Immune recognition of somatic mutations leading to complete durable regression in metastatic breast cancer
Nikolaos Zacharakis1, Harshini Chinnasamy1, Mary Black1
1Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Abstract:
Immunotherapy using either checkpoint blockade or the adoptive transfer of antitumor lymphocytes has shown effectiveness in treating cancers with high levels of somatic mutations-such as melanoma, smoking-induced lung cancers and bladder cancer-with little effect in other common epithelial cancers that have lower mutation rates, such as those arising in the gastrointestinal tract, breast and ovary1-7. Adoptive transfer of autologous lymphocytes that specifically target proteins encoded by somatically mutated genes has mediated substantial objective clinical regressions in patients with metastatic bile duct, colon and cervical cancers8-11. We present a patient with chemorefractory hormone receptor (HR)-positive metastatic breast cancer who was treated with tumor-infiltrating lymphocytes (TILs) reactive against mutant versions of four proteins-SLC3A2, KIAA0368, CADPS2 and CTSB. Adoptive transfer of these mutant-protein-specific TILs in conjunction with interleukin (IL)-2 and checkpoint blockade mediated the complete durable regression of metastatic breast cancer, which is now ongoing for >22 months, and it represents a new immunotherapy approach for the treatment of these patients.
Insights
This study demonstrates a novel immunotherapy approach for hormone receptor-positive metastatic breast cancer. Tumor-infiltrating lymphocytes (TILs) targeting specific mutant proteins induced a durable complete regression, offering new hope for patients.
Area of Science:
- Oncology
- Immunology
- Cancer Research
Background:
- Immunotherapy, including checkpoint blockade and adoptive lymphocyte transfer, is effective for cancers with high somatic mutation rates.
- Epithelial cancers with lower mutation rates, such as breast cancer, have shown limited response to current immunotherapies.
- Adoptive transfer of lymphocytes targeting mutated genes has shown promise in specific metastatic cancers.
Purpose of the Study:
- To investigate the efficacy of adoptive transfer of tumor-infiltrating lymphocytes (TILs) targeting mutant proteins in a patient with hormone receptor-positive metastatic breast cancer.
- To evaluate a novel immunotherapy combination for refractory breast cancer.
Main Methods:
- Treatment of a patient with chemorefractory hormone receptor-positive metastatic breast cancer.
- Utilized tumor-infiltrating lymphocytes (TILs) specifically reactive against mutant proteins (SLC3A2, KIAA0368, CADPS2, CTSB).
- Administered adoptive transfer of these mutant-protein-specific TILs combined with interleukin-2 (IL-2) and checkpoint blockade.
Main Results:
- Achieved a complete and durable regression of metastatic breast cancer, ongoing for over 22 months.
- Demonstrated the effectiveness of targeting mutant proteins in a low-mutation-rate cancer.
Conclusions:
- Adoptive transfer of mutant-protein-specific TILs, combined with IL-2 and checkpoint blockade, represents a promising new immunotherapy strategy for hormone receptor-positive metastatic breast cancer.
- This approach offers a potential treatment option for patients with refractory disease.
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