Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA.
Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA.
J Immunother Cancer. 2024 Nov 14;12(11):e010058. doi: 10.1136/jitc-2024-010058.
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.
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.
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.
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.
肿瘤微环境（TME）中更高的细胞毒性 T 淋巴细胞（CTL）数量可预测新辅助化疗（NAC）的病理完全缓解（pCR）和三阴性乳腺癌（TNBC）的阳性长期结果。只有 30-40%的患者能达到 NAC 的 pCR。NAC 联合 pembrolizumab 增加了 pCR 率，但代价是免疫相关不良事件（irAE）。基于这些考虑，我们测试了全身性输注趋化因子调节方案（CKM；选择性 Toll 样受体 3（TLR3）激动剂瑞替莫德、干扰素（IFN）-α2b 和环氧化酶-2（COX-2）抑制剂塞来昔布）方案是否可以与 NAC 安全联合，以增强肿瘤内 CTL 数量和 NAC 效果。
I 期研究 NCT04081389 评估了 9 名早期 TNBC 患者，他们接受了 3 周紫杉醇加 CKM（IFN-α2b 剂量递增）治疗，随后单独接受 9 周紫杉醇、密集多柔比星和环磷酰胺治疗，然后进行手术。主要和次要终点分别为安全性和临床疗效。
联合治疗耐受良好，无剂量限制毒性或 irAE。9 例患者中有 5 例达到 pCR，1 例患者有微小浸润性疾病（ypTmic）。我们观察到所有接受治疗的患者血液中的 IFN 特征升高，CTL 数量均匀下降（平均 8.3 倍）。这伴随着 TME 中 CD8β（总体 5.9 倍）、CD8α/FoxP3（2.11 倍）和 CCL5（4.73 倍）转录物的均匀反向增加，在 pCR 患者中尤为明显。多重免疫组化显示，在肿瘤的上皮和基质肿瘤区室中 CTL（但不是调节性 T 细胞）的数量选择性增加，在所有 pCR 患者的肿瘤中，αSMA 血管/基质细胞的数量早期减少。
联合紫杉醇/CKM 方案安全，TME 变化理想，pCR+ypTmic 率为 66%，与 NAC 联合 pembrolizumab 相当。
