Background Systemic administration of immunotherapy via intravenous injection is frequently associated with off-target toxicity throughout the body. In contrast, intratumoral injection has emerged as a promising strategy to mitigate systemic adverse effects. However, data regarding the safety of CT-guided intratumoral immunotherapy remain limited. Methods This pooled prospective cohort study included patients from several single-arm clinical trials. Eligible participants had histologically confirmed advanced solid tumors that were refractory or intolerant to standard therapies. Each participant had at least one measurable tumor lesion accessible for puncture under imaging guidance. All patients received CT-guided intratumoral injection of various ICIs (PD-1, PD-L1, and CTLA-4 inhibitors) either alone or in combination, or of CAR-T cells. The primary endpoint was safety of the treatment. Results A total of 169 patients were included in the study cohort, with a median follow-up duration of 8.4 months (range, 1.0–38.0 months). Grade 3–4 adverse events occurred in 15 patients (8.88%), comprising 10 (5.92%) grade 3 and 5 (2.96%) grade 4 events; no treatment-related deaths were observed. Efficacy outcomes included 4 patients (2.37%) with complete response (CR), 15 (8.88%) with partial response (PR), 142 (84.02%) with stable disease (SD), and 8 (4.73%) with progressive disease (PD). The objective response rate (ORR) was 11.24%, and the disease control rate (DCR) was 95.27%. The median progression-free survival (PFS) was 3.6 months (95% CI, 3.1–4.1 months), and the median overall survival (OS) was 8.8 months (95% CI, 8.2–9.3 months). Conclusion This study indicates the safety and preliminary therapeutic potential of intratumoral injection. Intratumoral injection may be a promising strategy for mitigating systemic toxicity; however, further research is necessary to validate its therapeutic efficacy. Clinical trial registrationhttps://clinicaltrials.gov, identifier NCT03198052, NCT03769129, NCT03755739, NCT03952065, and NCT05341492.
Yong Ou, Jian Zhang, H. Tan et al.· Frontiers in Immunology· 0 citations
Abstract Background Renal cell carcinoma (RCC) frequently exhibits upregulation of CD70, a tumor-associated antigen implicated in immune evasion and disease progression, making it an attractive therapeutic target. Cusatuzumab, an Fc-enhanced anti-CD70 monoclonal antibody, has demonstrated the ability to mediate antibody-dependent cellular cytotoxicity (ADCC); however, its clinical efficacy is limited by insufficient effector cell engagement, antigen heterogeneity, and adaptive resistance mechanisms within the tumor microenvironment. Methods To overcome these limitations, we developed a universal, off-the-shelf natural killer T (NKT) cell product derived from hematopoietic stem cells (HSCs) through genetic engineering of an invariant T cell receptor (TCR) and a high-affinity, non-cleavable CD16 receptor. These CD16-enhanced HSC-derived NKT (CD16HSC-NKT) cells were generated using a feeder-free differentiation platform, yielding high purity and scalability while preserving canonical NKT cell phenotypes and effector functions. Results Functionally, CD16HSC-NKT cells exhibited potent intrinsic cytotoxicity and multimodal tumor-targeting capabilities. In combination with cusatuzumab, these cells demonstrated robust ADCC against CD70-positive RCC cells both in vitro and in vivo, significantly enhancing tumor cell killing compared to antibody monotherapy. Moreover, CD16HSC-NKT cells displayed improved persistence and functional stability, supporting sustained antitumor activity. Importantly, CD16HSC-NKT cells contributed to remodeling of the tumor microenvironment by selectively depleting immunosuppressive populations, including tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs). Safety assessments indicated a favorable profile, with no evidence of uncontrolled activation or off-target toxicity. Conclusions Collectively, our findings establish CD16HSC-NKT cells as a versatile and scalable cellular platform that synergizes with cusatuzumab to enhance therapeutic efficacy against RCC. This combinatorial strategy represents a promising approach to overcoming current limitations of monoclonal antibody therapy and advancing next-generation immunotherapies for solid tumors.
Yan-Ruide Li, Yi-Chen Zhu, Yu-Ning Chen et al.· The Oncologist· 0 citations
Summary Adoptive T cell therapy for solid tumors is limited by autologous manufacturing complexity and, in allogeneic settings, risks including graft-versus-host disease (GvHD), HLA restriction, and donor variability. We develop a scalable, feeder-free platform to differentiate gene-engineered hematopoietic stem and progenitor cells (HSPCs) into allogeneic, NY-ESO-1-specific cytotoxic T (AlloESO-T) cells. Product phenotype, function, tumor homing, and safety are assessed against solid tumor models and benchmarked to peripheral blood mononuclear cell (PBMC)-derived TCR-engineered T cells. AlloESO-T cells display a uniform cytotoxic phenotype, with dual tumor targeting through a transgenic TCR and natural killer receptors. Relative to PBMC-derived counterparts, AlloESO-T cells show superior cytotoxicity, selective solid-tumor homing, durable killing persistence, and resilience to immune evasion. They also maintain low GvHD and cytokine release syndrome risk, while retaining stable hypoimmunogenic features. These findings establish HSPC-derived AlloESO-T cells as an off-the-shelf, mono-specific cytotoxic T cell therapy with scalable manufacturing, enhanced efficacy, and improved safety, which support broad applicability of AlloESO-T cells across solid tumors.
Yi-Chen Zhu, Jia-Ji Yu, Y. J. Kim et al.· Cell Reports Medicine· 0 citations
The biology, disease-associated functions, and therapeutic targeting of nonclassical MHC-I molecules are synthesized, integrating immune checkpoint blockade, antibody-based therapeutics, and MR1- and CD1-restricted cellular immunotherapies into a unified framework.
