CLINICAL TRIAL article
Front. Immunol.
Sec. Cancer Immunity and Immunotherapy
This article is part of the Research TopicAdvancing Next-Generation Immunotherapy and Biomarker Discovery: Pioneering the Future of Treatment Strategies in Solid TumorsView all 4 articles
Intratumoral delivery of PD-1/PD-L1and CTLA-4 inhibitors for recurrent/refractory solid tumors: a proof-of-concept treatment strategy
Provisionally accepted
Hongye Tan1
Noor Ul Huda Shah1*
Bingjia He1
Tianrun Liu2Tianheng Li1Manting Liu1
Yingying Gu3
Zhi Cheng1
Yongqiong Ou1Junhao Huang1Ming Li1Shenghua Zuo1Dongni Chen1Ruzhai Qin1Hainan Yang1Xufeng Li1Hui Lian1
Qing-de Wu4
Rom Leidner5Rui Chen3
Ankui Yang3
Lili Yang3
Zhenfeng Zhang1*- 1Guangzhou Medical University Second Affiliated Hospital, Guangzhou, China
- 2Sun Yat-sen University Sixth Affiliated Hospital, Guangzhou, China
- 3Sun Yat-Sen University, Guangzhou, China
- 4Guangzhou University of Traditional Chinese Medicine ShunDe Traditional Chinese Medicine Hospital, Foshan, China
- 5Earle A Chiles Research Institute, Portland, United States
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Abstract Immune checkpoint inhibitors (ICIs) are a leading immunotherapy. However, their application has not universally translated into significant benefits. A substantial number of patients either show resistance or relapse post-initial response, which emphasizes the need for more sophisticated therapeutic approaches. The drug combination is one promising route. The cancer-immunity cycle reveals the anti-tumor immune-related rate limiting steps of tumors. Theoretically, focusing on different phases of the cancer-immunity cycle can enhance therapeutic results. However, combination therapy includes a higher risk of adverse effects, which demand careful consideration. In this study, we combined programmed death-1 (PD-1)/ programmed death ligand-1 (PD-L1) and cytotoxic T Lymphocyte antigen 4 (CTLA-4) inhibitors with a reduced dosage but via an intra-tumor drug delivery strategy to treat recurrent/refractory (R/R) advanced solid tumors. This clinical trial had registered (ClinicalTrials.gov number: NCT03755739). During this study, intratumoral co-delivery of PD-1/PD-L1 and CTLA-4 inhibitors with reduced dosage shows promising efficacy and safety in R/R advanced solid tumors. Herein, we report four patients with favorable outcomes (complete response for more than 2 years).
Keywords: PD-1/PD-L1 inhibitors, CTLA-4 inhibitor, Recurrent/Refractory advancedsolid tumor, INTRATUMORAL INJECTION, Clinical Trial
Received: 20 Jul 2025; Accepted: 26 Nov 2025.
Copyright: © 2025 Tan, Shah, He, Liu, Li, Liu, Gu, Cheng, Ou, Huang, Li, Zuo, Chen, Qin, Yang, Li, Lian, Wu, Leidner, Chen, Yang, Yang and Zhang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Noor Ul Huda Shah
Zhenfeng Zhang
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