Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Washington, Seattle, Washington, USA
Cancer Vaccine Institute, University of Washington, Seattle, Washington, USA.
J Immunother Cancer. 2024 Nov 9;12(11):e010251. doi: 10.1136/jitc-2024-010251.
For best efficacy, vaccines must provide long-lasting immunity. To measure longevity, memory from B and T cells are surrogate endpoints for vaccine efficacy. When antibodies are insufficient for protection, the immune response must rely on T cells. The magnitude and differentiation of effective, durable immune responses depend on antigen-specific precursor frequencies. However, development of vaccines that induce durable T-cell responses for cancer treatment has remained elusive.
To address long-lasting immunity, patients with HER2+ (human epidermal growth factor receptor 2) advanced stage cancer received HER2/neu targeted vaccines. Interferon-gamma (IFN-γ) enzyme-linked immunosorbent spot measuring HER2/neu IFN-γ T cells were analyzed from 86 patients from three time points: baseline, 1 month after vaccine series, and long-term follow-up at 1 year, following one in vitro stimulation. The baseline and 1-month post-vaccine series responses were correlated with immunity at long-term follow-up by logistic regression. Immunity was modeled by non-linear functions using generalized additive models.
Antigen-specific T-cell responses at baseline were associated with a 0.33-log increase in response at long-term follow-up, 95% CI (0.11, 0.54), p=0.003. 63% of patients that had HER2/neu specific T cells at baseline continued to have responses at long-term follow-up. Increased HER2/neu specific T-cell response 1 month after the vaccine series was associated with a 0.47-log increase in T-cell response at long-term follow-up, 95% CI (0.27, 0.67), p=2e-5. 74% of patients that had an increased IFN-γ HER2 response 1 month after vaccines retained immunity long-term. As the 1-month post-vaccination series precursor frequency of HER2+IFN-γ T-cell responses increased, the probability of retaining these responses long-term increased (OR=1.49 for every one natural log increase of precursor frequency, p=0.0002), reaching an OR of 20 for a precursor frequency of 1:3,000 CONCLUSIONS: Patients not destined to achieve long-term immunity can be identified immediately after completing the vaccine series. Log-fold increases in antigen-specific precursor frequencies after vaccinations correlate with increased odds of retaining long-term HER2 immune responses. Further vaccine boosting or immune checkpoint inhibitors or other immune stimulator therapy should be explored in patients that do not develop antigen-specific T-cell responses to improve overall response rates.
为了达到最佳疗效，疫苗必须提供持久的免疫力。为了衡量其有效期，B 细胞和 T 细胞的记忆可作为疫苗疗效的替代终点。当抗体不足以提供保护时，免疫反应必须依赖于 T 细胞。有效的、持久的免疫反应的幅度和分化取决于抗原特异性前体频率。然而，开发用于癌症治疗的可诱导持久 T 细胞反应的疫苗一直难以实现。
为了实现长期免疫，HER2+（人表皮生长因子受体 2）晚期癌症患者接受了 HER2/neu 靶向疫苗。从 86 名患者的三个时间点（基线、疫苗系列接种后 1 个月和 1 年后的长期随访）分析了针对 HER2/neu 的干扰素-γ（IFN-γ）酶联免疫斑点测量 HER2/neu IFN-γ T 细胞。使用逻辑回归分析了基线和疫苗系列接种后 1 个月的反应与长期随访时的免疫反应的相关性。使用广义加性模型通过非线性函数对免疫进行建模。
基线时的抗原特异性 T 细胞反应与长期随访时的反应增加 0.33 对数相关，95%置信区间（0.11，0.54），p=0.003。63%的基线时具有 HER2/neu 特异性 T 细胞的患者在长期随访时仍有反应。疫苗系列接种后 1 个月时增加的 HER2/neu 特异性 T 细胞反应与长期随访时 T 细胞反应增加 0.47 对数相关，95%置信区间（0.27，0.67），p=2e-5。74%的疫苗接种后 1 个月 IFN-γ HER2 反应增加的患者长期保持免疫。随着疫苗接种后 1 个月时 HER2+IFN-γ T 细胞反应的前体频率增加，长期保留这些反应的可能性增加（前体频率每增加一个自然对数，OR=1.49，p=0.0002），达到 1:3000 的前体频率时 OR 为 20。
在完成疫苗系列接种后，可立即识别出无法获得长期免疫的患者。疫苗接种后抗原特异性前体频率的对数增加与保留长期 HER2 免疫反应的几率增加相关。对于未产生抗原特异性 T 细胞反应的患者，应进一步探索疫苗加强或免疫检查点抑制剂或其他免疫刺激剂治疗，以提高总体反应率。
