others, have examined methods to increase radiosensitivity of the tumor, particularly with the application of chemotherapeutic drugs that may provide antitumor effects in and of themselves. Indeed, several preclinical studies of various tumor types (colorectal, 48 -51 breast, 52-54 medullary thyroid [55][56][57] and the more radiosensitive hematologic cancers 58,59 ) have examined this issue, with the majority reporting enhanced antitumor activity of the combined treatment modality as compared to either treatment arm alone. To date, clinical experience in solid tumors is limited.…”

Anti-CD22 ligand-blocking antibody HB22.7 has independent lymphomacidal properties and augments the efficacy of90Y-DOTA-peptide-Lym-1 in lymphoma xenografts

“…90 Y-DOTA-peptide-Lym-1 was prepared as previously described. 43 Assessment by high-performance liquid chromatography (HPLC), thin-layer chromatography (TLC), and cellulose acetate electrophoresis revealed that 90 Y-DOTA-peptide-Lym-1 was prepared to 98% radiochemical purity with less than 5% aggregate content.…”

“…Multiple preclinical and clinical studies with sodium iodine-131( 131 I), copper-67 ( 67 Cu), and yttrium-90 ( 90 Y)-labeled Lym-1 have demonstrated significant efficacy in relapsed and refractory NHL. 8,9,[17][18][19][20] In an MTD trial in which heavily pretreated NHL patients were treated with 131 I-Lym-1, 85% had tumor regression, and 19% achieved complete response (CR). 8 Combined modality therapy (CMT) consists of the concurrent or sequential use of chemotherapy and external beam radiation.…”

“…27 Another approach to improve efficacy involves the enhancement of tumoricidal effects of RIT by combining RIT with chemotherapeutic agents or, as described herein, antibodies. 19,[28][29][30] Conventional CMT has proven clinically useful for locally advanced malignancies. [31][32][33][34][35] Combined modality immunotherapy (CMIT) goes one step further by pairing the specific delivery of systemic radiation ( 90 Y-DOTA-peptide-Lym-1) to NHL with the systemic radiationsensitizing effects of an additional agent (mAb).…”

Changes in Lognormal Shape Parameter Guide Design of Patient-Specific Radiochemotherapy Cocktails

“…In another approach, radiolabeled chemotherapy agents have been used in an attempt to enhance cytotoxicity in both human cancer cells and apparently normal hamster fibroblasts (5). Chemotherapy has also been combined with radioimmunotherapy (6).…”