What this Trial Is About

Colorectal cancer (CRC) ranks as the fifth most common malignant tumor in the Chinese population. In current clinical practice, standard first- and second-line treatments for metastatic microsatellite-stable (MSS)/proficient mismatch repair (pMMR) CRC are based on multi-drug combination chemotherapy regimens combined with targeted therapies. These regimens include fluoropyrimidine-based chemotherapy (5-fluorouracil \[5-FU\], leucovorin, or capecitabine) in combination with oxaliplatin or irinotecan, with or without targeted monoclonal antibodies. After disease progression following second-line treatment, the approved treatment options in China include regorafenib, fruquintinib, and TAS-102; however, their clinical benefits remain unsatisfactory, with objective response rates (ORR) of 1-4%, progression-free survival (PFS) of 2-3 months, and overall survival (OS) of 6-9 months according to the respective drug labels. Immunotherapy is currently approved only for metastatic CRC with microsatellite instability-high (MSI-H) or deficient mismatch repair (dMMR) status. In summary, the treatment efficacy for advanced CRC remains limited, highlighting the urgent need for novel drugs and therapeutic strategies to improve patient outcomes. IBI363 is a recombinant bispecific molecule consisting of an anti-programmed death receptor 1 (PD-1) antibody fused with interleukin-2 (IL-2), administered as an injectable formulation. It blocks the PD-1/PD-L1 pathway while activating the IL-2 signaling pathway, thereby reversing T-cell exhaustion and promoting T/NK cell activation. As of July 31, 2023, a total of 169 participants were enrolled in the CIBI363A102 study, including 22 participants in Part A (accelerated titration and BOIN phase) and 147 in Part B (dose expansion phase). Regarding efficacy, in the dose-escalation phase, 21 participants were evaluable for efficacy, with three participants in the 100-300 μg/kg QW dose group achieving a best tumor response of partial response (PR). In the dose-expansion phase, 76 participants were evaluable for efficacy, with six participants in the 100-1000 μg/kg QW dose group achieving PR. It is well established that the immune system can eliminate tumor cells through the cancer-immunity cycle. However, this process is not sustained, as tumors can gradually shape the tumor immune microenvironment (TIME) into an immunosuppressive state to counteract host immunity. The balance between pro-tumor and anti-tumor inflammatory mediators may determine tumor progression (Figure 1). Anti-tumor immune cells primarily include effector T cells (such as cytotoxic CD8+ T cells and effector CD4+ T cells), natural killer (NK) cells, dendritic cells (DCs), and M1-polarized macrophages. Pro-tumor immune cells mainly consist of regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs), M2-polarized macrophages, N2-polarized neutrophils, and type 2 innate lymphoid cells (ILC2s). Tumors have evolved various mechanisms to evade immune surveillance, such as defective antigen presentation, upregulation of negative immune regulatory pathways, and recruitment of pro-tumor immune cells. As a result, the function of anti-tumor immune cells is suppressed, and the anti-tumor immune response is difficult to sustain. The goal of immunotherapy is to restore the cytotoxic function of anti-tumor immune cells, particularly cytotoxic T lymphocytes (CTLs), against tumors. Therefore, investigating the function and mechanisms of different immune components within the TIME will help improve immunotherapy response rates and facilitate the development of novel immunotherapeutic strategies. Figure 1.Tumor-associated immune cells in the tumor microenvironment With the rapid development and iteration of omics technologies such as multiplex immunohistochemistry (mIHC), single-cell transcriptome sequencing (scRNA-seq), and spatial transcriptome sequencing (stRNA-seq), we can now investigate individual cells or specific cellular subpopulations at a higher resolution. This study aims to enroll patients with advanced MSS/pMMR colorectal cancer (CRC) and perform single-cell transcriptome sequencing on baseline and follow-up tissue samples. The objective is to dynamically map the spatial heterogeneity and evolutionary landscape of the tumor immune microenvironment (TIME) throughout the disease course, from initial diagnosis to disease progression. By analyzing TIME at different time points, we seek to elucidate the potential mechanisms of action of IBI363 in colorectal cancer. Furthermore, we will leverage spatiotemporal transcriptomic analyses to validate cell subpopulation interactions in situ within the tumor microenvironment.

Exploration of the Dynamic Changes and Mechanisms of the Immune Microenvironment in Advanced Colorectal Cancer Treated With IBI363 Combination Therapy