Systemic chemokine-modulatory regimen combined with neoadjuvant chemotherapy in patients with triple-negative breast cancer
Background Higher cytotoxic T lymphocyte (CTL) numbers in the tumor microenvironment (TME) predict pathologic complete response (pCR) to neoadjuvant chemotherapy (NAC) and positive long-term outcomes in triple-negative breast cancer (TNBC). pCR to NAC is achieved only in 30–40% of patients. The comb...
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BMJ Publishing Group
2024-11-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/12/11/e010058.full |
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| author | Jessica Young Pawel Kalinski Mateusz Opyrchal Kathleen M Kokolus Sacha Gnjatic Jianming Wang Shipra Gandhi Kristopher Attwood Tracey O’Connor Kazuaki Takabe Victoria Fitzpatrick Eduardo Cortes Gomez Stephen Edge Janine Miller Ronald T Slomba Ellis G Levine Sinem Ozbey Giorgio Ioannou Cayla Janes Igor De Souza Vladimir Roudko Prasanna Kumar Suresh Kalathil Helen Cappuccino |
| author_facet | Jessica Young Pawel Kalinski Mateusz Opyrchal Kathleen M Kokolus Sacha Gnjatic Jianming Wang Shipra Gandhi Kristopher Attwood Tracey O’Connor Kazuaki Takabe Victoria Fitzpatrick Eduardo Cortes Gomez Stephen Edge Janine Miller Ronald T Slomba Ellis G Levine Sinem Ozbey Giorgio Ioannou Cayla Janes Igor De Souza Vladimir Roudko Prasanna Kumar Suresh Kalathil Helen Cappuccino |
| author_sort | Jessica Young |
| collection | DOAJ |
| description | Background Higher cytotoxic T lymphocyte (CTL) numbers in the tumor microenvironment (TME) predict pathologic complete response (pCR) to neoadjuvant chemotherapy (NAC) and positive long-term outcomes in triple-negative breast cancer (TNBC). pCR to NAC is achieved only in 30–40% of patients. The combination of NAC with pembrolizumab increases the pCR rate but at the cost of immune-related adverse events (irAEs). Based on these considerations, we tested if systemic infusion of the chemokine modulatory regimen (CKM; selective toll-like receptor 3 (TLR3) agonist rintatolimod, interferon (IFN)-α2b, and cyclooxygenase-2 (COX-2) inhibitor celecoxib) regimen can be safely combined with NAC to enhance intratumoral CTL numbers and NAC effectiveness.Methods Phase I study NCT04081389 evaluated nine patients with early-stage TNBC who received 3 weeks of paclitaxel with CKM (dose-escalation of IFN-α2b), followed by 9 weeks of paclitaxel alone, dose-dense doxorubicin and cyclophosphamide, and surgery. Primary and secondary endpoints were safety and clinical efficacy, respectively.Results The combination treatment was well-tolerated with no dose-limiting toxicities or irAEs. 5/9 patients achieved pCR and one patient had microinvasive disease (ypTmic). We observed elevated IFN signature and uniform decreases in CTL numbers (average 8.3-fold) in the blood of all treated patients. This was accompanied by reciprocal uniform increases in CD8β (overall 5.9-fold), CD8α/FoxP3 (2.11-fold), and CCL5 (4.73-fold) transcripts in TME, particularly pronounced in patients with pCR. Multiplex immunohistochemistry revealed selectively increased numbers of CTL (but not regulatory T cells) in both the epithelial and stromal tumor compartments and early decreases in the numbers of αSMA+ vascular/stromal cells in the tumors of all pCR patients.Conclusions Combined paclitaxel/CKM regimen was safe, with desirable TME changes and preliminary indications of promising pCR+ypTmic of 66%, comparable to the combination of NAC with pembrolizumab. |
| format | Article |
| id | doaj-art-d569717b5be14a588e378c08cde71fa3 |
| institution | OA Journals |
| issn | 2051-1426 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | BMJ Publishing Group |
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| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-d569717b5be14a588e378c08cde71fa32025-08-20T01:52:14ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262024-11-01121110.1136/jitc-2024-010058Systemic chemokine-modulatory regimen combined with neoadjuvant chemotherapy in patients with triple-negative breast cancerJessica Young0Pawel Kalinski1Mateusz Opyrchal2Kathleen M Kokolus3Sacha Gnjatic4Jianming Wang5Shipra Gandhi6Kristopher Attwood7Tracey O’Connor8Kazuaki Takabe9Victoria Fitzpatrick10Eduardo Cortes Gomez11Stephen Edge12Janine Miller13Ronald T Slomba14Ellis G Levine15Sinem Ozbey16Giorgio Ioannou17Cayla Janes18Igor De Souza19Vladimir Roudko20Prasanna Kumar21Suresh Kalathil22Helen Cappuccino23Department of Surgery, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USADepartment of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USADepartment of Medicine, Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, Indiana, USADepartment of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA11 Icahn School of Medicine at Mount Sinai, New York, New York, USADepartment of Epidemiology, Key Laboratory of Public Health Safety and Emergency Prevention and Control Technology of Higher Education