Cheng Zu

Immune checkpoint molecules are essential regulators of immune homeostasis, maintaining the balance between activation and tolerance. In cancer, tumours exploit checkpoint pathways to suppress antitumour immunity and promote progression. The advent of immune checkpoint inhibitors, particularly those that target the clinically validated PDL1-PD1 and CTLA4 axes, has transformed cancer therapy, and the LAG3 axis has recently entered clinical practice, yet most patients experience limited or transient benefit, often because the checkpoint molecules become dysregulated. Here, we examine how multilayered regulatory mechanisms operating at the genetic, epigenetic, transcriptional, post-transcriptional, translational and post-translational levels collectively shape checkpoint abundance and function in tumour and immune cells. We further connect these regulatory processes to immune evasion and therapeutic resistance and highlight how this knowledge informs biomarker development and mechanism-guided strategies to improve immunotherapy outcomes.

Patients with relapsed or refractory hematologic cancers have a poor prognosis. Chimeric antigen receptor (CAR) T-cell therapy as a bridge to allogeneic hematopoietic stem-cell transplantation (HSCT) has the potential for long-term tumor elimination. However, pre-HSCT myeloablation and graft-versus-host disease (GVHD) prophylaxis agents have toxic effects and could eradicate residual CAR T cells and compromise antitumor effects. Whether the integration of CAR T-cell therapy and allogeneic HSCT can preserve CAR T-cell function and improve tumor control is unclear. We tested a novel "all-in-one" strategy consisting of sequential CD7 CAR T-cell therapy and haploidentical HSCT in 10 patients with relapsed or refractory CD7-positive leukemia or lymphoma. After CAR T-cell therapy led to complete remission with incomplete hematologic recovery, patients received haploidentical HSCT without pharmacologic myeloablation or GVHD prophylaxis drugs. Toxic effects and efficacy were closely monitored. After CAR T-cell therapy, all 10 patients had complete remission with incomplete hematologic recovery and grade 4 pancytopenia. After haploidentical HSCT, 1 patient died on day 13 of septic shock and encephalitis, 8 patients had full donor chimerism, and 1 patient had autologous hematopoiesis. Three patients had grade 2 HSCT-associated acute GVHD. The median follow-up was 15.1 months (range, 3.1 to 24.0) after CAR T-cell therapy. Six patients remained in minimal residual disease-negative complete remission, 2 had a relapse of CD7-negative leukemia, and 1 died of septic shock at 3.7 months. The estimated 1-year overall survival was 68% (95% confidence interval [CI], 43 to 100), and the estimated 1-year disease-free survival was 54% (95% CI, 29 to 100). Our findings suggest that sequential CD7 CAR T-cell therapy and haploidentical HSCT is safe and effective, with remission and serious but reversible adverse events. This strategy offers a feasible approach for patients with CD7-positive tumors who are ineligible for conventional allogeneic HSCT. (Funded by the National Natural Science Foundation of China and the Key Project of Science and Technology Department of Zhejiang Province; ClinicalTrials.gov numbers, NCT04599556 and NCT04538599.).

B-cell maturation antigen (BCMA)-targeted chimeric antigen receptor-T cell (CAR-T) therapy is used for refractory or relapsed multiple myeloma (r/r MM). Concern of the safety and efficacy of CAR-T cell therapy in patients with chronic or resolved HBV infection is raised. In this study, we retrospectively reviewed 99 patients with r/r MM treated with BCMA-targeted CAR-T cell therapy, of which 7 (7.1%) patients had chronic HBV infection, 43 (43.4%) with resolved HBV infection, and the remaining 49 (49.49%) HBV-uninfected. Patients’ characteristics before CAR-T cell administration were comparable in different status of HBV infection. Patients’ liver function, cytokine levels, CAR-T cell expansion and cytokine release syndrome (CRS) grade after CAR-T cell therapy did not differ in different HBV serologic status. Furthermore, chronic HBV infection or resolved HBV infection did not affect clinical response, progress-free survival (PFS), or overall survival (OS). Four (4.04%) patients experienced HBV reactivation, 3 (6.98%) with resolved HBV infection, and 1 (14.29%) chronic HBV infection. Of 4 patients with HBV reactivation, 2 cases (50%) of severe hepatitis were noted and reported. Drops of serum IgG and elevation of alanine aminotransferase (ALT), alanine aminotransferase (AST), total bilirubin (TB) were observed in all four patients around the date of HBV reactivation.

目的：研究BCMA为靶点的CAR-T细胞治疗难治/复发多发性骨髓瘤（R/R MM）患者合并HLH的临床特点、高危因素和治疗方案。 方法：浙江大学医学院附属第一医院骨髓移植中心接受BCMA CAR-T治疗的96名R/R MM患者和3名浆细胞白血病患者中，20例确诊为carHLH。收集carHLH组和非carHLH组的临床资料，运用Mann-Whitney秩和检验、Fisher精确检验、χ2检验、Cochran-Armitage检验等统计方法对不同类型的资料进行统计分析。 结果：carHLH组与非carHLH组相比，患者骨髓具有高浆细胞比例（P = 0.0147）。CAR-T细胞扩增高峰在carHLH组比非carHLH组高（P = 0.0096），血清细胞因子IL-6、IL-10和IFN-γ的最高水平在两组中均具有显著性差异（P = 0.0025、P = 3×10-5、P = 1×10-7）。carHLH组患者完全缓解（CR）率为100%，非carHLH组CR率为61.04%（P = 0.0001）。所有患者carHLH在糖皮质激素和托珠单抗为主的治疗后均好转，7例单独使用托珠单抗，5例单独使用激素，6例同时使用两者，2例两者均未使用。 结论：骨髓中高浆细胞比例是carHLH发生的高危因素；治疗后CAR-T细胞扩增和细胞因子水平与carHLH发生密切相关；carHLH的发生与更好的疗效相关；以糖皮质激素和IL-6受体拮抗剂为主的方案可有效治疗carHLH。

Cytomegalovirus (CMV) retinitis is a rare end-organ disease of CMV infection and is a marker of severe immunosuppression, especially in human immunodeficiency virus (HIV)-positive patients. In multiple myeloma (MM) patients, CMV retinitis has been reported in the post-transplant setting, with an incidence lower than 0.2%, and in patients receiving lenalidomide. Here, we describe the first case of CMV retinitis in myeloma patients following B-cell maturation antigen (BCMA)-targeted chimeric antigen receptor T (BCMA CAR-T) cell therapy. In addition to CMV, the patient developed multiple infections including a mouth ulcer, pneumonia, and fungal enteritis. While the complete remission (CR) status of MM was maintained, he regained a visual acuity of 20/1000 after appropriate ophthalmologic treatment. This single case illustrates the potential of BCMA CAR-T therapy to induce profound humoral immunosuppression, and demonstrates an imperative need for an established standard of monitoring and prophylaxis of post-CAR-T infections.