Combination regimens with PD-1/PD-L1 immune checkpoint inhibitors for gastrointestinal malignancies

Abstract

Gastrointestinal (GI) malignant neoplasms have a high global incidence and treatment prospects for patients with advanced GI tumors are dismal. PD-1/PD-L1 inhibitors emerged as a frontline treatment for several types of cancer. However, the shortcomings of PD-1/PD-L1 inhibitors have been observed, including low objective response rates and acquired tumor resistance, especially in patients receiving PD-1/PD-L1 inhibitors as a single treatment. Accumulating evidence from clinical trials increasingly suggests that combined immunotherapies enhance therapeutic responses in patients with malignances, especially for GI tumors which have a complex matrix, and significant molecular and immunological differences. Preclinical and clinical studies suggest there are advantages to combined immunological regimens, which represents the next logical step in this field, although further research is necessary. This literature review explores the current limitations of monotherapies, before critically discussing the rationale behind combination regimens. Then, we provide a summary of the clinical applications for gastrointestinal cancers.

Keywords: Clinical application; Clinical trial; Combination immunotherapy; Gastrointestinal malignancies; Immune checkpoint inhibitor; PD-1/PD-L1 blockade; Rationale.

Fig. 1

Limitations of PD-1/L1 blockade monotherapy and advantages of combination immunotherapy. There are currently many limitations of single-drug therapy with PD-1 inhibitors, including the five aspects shown above, but combined immunotherapy may help to solve some of the limitations of single-drug therapy. Specific combination immunotherapy strategies include combined radiotherapy, chemotherapy, targeted therapy, and another related immunotherapy

Fig. 2

Combination strategy in tumor immune circulation. As described in the cancer-immunity cycle, there are three main stages involving the presentation of tumor cell antigen by the APC cells, primary activation of T cells in the lymph node, and migration of cytotoxic T cells from the vessel to kill the tumor cells. Several other types of antitumor therapy, such as radiotherapy, chemotherapy, another immunotherapy, and targeted therapy, can participate in the cancer-immunity cycle by destroying the tumor matrix, increasing antigen exposure, removing the immunosuppressive factors, promoting the infiltration of T cells, etc.