{"doi":"10.1136/jitc-2024-010058","title":"Systemic chemokine-modulatory regimen combined with neoadjuvant chemotherapy in patients with triple-negative breast cancer","abstract":"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.","journal":"Journal for ImmunoTherapy of Cancer","year":2024,"id":443663,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":8,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.954,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1070215,"name":"Ronald Slomba","orcid":null,"position":1,"is_corresponding":false},{"id":1258858,"name":"Cayla Janes","orcid":null,"position":2,"is_corresponding":false},{"id":1258859,"name":"Victoria Fitzpatrick","orcid":null,"position":3,"is_corresponding":false},{"id":1258304,"name":"Janine Miller","orcid":"0000-0003-1364-7287","position":4,"is_corresponding":false},{"id":260451,"name":"Kristopher Attwood","orcid":"0000-0002-7229-5472","position":5,"is_corresponding":false},{"id":590472,"name":"Giorgio Ioannou","orcid":"0000-0001-7956-7605","position":6,"is_corresponding":false},{"id":1258305,"name":"Sinem Ozbey","orcid":"0000-0001-5636-4709","position":7,"is_corresponding":false},{"id":1258860,"name":"Igor De Souza","orcid":null,"position":8,"is_corresponding":false},{"id":86516,"name":"Vladimir Roudko","orcid":"0000-0002-3835-6737","position":9,"is_corresponding":false},{"id":1258306,"name":"Prasanna Kumar","orcid":"0000-0002-3729-9128","position":10,"is_corresponding":false},{"id":330833,"name":"Suresh Kalathil","orcid":"0000-0002-7800-3151","position":11,"is_corresponding":false},{"id":1026415,"name":"Kathleen M. 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