Targeting Metastatic Colorectal Cancer with Immune Oncological Therapies

Abstract

Metastatic colorectal cancer carries poor prognosis, and current therapeutic regimes convey limited improvements in survival and high rates of detrimental side effects in patients that may not stand to benefit. Immunotherapy has revolutionised cancer treatment by restoring antitumoural mechanisms. However, the efficacy in metastatic colorectal cancer, is limited. A literature search was performed using Pubmed (Medline), Web of Knowledge, and Embase. Search terms included combinations of immunotherapy and metastatic colorectal cancer, primarily focusing on clinical trials in humans. Analysis of these studies included status of MMR/MSS, presence of combination strategies, and disease control rate and median overall survival. Evidence shows that immune checkpoint inhibitors, such as anti-PD1 and anti-PD-L1, show efficacy in less than 10% of patients with microsatellite stable, MMR proficient colorectal cancer. In the small subset of patients with microsatellite unstable, MMR deficient cancers, response rates were 40-50%. Combination strategies with immunotherapy are under investigation but have not yet restored antitumoural mechanisms to permit durable disease regression. Immunotherapy provides the potential to offer additional strategies to established chemotherapeutic regimes in metastatic colorectal cancer. Further research needs to establish which adjuncts to immune checkpoint inhibition can unpick resistance, and better predict which patients are likely to respond to individualised therapies to not just improve response rates but to temper unwarranted side effects.

Keywords: anti-PD1; colorectal cancer; immune checkpoint inhibitors; immunotherapy; metastases; microsatellite instability; mismatch repair; targeted therapy; tumour microenvironment; tumour-associated macrophages.

Figure 1

Cellular interactions in colorectal cancer metastasis. This proposed model illustrates the key changes in immune cells in an immunosuppressive tumour microenvironment, preventing surveillance, control and elimination of invading metastatic tumour cells. IDO, indoleamine 2,3-dioxygenase; IL, interleukin; MDSC, myeloid derived suppressor cells; MMP, matrix metalloproteinase; NO, nitric oxide; PD-1, programmed cell death receptor 1; PD-L1, programmed cell death receptor ligand 1; Treg, T regulatory cell; TAM, tumour associated macrophage; TAN, tumour-associated neutrophil; TGF, transforming growth factor; VEGF, vascular endothelial growth factor.

Figure 2

Proposed model for immunotherapy in metastatic colorectal cancer. TME, tumour microenvironment; PD-1, programmed cell death receptor 1; PD-L1, programmed cell death receptor ligand 1; CTLA4, T-lymphocyte associated protein 4; LAG3, lymphocyte activating gene 3; TIM3, T cell immunoglobulin mucin receptor 3; CSF1R, colony-stimulating factor 1 receptor; IDO, indoleamine 2,3-dioxygenase; TGF, transforming growth factor; CAR-T, chimeric antigen receptor T-cell; TACE, transhepatic arterial chemoembolisation; RFA, radiofrequency ablation; KRAS, Kirsten rat associated sarcoma; BRAF, B-type RAF; POLE, DNA polymerase epsilon.