Novel radioimmunotherapy reverses resistance to generally used lymphoma drug
177Lu-lilotomab in combination with rituximab in mice with rituximab-resistant Raji2R tumor xenografts. Credit: Dr. Ada HV Repetto-Llamazares “Width =” 800 “Height =” 480 “/> Synergistic effect of 177Lu-Lilotomab in combination with rituximab in mice with rituximab-resistant Raji2R tumor xenografts. Credit: Dr. Ada HV Repetto-Llamazares
A new radioimmunotherapy has been shown to be effective in reversing resistance to the most widely used lymphoma drug, rituximab. This is evident from research published in the October issue of the Journal of Nuclear Medicine. In combination with rituximab, it was shown that 177Lu-lilotomab-satetraxetan significantly increased rituximab binding and rituximab-mediated antibody-dependent cellular cytotoxicity (ADCC), resulting in a significant delay in tumor growth in a non-Hodgkin lymphoma mouse model.
According to the American Cancer Society, non-Hodgkin lymphoma is the most common blood cancer with the eleventh highest mortality rate of all malignancies worldwide in 2018. The monoclonal antibody rituximab was approved for the treatment of non-Hodgkin lymphoma more than 20 years ago and is currently the standard the treatment. However, many patients eventually develop resistance to rituximab, which is often associated with changes in the expression of the CD20 antigen.
177Lu-Lilotomab-Satetraxetan (177Lu-Lilotomab) – a next-generation b-particle emitting radioimmunoconjugate – has been shown to increase CD20 expression in various rituximab-sensitive non-Hodgkin lymphoma cell lines and synergistically with rituximab in a non-Hodgkin acts Hodgkin lymphoma animal model. Therefore, the researchers hypothesized that 177Lu-lilotomab could be used to reverse rituximab resistance in non-Hodgkin lymphoma.
In the study, two non-Hodgkin lymphoma cell lines – Raji (parent line) and Raji2R (rituximab-resistant line) – were cultured and incubated with either lilotomab, 177Lu-lilotomab, or saline. Xenografted mice then received either saline, rituximab monotherapy, 177Lu-lilotomab monotherapy, or a combination therapy of 177Lu-lilotomab-satetraxetan and rituximab. Tumor volume and survival time were calculated and analyzed.
Exposure of the cell lines to 177Lu-Lilotomab resulted in an increase in rituximab binding compared to control cells. Without exposure to 177Lu-Lilotomab, the binding in the rituximab-resistant Raji2R cells averaged 36 ± 5 percent compared with untreated Raji cells. After treatment with 177Lu-Lilotomab, rituximab binding in Raji2R cells increased to 53 ± 3 percent. In contrast, treatment with unlabelled lilotomab or saline did not affect rituximab binding. Treatment with 177Lu-lilotomab also increased ADCC induction to 30 ± 3 percent of Raji cells, an increase of 50 percent.
In the xenotransplanted mice, the combination of rituximab with 177Lu-lilotomab synergistically suppressed the growth of the RajiR2 tumor. The median survival of mice treated with this combination doubled compared to survival of mice given 177Lu-lilotomab monotherapy and was five times longer than that of mice given rituximab monotherapy.
“This work is potentially very important as it could be a last resort for patients who have become resistant to rituximab. When these patients are injected with 177Lu-Lilotomab-Satetraxetan, they can be re-treated with rituximab and have an improved effect “said Dr. Jostein Dahle, Ph.D., Scientific Director at Nordic Nanovector. “In a Phase 1b clinical study, 100 percent complete remission was achieved in the first group of patients treated with 177Lu-Lilotomab-Satetraxetan followed by Rituximab. Achieving complete remission is very important as it is usually correlated with improved duration of response and overall survival. “
Dahle continued, “Combination treatments are the future for cancer therapy. By exploring strategies that use radioimmunotherapy in conjunction with other drugs, nuclear medicine can play an important role in lymphoma therapy.”
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Marion M. Malenge et al., 177Lu-Lilotomab Satetraxetan has the potential to counteract resistance to rituximab in non-Hodgkin’s lymphoma, Journal of Nuclear Medicine (2020). DOI: 10.2967 / jnumed.119.237230
Provided by the Society of Nuclear Medicine and Molecular Imaging
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