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Injection of Syngeneic Murine Melanoma Cells to Determine Their Metastatic Potential in the Lungs
Published on: May 24, 2016
Humoral immune response to a ricin A chain immunotoxin in patients with metastatic melanoma
A A Hertler1, L E Spitler, A E Frankel
1Division of Hematology and Oncology, Duke University Medical Center, Durham, NC.
Abstract:
Immunotoxins, hybrid molecules consisting of a monoclonal antibody linked to a polypeptide toxin have shown anti-tumor activity in both animal models and early clinical trials. However, their potential value in the treatment of human cancer may be limited by the development of host antibodies against the conjugate. Such antibodies could potentially alter immunotoxin pharmacokinetics and pharmacodynamics as well as precipitate serum sickness or anaphylaxis. Using a radioimmunoassay we have measured serial anti-ricin A chain (anti-RTA) and anti-murine immunoglobulin (anti-MIG) titers in 22 patients who received the anti-melanoma immunotoxin XomaZymeR-Mel. Significant titers of anti-RTA and/or anti-MIG were detected in 17 of 21 evaluable patients. Of the four patients not developing antibodies, two were likely immunosuppressed secondary to dexamethasone, and CCNU and dexamethasone respectively. Both patients who received immunotoxin at a time when they had detectable anti-immunotoxin antibodies experienced infusion reactions consistent with immune mediated allergic responses. There was a decrease in peak immunotoxin level in the one patient who had serum immunotoxin levels measured at a time when anti-RTA was present. Strategies to suppress the human immune response to immunotoxins are required before repetitive courses of immunotoxin of this design may be administered.
Insights
Patients receiving cancer-treating immunotoxins often develop antibodies against the toxin and mouse proteins. These immune responses can cause allergic reactions and reduce treatment effectiveness, necessitating strategies to suppress them for repeated dosing.
Area of Science:
- Oncology
- Immunology
- Biotechnology
Background:
- Immunotoxins, combining antibodies with toxins, show anti-tumor potential.
- Host antibody development against immunotoxins can limit their therapeutic efficacy and safety.
- Adverse immune reactions like serum sickness and anaphylaxis are concerns.
Purpose of the Study:
- To investigate the incidence and impact of host antibody responses to an anti-melanoma immunotoxin.
- To assess the clinical implications of anti-immunotoxin antibodies in cancer patients.
Main Methods:
- Radioimmunoassay was used to measure serial anti-ricin A chain (anti-RTA) and anti-murine immunoglobulin (anti-MIG) titers.
- Patient cohorts receiving XomaZymeR-Mel were monitored for antibody development.
- Infusion reactions and immunotoxin serum levels were evaluated in relation to antibody presence.
Main Results:
- 17 out of 21 evaluable patients developed significant anti-RTA and/or anti-MIG titers.
- Patients with pre-existing anti-immunotoxin antibodies experienced infusion reactions.
- A decrease in peak immunotoxin levels was observed in a patient with anti-RTA antibodies.
- Immunosuppression may reduce antibody development.
Conclusions:
- The human immune response to immunotoxins is a significant challenge for repeated administration.
- Strategies to mitigate host antibody responses are crucial for the clinical application of immunotoxins.
- Further research is needed to develop methods for immune suppression in patients receiving immunotoxin therapy.
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