Complete response in patients with locally advanced rectal cancer after neoadjuvant treatment with nivolumab

Abstract

Introduction: PD-1 inhibitors have been approved for the treatment of dMMR patients with metastatic colorectal cancer, but the efficacy of neoadjuvant treatment with PD-1 in dMMR locally advanced rectal cancer (LARC) patients has not yet been defined. Patients and methods: Two patients with LARC received Nivolumab as neoadjuvant treatment in July 2017. Whole-exome sequencing (WES) and multiplex immunofluorescence analysis were performed. Results: Of the two patients, one achieved pathological complete response after six cycles of nivolumab followed by surgery. The other patient was confirmed to be clinical complete response after six cycles of nivolumab. "Watch and wait" strategy was performed for anal preservation. WES showed high tumor mutation burden. Multiplex immunofluorescence analysis showed immune microenvironment alternation between pretreatment specimen and post-treatment specimen. Conclusion: Neoadjuvant nivolumab induced complete response in both of the two patients with LARC. Immunotherapy might be an alternative strategy for neoadjuvant treatment for dMMR/MSI rectal cancer.

Keywords: Locally advanced rectal cancer; complete response; neoadjuvant treatment; nivolumab.

Figure 1.

Radiologic and pathological response to neoadjuvant treatment with nivolumab. Panel A shows pelvic MRI of patient 1 with stage cT4bN2M0 rectal cancer before and after the administration of nivolumab. In the upper row, the pretreatment scan shows a large mass in the upper middle of rectum was adhered to left seminal vesicle gland, the posterior wall of the bladder and the presacral space (arrow). The distance from inferior margin of tumor to the anal verge was 6.4 cm and the tumor length was 8.0 cm. A scan performed before surgery shows greatly shrinkage of the tumor. In the lower row, shown are representative sections of tumor specimens obtained from patient 1 before the administration of nivolumab (left) and after the administration (right) (hematoxylin and eosin staining). This patient had 100% pathological regression of the primary tumor. Panel B shows Pelvic MRI of patient 2 with stage cT4bN2M0 rectal cancer, who received six cycles of nivolumab as neoadjuvant treatment. In the upper row, before the infusion of nivolumab (left), the tumor grows out of intestine and invaded the vaginal inferior wall, the perineal shallow area, the posterior wall of the vaginal vestibule, the anal canal, and the right levator ani muscle (arrow). After six cycles of nivolumab, no extraluminal infiltration was observed. The lesion was significantly shrunk and scarring. In the lower row, shown are representative sections of tumor specimens from patient 2 before the administration of nivolumab (left) and after administration (right) (hematoxylin and eosin staining). Tumor cells are present throughout the pretreatment specimen, whereas in the post-treatment biopsy specimen, there were no viable cancer cells.

Figure 2.

Pathological assessment of response to neoadjuvant blockade of PD-1. Multiplex immunofluorescence staining was performed on specimens obtained from patient 1 (upper row) and patient 2 (lower row) before (left) and after (right) neoadjuvant administration of nivolumab. With this staining technique, visible structures include cytokeratin (CK) positive tumor cells (magenta), DAPI positive cells (dark blue), CD68+ macrophages (green), FoxP3+ regulatory T cells (light-blue), CD8 + T cells (purple), PD-1 + cells (yellow-green), and PD-L1 + cells (orange). In the pretreatment specimen, PD-L1 positive and CD68+ macrophages abutting PD-1 positive, CD8 + T cells. There are multiple foci where PD-L1 and PD-1 are expressed in close proximity to each other. After administration of nivolumab, CD8+ and PD-1+ immune cells infiltration was observed. PD-L1 expression was observed on macrophages and other infiltrating immune cells.