High-dose radioimmunotherapy combined with extracorporeal depletion in a syngeneic rat tumor model: evaluation of toxicity, therapeutic effect, and tumor model.
BACKGROUND
The aim of the current study was to investigate the possibility of increasing the maximal tolerated dose (MTD) of a tumor-selective radiolabeled antibody when radioimmunotherapy (RIT) is combined with extracorporeal depletion of radioimmunoconjugates from the circulation. Furthermore, the authors evaluated whether this increase in dose improved the therapeutic effect on solid manifest tumors in an immunocompetent animal model.


METHODS
Rats were injected with high activities/body weight of lutetium ((177)Lu)- or yttrium ((90)Y)-labeled antibody conjugates (monoclonal antibody tetraazacyclododecanetetraacetic acid-biotin) and subjected to removal of the conjugate from the circulation by extracorporeal affinity adsorption treatment 24 hours postinjection. Myelotoxicity was assessed by analysis of blood parameters for 12 weeks. The effect of increased doses in combination with extracorporeal affinity adsorption treatment was evaluated with respect to myelotoxicity and therapeutic effect in a syngeneic rat colon cancer model.


RESULTS
The MTD of (177)Lu- or (90)Y-labeled immunoconjugates could be increased 2.0x or 1.5x, respectively, when RIT was combined with extracorporeal affinity adsorption treatment. All animals treated with (177)Lu- or (90)Y-labeled antibodies showed persistent complete response of manifest tumors (approximately 10 x 15 mm) within 16 days postinjection. However, several animals showed disseminated disease 1.5 to 3 months postinjection.


CONCLUSIONS
Extracorporeal affinity adsorption treatment is a method that safely and efficiently reduces myelotoxicity associated with RIT. Extracorporeal affinity adsorption treatment allows increased administered activity without increased toxicity, with the aim of increasing the absorbed dose to the tumor. However, because tumor/normal tissue radiosensitivity ratios are more favorable in rodents, it is not possible to draw any conclusions concerning the therapeutic efficacy of increased administered activity in combination with extracorporeal affinity adsorption treatment in this study. Targeted RIT with beta-emitting radionuclides seems not to be effective in microscopic disease, because metastases developed at sites without previously known disease.
Mårtensson
Linda
L
Department of Oncology, Lund University, Lund, Sweden.
Nilsson
Rune
R
Ohlsson
Tomas
T
Sjögren
Hans-Olov
HO
Strand
Sven-Erik
SE
Tennvall
Jan
J
D000327:Adsorption; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D001855:Bone Marrow Diseases / Q000517:prevention & control; D003110:Colonic Neoplasms / Q000628:therapy*; D004195:Disease Models, Animal; D005112:Extracorporeal Circulation; D018796:Immunoconjugates / Q000627:therapeutic use*; D007205:Indium Radioisotopes / Q000627:therapeutic use; D020714:Maximum Tolerated Dose; D011836:Radiation Tolerance; D016499:Radioimmunotherapy / Q000009:adverse effects / Q000379:methods*; D011868:Radioisotopes / Q000378:metabolism / Q000627:therapeutic use*; D051381:Rats; D011914:Rats, Inbred BN; D000068878:Trastuzumab
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; C507851:BR96 monoclonal antibody; D018796:Immunoconjugates; D007205:Indium Radioisotopes; D011868:Radioisotopes; D000068878:Trastuzumab