Principles of cancer immunotherapy: exploring the immune response against cancer
Module 1: Immunotherapy principles
Click on the modules below to explore how the immune system fights cancer and how tumours may evade this response.
The process by which the immune system kills cancer cells is described by the cancer-immunity cycle
The cancer immunity cycle describes a natural process of how one’s own immune system protects the body against cancer. When performing optimally, the cycle is self-sustaining. With subsequent revolutions of the cycle, the breadth and depth of the immune response can be increased.1
By disrupting the processes of the cancer immunity cycle, tumours can avoid detection by the immune system and limit the extent of immune destruction.1-3
The growing body of research into the mechanisms of immune evasion by tumours has even led to its addition as an emerging hallmark of cancer, a distinct biological capability co-opted by tumours to grow and metastasize.3
The immune response against the tumour is diminished through the disruption of multiple processes:1-3
Figure 2: Evasion of immune destruction.1-3
Exploring the pathways underlying cancer immune evasion
Tumours can inhibit the antitumor immune response by disrupting the balance governing the steps of the cancer immunity cycle through multiple mechanisms. The goal of cancer immunotherapy research is to understand these mechanisms to counteract the tumour’s ability to suppress the immune response. These pathways may include1,4
- Stimulatory factors that promote the immune response against cancer
- Inhibitory factors that keep the cycle in check to prevent autoimmunity
Figure 3: Stimulatory and inhibitory factors involved in the cancer immunity cycle1,5-7
ATP=adenosine triphosphate; BTLA=B- and T-lymphocyte attenuator; CDN=cyclic dinucleotide; CSF-1R=colony-stimulating factor 1; CTLA4=cytotoxic T-lymphocyte antigen-4; CXCL/CCL=chemokine motif ligands; GITR=glucocorticoid-induced TNFR family-related gene; HMGB1=high-mobility group protein B1; HVEM=herpes virus entry mediator; ICAM1=intracellular adhesion molecule 1; IDO=indoleamine 2,3-dioxygenase; IFN=interferon; IL=interleukin; LAG-3=lymphocyte-activation gene 3 protein; LFA1=lymphocyte function-associated antigen-1; MIC=MHC class I polypeptide-related sequence protein; PD-L1=programmed death-ligand 1; TGF=transforming growth factor; TIM-3=T-cell immunoglobulin domain and mucin domain-3; TLR=toll-like receptor; TNF=tumour necrosis factor; VEGF=vascular endothelial growth factor; VISTA=V-domain Ig suppressor of T-cell activation.
Cancer immunotherapy strategies are designed to engage the immune system against tumours. This approach is unique in the oncology setting and introduces new considerations for cancer management:2,8
Duration of response
The immune response has the ability to adapt with cancer as it evolves, and can become self-propagating once the cancer immunity cycle is initiated. Immune-directed strategies aim to leverage these attributes, with the goal of inducing a durable antitumour effect.1,4,9
T-cell infiltration to the tumour site may cause an apparent increase in tumour size or the appearance of new lesions. This inflammatory effect can be misinterpreted as progressive disease, as it can be difficult to differentiate the different cell types in radiographic imaging. New criteria have been developed to better capture immune-related response patterns, and may guide evaluation of immunotherapies in clinical trials, and potentially in clinical care8,10
Figure 4: Tumour pseudo-progression.
Immune-related adverse events
While the goal of cancer immunotherapy research is to understand how to activate specific components of the immune response, the potential for off-target effects exists. Adverse event profiles may vary among different immune-directed strategies. As strategies grow more targeted, the recognition and management of immune-related adverse events will evolve.1,2
- Chen DS, Mellman I. Oncology meets immunology: the cancer-immunity cycle. Immunity. 2013;39:1-10. PMID: 23890059
- Mellman I, Coukos G, Dranoff G. Cancer immunotherapy comes of age. 2011;480:480-489. PMID: 22193102
- Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. 2011;144:646-674. PMID: 21376230
- Chen DS, Irving BA, Hodi FS. Molecular pathways: next-generation immunotherapy—inhibiting programmed death-ligand 1 and programmed death-1. Clin Cancer Res. 2012;18:6580-6587. PMID: 23087408
- US. National Institutes of Health: Study NCT02471846 on ClinicalTrial.gov. Accessed June 15, 2016.
- US. National Institutes of Health: Study NCT02543645 on ClinicalTrial.gov. Accessed June 15, 2016.
- Roche, Product development portfolio. Accessed June 15, 2016.
- Hoos A, Eggermont AM, Janetzki S, et al. Improved endpoints for cancer immunotherapy trials. J Natl Cancer Inst.2010;102:1388-1397.PMID: 20826737
- Topalian SL, Weiner GJ, Pardoll DM. Cancer immunotherapy comes of age. J Clin Oncol.2011;29:4828-4836. PMID: 22042955
- Wolchok JD, Hoos A, O’Day S, et al. Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin Cancer Res.2009;15:7412-7420. PMID: 19934295