Meta-analysis of neoadjuvant immunotherapy for non-metastatic colorectal cancer

Abstract

BackgroundImmunotherapy has been approved for the treatment of metastatic colorectal cancer. The efficacy and safety of neoadjuvant immunotherapy for the treatment of non-metastatic colorectal cancer remains unclear. We tried to explore clinical effect of neoadjuvant immunotherapy in the treatment of non-metastatic colorectal cancer.MethodsWe searched the databases (PubMed, Wanfang Embase, Cochrane Library and China National Knowledge Infrastructure databases) to obtain suitable articles up to September 2022. The primary outcomes of pathological complete response (pCRs), major pathological response (MPR), objective response rate (ORR), R0-resection and anus preserving rate were collected and evaluated. Secordary outcomes (pCRs and MPR) of subgroup analysis between deficient mismatch repair/microsatellite instability-high group (dMMR/MSI-H) and proficient mismatch repair/microsatellite stable group (pMMR/MSS) and outcomes for rectal cancer were analyzed for the final results.ResultsWe included ten articles and 410 cases of non-metastatic colorectal cancer with neoadjuvant immunotherapy. There were 113 (27.5%) cases with the dMMR/MSI-H status and 167 (40.7%) cases with the pMMR/MSS status. pCRs was found in 167/373 (44.6%) patients (ES: 0.49, 95% CI: 0.36 to 0.62, P<0.01, chi2 = 65.3, P<0.01, I2 = 86.2%) and MPR was found in 194/304 (63.8%) patients (ES: 0.66, 95% CI: 0.54 to 0.78, P<0.01, chi2 = 42.55, P<0.01, I2 = 81.2%) with the random-effects model and huge heterogeneity. In the subgroup analysis, pCRs was higher in the dMMR/MSI-H group than the pMMR/MSS group in the fixed-effects model with minimal heterogeneity (OR: 3.55, 95% CI: 1.74 to 7.27, P<0.01, chi2 = 1.86, P=0.6, I2 = 0%). pCRs was found in 58/172 (33.9%) rectal cancer patients (ES: 0.33, 95% CI: 0.26 to 0.40, P<0.01, chi2 = 3.04, P=0.55, I2 = 0%) with the fixed-effects model and little heterogeneity.ConclusionNeoadjuvant immunotherapy could increase pCRs and MPR rate for non-metastatic colorectal cancer. Neoadjuvant immunotherapy could achieve better pCRs rate in dMMR/MSI-H group than in the pMMR/MSS group. Neoadjuvant immunotherapy could be another treatment option for non-metastatic colorectal cancer.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/#myprospero, identifier CRD42022350523.

Cellular mechanisms underlying beneficial versus detrimental effects of bacterial antitumor immunotherapy

“…Examination of tumors at the endpoint of tumor growth (15-20 days after IT Lm injection) also revealed a significant increase in the infiltration of CD8 T cells, but not a significant increase in CD4 T cells, in tumors of mice treated with IV+IT Lm compared to other groups (Figures 5A-C, S5A-B). Intratumoral regulatory T cells (Tregs) that are known to be immunosuppressive in the TME, were not significantly reduced with the IV+IT regimen compared to IV or IT alone, although they were reduced compared to the PBS treated mice (Figures S5C-D) 15,[31][32][33][66][67][68] . Next, we assessed the functionality of the CD8 T cells by IFNγ and TNFα production 8 days after IT Lm or PBS injection.…”

“…Recently, the discovery that bacteria naturally colonize many solid tumors has uncovered the potential of bacteria to serve as a drug delivery system or even as a cancer detection probe [5][6][7][8][9][10][11][12][13][14] . Improved methods to genetically manipulate bacterial genomes has also made it feasible to engineer bacteria that express tumor antigens, cytokines or cytotoxic proteins to control cancer [15][16][17][18] . Hence, multiple breakthroughs in manipulating bacteria and their activity in the tumor microenvironment has reignited interest in the potential for effective bacterial-based cancer immunotherapies.…”

“…Effective antitumor immunity requires a robust pool of antitumor immune cells and a permissive tumor microenvironment (TME) that allows for antitumor immune cells to function 15,[31][32][33] . However, the TME is often highly immunosuppressive, allowing cancer cells to evade the immune system despite the presence of tumor-specific cytotoxic CD8 T cells 34,35 .…”

Evolution of therapy for locally advanced rectal cancer

“…The use of these inhibitors in MMR deficient tumors, significantly reduced disease progression and incidence of death with increasing response rates compared to MMR proficient tumors. 38,39 There are also studies that have observed complete response following immune-checkpoint inhibitor therapy without the need for chemoradiation or surgery while still preventing local or distant recurrence in 1 year following treatment. 40,41 Given this, it is important to understand the genetics of rectal tumors as it can have an impact on management.…”

“…There is data comparing the use of immune‐checkpoint inhibitors in patients with MMR deficient and MMR proficient colorectal cancer. The use of these inhibitors in MMR deficient tumors, significantly reduced disease progression and incidence of death with increasing response rates compared to MMR proficient tumors 38,39 . There are also studies that have observed complete response following immune‐checkpoint inhibitor therapy without the need for chemoradiation or surgery while still preventing local or distant recurrence in 1 year following treatment 40,41 .…”