Neoadjuvant Immunochemotherapy Shows Promising Results in Locally Advanced Oral Squamous Cell Carcinoma
核心洞察
Neoadjuvant immunochemotherapy with camrelizumab plus nab-paclitaxel and cisplatin demonstrated a favorable pathological response in patients with locally advanced oral squamous cell carcinoma (搜索), achieving a 69% major pathological response rate and 41.4% pathological complete response rate.
The treatment regimen showed a manageable safety profile with only 6.5% of patients experiencing grade 3-4 treatment-related adverse events, and no delays in surgery occurred due to treatment-related toxicity.
Single-cell analysis revealed that CD4+CXCL13 (搜索)+ T follicular helper cells may serve as a potential predictive biomarker for treatment response, with higher baseline levels correlating with better pathological outcomes.
Researchers from West China Hospital, Sichuan University (搜索) have reported promising results from a phase II clinical trial evaluating neoadjuvant immunochemotherapy (NAIC) in patients with locally advanced oral squamous cell carcinoma (搜索) (LA-OSCC). The study, published in Nature Communications, demonstrates that the combination of camrelizumab (an anti-PD-1 (搜索) antibody) with nab-paclitaxel and cisplatin produced significant pathological responses with manageable toxicity.
Study Design and Patient Characteristics
The single-arm, phase II trial enrolled 31 patients with previously untreated, resectable stage III-IVB LA-OSCC. Patients received two cycles of NAIC consisting of camrelizumab 200 mg and nab-paclitaxel 260 mg/m² on days 1 and 22, plus cisplatin 75 mg/m² (divided over 3 days) on days 1-3 and 22-24. Surgery was performed within 2-4 weeks after completion of NAIC, followed by appropriate adjuvant therapy and maintenance immunotherapy.
The patient cohort had a mean age of 54 ± 11 years, with a predominance of male patients (87.1%). Most patients (58.1%) had clinical stage IVA disease at baseline. Of the 31 enrolled patients, 29 (93.5%) underwent radical surgery after completing NAIC, while two patients declined surgery.
Impressive Pathological Responses
The primary endpoint of major pathological response (MPR), defined as ≤10% residual viable tumor, was achieved in 69.0% of patients (20/29, 95% CI: 49.2-84.7%). Notably, 41.4% of patients (12/29, 95% CI: 23.5-61.1%) achieved pathological complete response (pCR), indicating no detectable tumor cells in the surgical specimen.
The objective response rate (ORR) according to RECIST v1.1 criteria was 82.8% (24/29, 95% CI: 64.2-94.2%), with 7 patients achieving complete response, 17 showing partial response, and 5 with stable disease. No patients experienced disease progression during the neoadjuvant treatment phase.
A significant correlation was observed between radiographic response and the percentage of residual viable tumor (Spearman's r = -0.7318, p < 0.0001), suggesting that imaging assessments may help predict pathological outcomes.
Favorable Safety Profile
The treatment regimen demonstrated a manageable safety profile. While all patients experienced treatment-related adverse events (TRAEs) of any grade, only 6.5% (2/31) developed grade 3 or 4 TRAEs, which included grade 4 neutropenia and grade 3 thrombocytopenia. These events led to dose reductions of nab-paclitaxel and cisplatin in the second cycle. No grade 5 (fatal) TRAEs were reported.
The most common immune-related adverse event was grade 1 reactive cutaneous capillary endothelial proliferation, occurring in 16.1% of patients. Importantly, no delays in surgery occurred due to NAIC-related toxicity, and surgical complications were generally mild and resolved within 2-4 weeks with symptomatic treatment.
Biomarker Analysis and Mechanistic Insights
The study included comprehensive biomarker analyses using single-cell RNA sequencing (scRNA-seq), T cell receptor sequencing (scTCR-seq), and multiplex immunofluorescence to understand the immunological mechanisms underlying treatment response.
A key finding was the identification of CD4+CXCL13 (搜索)+ T follicular helper (Tfh) cells as a potential predictive biomarker for NAIC response. Patients who achieved MPR had higher densities of these cells both before and after treatment compared to non-MPR patients. The density of pre-treatment CD4+CXCL13+ cells showed a strong negative correlation with residual viable tumor percentage (Spearman's r = -0.6412, p = 0.0002) and demonstrated high predictive accuracy for pathological response (AUC = 0.9251).
Post-treatment analysis revealed significant increases in tertiary lymphoid structures (TLS) in MPR patients, along with enrichment of CD8+ T cells, CD20+ B cells, CD56+ natural killer cells, and CD11c+ dendritic cells. Conversely, there was decreased infiltration of CD68+CD163+ tumor-associated macrophages in these patients.
Cell-cell communication analysis suggested that CXCL13 (搜索) produced by CD4+ Tfh cells interacts with CXCR5 (搜索) on B cells, potentially driving TLS formation and anti-tumor immune responses. This interaction was further validated through multiplex immunofluorescence, which showed co-localization of CD4+CXCL13+ cells with CD20+CXCR5+ B cells in TLS.
In Vivo Validation
To further validate these findings, the researchers conducted experiments using SCC7-bearing mice. The combination of anti-PD-1 (搜索) therapy with chemotherapy (nab-paclitaxel and cisplatin) significantly suppressed tumor growth and prolonged survival compared to monotherapy or control groups.
Flow cytometry analyses showed increased percentages of CD4+CXCL13 (搜索)+, CD3-CD19+, and CD3+CD8+ cells in mice treated with anti-PD-1 (搜索) alone or in combination with chemotherapy. Additional experiments demonstrated that recombinant CXCL13 enhanced the anti-tumor effects of immunochemotherapy, with two of five tumors in the combination group showing complete regression.
Comparison with Other Neoadjuvant Approaches
The authors note that their regimen achieved comparable or superior pathological response rates compared to other neoadjuvant approaches in head and neck squamous cell carcinoma (HNSCC). Previous studies have reported MPR rates ranging from 5.9-35% with neoadjuvant mono/dual immune checkpoint blockade, 40-60% with immune checkpoint blockade combined with targeted therapy ± chemotherapy, and 27.8-74.1% with immune checkpoint blockade combined with chemotherapy.
The 69% MPR rate and 41.4% pCR rate observed in this study are particularly notable given that only two cycles of NAIC were administered, compared to three cycles in some comparable studies.
Future Directions
While the results are promising, the authors acknowledge several limitations of their study, including its single-center design, relatively small sample size, and the need for longer follow-up to assess survival outcomes. The median follow-up duration was 18.6 months, with an 18-month overall survival probability of 96.77% (95% CI: 79.23-99.54%) for all treated patients.
The identification of CD4+CXCL13 (搜索)+ Tfh cells as a potential predictive biomarker warrants further validation in larger studies. If confirmed, this biomarker could help identify patients most likely to benefit from NAIC, potentially enabling more personalized treatment approaches.
Conclusion
This phase II trial demonstrates that neoadjuvant immunochemotherapy with camrelizumab plus nab-paclitaxel and cisplatin is an effective and well-tolerated approach for patients with locally advanced oral squamous cell carcinoma (搜索). The high rates of major pathological response and pathological complete response, coupled with a favorable safety profile, suggest that this regimen may represent an important advance in the treatment of this challenging disease.
The identification of CD4+CXCL13 (搜索)+ Tfh cells as a potential predictive biomarker provides valuable insights into the immunological mechanisms underlying treatment response and may help guide patient selection in future studies. Further research, including phase III trials, is needed to confirm these findings and establish the long-term survival benefits of this promising approach.