Total neoadjuvant treatment and PD-1/PD-L1 checkpoint inhibitor in locally advanced rectal cancer

Abstract

For local advanced rectal cancer (LARC), total neoadjuvant treatment (TNT) has shown more complete response (CR), reduced risk of distant metastasis (DM) and increase of the sphincter preservation rate. Now it is the one and only recommendation for high-risk group of LARC according to National Comprehensive Cancer Network (NCCN) rectal cancer guideline, while it is also preferentially recommended for low-risk group of LARC. TNT is also beneficial for distant rectal cancer patients who have need for organ preservation. Even though the prognostic value of programmed cell death-ligand 1 (PD-L1) in the neoadjuvant chemoradiotherapy (NACRT) of LARC patients is undetermined yet, the combination of NACRT and programmed cell death-1 (PD-1)/PD-L1 antibodies seem bring new hope for mismatch repair proficient (pMMR)/microsatellite stable (MSS) LARC patients. Accumulating small sample sized studies have shown that combining NACRT with PD-1/PD-L1 antibody yield better short-term outcomes for pMMR/MSS LARC patients than historic data. However, ideal total dose and fractionation of radiotherapy remains one of unresolved issues in this combination setting. Thorough understanding the impact of radiotherapy on the tumor microenvironment and their interaction is needed for in-depth understanding and exquisite design of treatments combination model.

Synergistic Immunoregulation: harnessing CircRNAs and PiRNAs to Amplify PD-1/PD-L1 Inhibition Therapy

“…Consequently, there has been a concerted effort to investigate combination therapies aimed at augmenting the response rates of PD-1/PD-L1 inhibitors. [6][7][8][9] As a key point of PD-1/PD-L1 inhibition therapy, the level of PD-L1 expression has been found to influence therapeutic outcomes. [42][43][44][45][46] For instance, the evidence indicates that tumors exhibiting higher levels of PD-L1 expression tend to exhibit a more favorable response to PD-1/PD-L1 inhibition therapy.…”

Systemic Inflammatory Response Following Preoperative Chemoradiotherapy Can Affect Oncologic Outcomes in MSI-H/dMMR Rectal Cancer

“…Therefore, the identification of immune response related biomarkers is essential for facilitating patient selection and increasing the clinical benefit from a novel treatment including ICIs in rectal cancer. 7 8 …”

Editorial: The role of radiotherapy in reshaping tumor immune microenvironment

“…Due to the synergistic effect between RT and immunotherapy, RT can release tumor antigens, reshape the immune microenvironment, and increase the anti-tumor immune response, thereby producing a synergistic therapeutic effect. Numerous prospective phase II studies suggest that the combination of RT with immunotherapy, used for pMMR/MSS locally advanced rectal cancer, has achieved a higher rate of complete pathological response (pCR) ( 6 ).…”

“…In recent years, numerous in vivo studies have revealed the synergistic tumoricidal effects of combining RT with PD-1/-L1 inhibitors. The dynamic nature of the PD-1/-L1 axis, however, has confounded efforts towards a consensus on the optimal timing or dose-fractionation strategy for doing so ( 6 ). Understanding the synergistic effects of combining RT with PD-1/PD-L1 blockade requires investigation into the dynamic changes in tumor immune status and circulating biomarkers induced by RT in relation to PD-1/PD-L1 expression.…”