Institutions in Jiangsu Province, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, ChinaDepartment of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USADepartment of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USADepartment of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USARoswell Park Comprehensive Cancer Center, Buffalo, New York, USARoswell Park Comprehensive Cancer Center, Buffalo, New York, USADepartment of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USADepartment of Surgery, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USADepartment of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USADepartment of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USARoswell Park Comprehensive Cancer Center, Buffalo, New York, USADepartment of Pathology, Mount Sinai School of Medicine, New York, New York, USADepartment of Pathology, Mount Sinai School of Medicine, New York, New York, USARoswell Park Comprehensive Cancer Center, Buffalo, New York, USADepartment of Pathology, Mount Sinai School of Medicine, New York, New York, USAHuman Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, NY, USAClinical Immunology and Rheumatology, King George`s Medical University, Lucknow, Uttar Pradesh, IndiaDepartment of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USADepartment of Surgery, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USABackground Higher cytotoxic T lymphocyte (CTL) numbers in the tumor microenvironment (TME) predict pathologic complete response (pCR) to neoadjuvant chemotherapy (NAC) and positive long-term outcomes in triple-negative breast cancer (TNBC). pCR to NAC is achieved only in 30–40% of patients. The combination of NAC with pembrolizumab increases the pCR rate but at the cost of immune-related adverse events (irAEs). Based on these considerations, we tested if systemic infusion of the chemokine modulatory regimen (CKM; selective toll-like receptor 3 (TLR3) agonist rintatolimod, interferon (IFN)-α2b, and cyclooxygenase-2 (COX-2) inhibitor celecoxib) regimen can be safely combined with NAC to enhance intratumoral CTL numbers and NAC effectiveness.Methods Phase I study NCT04081389 evaluated nine patients with early-stage TNBC who received 3 weeks of paclitaxel with CKM (dose-escalation of IFN-α2b), followed by 9 weeks of paclitaxel alone, dose-dense doxorubicin and cyclophosphamide, and surgery. Primary and secondary endpoints were safety and clinical efficacy, respectively.Results The combination treatment was well-tolerated with no dose-limiting toxicities or irAEs. 5/9 patients achieved pCR and one patient had microinvasive disease (ypTmic). We observed elevated IFN signature and uniform decreases in CTL numbers (average 8.3-fold) in the blood of all treated patients. This was accompanied by reciprocal uniform increases in CD8β (overall 5.9-fold), CD8α/FoxP3 (2.11-fold), and CCL5 (4.73-fold) transcripts in TME, particularly pronounced in patients with pCR. Multiplex immunohistochemistry revealed selectively increased numbers of CTL (but not regulatory T cells) in both the epithelial and stromal tumor compartments and early decreases in the numbers of αSMA+ vascular/stromal cells in the tumors of all pCR patients.Conclusions Combined paclitaxel/CKM regimen was safe, with desirable TME changes and preliminary indications of promising pCR+ypTmic of 66%, comparable to the combination of NAC with pembrolizumab.https://jitc.bmj.com/content/12/11/e010058.full |
| spellingShingle | Jessica Young Pawel Kalinski Mateusz Opyrchal Kathleen M Kokolus Sacha Gnjatic Jianming Wang Shipra Gandhi Kristopher Attwood Tracey O’Connor Kazuaki Takabe Victoria Fitzpatrick Eduardo Cortes Gomez Stephen Edge Janine Miller Ronald T Slomba Ellis G Levine Sinem Ozbey Giorgio Ioannou Cayla Janes Igor De Souza Vladimir Roudko Prasanna Kumar Suresh Kalathil Helen Cappuccino Systemic chemokine-modulatory regimen combined with neoadjuvant chemotherapy in patients with triple-negative breast cancer Journal for ImmunoTherapy of Cancer |
| title | Systemic chemokine-modulatory regimen combined with neoadjuvant chemotherapy in patients with triple-negative breast cancer |
| title_full | Systemic chemokine-modulatory regimen combined with neoadjuvant chemotherapy in patients with triple-negative breast cancer |
| title_fullStr | Systemic chemokine-modulatory regimen combined with neoadjuvant chemotherapy in patients with triple-negative breast cancer |
| title_full_unstemmed | Systemic chemokine-modulatory regimen combined with neoadjuvant chemotherapy in patients with triple-negative breast cancer |
| title_short | Systemic chemokine-modulatory regimen combined with neoadjuvant chemotherapy in patients with triple-negative breast cancer |
| title_sort | systemic chemokine modulatory regimen combined with neoadjuvant chemotherapy in patients with triple negative breast cancer |
| url | https://jitc.bmj.com/content/12/11/e010058.full |
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