Trastuzumab and interleukin-2 in HER2-positive metastatic breast cancer: a pilot study
Tanya Repka1, Elena G Chiorean, Juliette Gay
1Division of Hematology-Oncology and Transplantation, University of Minnesota Cancer Center, Minneapolis, Minnesota 55455, USA.
Purpose:
Trastuzumab as a single agent has activity in metastatic breast cancer; however, the mechanism of action for this clinical activity is uncertain. Whereas interruption of erbB family member signaling occurs, trastuzumab also mediates antibody-dependent cellular cytotoxicity in vitro and in vivo. Based on these data, a clinical trial was performed to test whether interleukin (IL)-2, by increasing FcRgammaIII(+) natural killer (NK) cell numbers and cytolytic function in vivo, when added to trastuzumab, can increase efficacy, be safely given, and avoid the use of chemotherapy.
Experimental Design:
In this Phase I trial, 10 patients with HER2-overexpressing metastatic breast cancer were treated with IL-2 (1.75 x 10(6) IU/m(2)/day, s.c.) for 7 weeks and trastuzumab (4 mg/kg load and then 2 mg/kg weekly) for 6 weeks. Safety, in vitro immune responses, and clinical responses were assessed.
Results:
Ten women received a total of 12 cycles of therapy (each cycle lasted 7 weeks). No significant toxicities were seen, and one patient required an IL-2 dose reduction. Among the evaluable patients (10 cycles), the responses were one partial response, five cases of stable disease, and four cases of progressive disease. In vitro immune assays showed NK cell expansion and trastuzumab-mediated increased NK cell killing of breast cancer targets (antibody-dependent cellular cytotoxicity) in a HER2-specific manner but did not correlate with clinical responses.
Conclusions:
Trastuzumab + IL-2 is a well-tolerated outpatient regimen that results in NK cell expansion with enhanced in vitro targeted killing of HER2-expressing cells. These preliminary data suggest that this strategy may benefit heavily pretreated metastatic breast cancer patients.
Insights
Adding interleukin-2 (IL-2) to trastuzumab therapy for metastatic breast cancer is safe and enhances natural killer (NK) cell activity. This combination shows promise for heavily pretreated patients, boosting immune response against HER2-expressing cells.
Area of Science:
- Oncology
- Immunology
- Pharmacology
Background:
- Trastuzumab is active in metastatic breast cancer, but its mechanism is unclear, involving both HER2 signaling inhibition and antibody-dependent cellular cytotoxicity (ADCC).
- Antibody-dependent cellular cytotoxicity (ADCC) is mediated by natural killer (NK) cells, suggesting that enhancing NK cell function could improve trastuzumab efficacy.
Purpose of the Study:
- To evaluate the safety and efficacy of combining interleukin-2 (IL-2) with trastuzumab in patients with HER2-overexpressing metastatic breast cancer.
- To determine if IL-2 can increase NK cell numbers and function, thereby enhancing trastuzumab-mediated ADCC.
- To assess if this combination regimen can be safely administered in an outpatient setting without chemotherapy.
Main Methods:
- A Phase I clinical trial was conducted involving 10 patients with HER2-overexpressing metastatic breast cancer.
- Patients received subcutaneous IL-2 for 7 weeks concurrently with weekly intravenous trastuzumab for 6 weeks.
- Safety, in vitro immune responses (NK cell expansion and ADCC), and clinical responses were assessed.
Main Results:
- The combination of IL-2 and trastuzumab was well-tolerated as an outpatient regimen, with no significant toxicities observed; one patient required an IL-2 dose reduction.
- In vitro assays demonstrated NK cell expansion and enhanced trastuzumab-mediated ADCC against HER2-expressing breast cancer cells.
- Clinical responses included one partial response, five cases of stable disease, and four cases of progressive disease among evaluable patients.
Conclusions:
- Trastuzumab plus IL-2 is a safe and tolerable outpatient regimen that effectively expands NK cells and enhances their targeted killing of HER2-expressing cells in vitro.
- These preliminary findings suggest that this therapeutic strategy may offer benefits for heavily pretreated patients with metastatic breast cancer.
- Further investigation is warranted to confirm the clinical benefit of this combination therapy.
