Precision Medicine Immuno-oncology – Harnessing immune system to fight cancer

The previous article on precision medicine was focused on Pharmacogenomics as a fundamental aspect of cancer therapeutics. In this sequel, emphasis would be on the role of immuno-oncology in personalization of cancer therapy, citing anti PD therapy as an example with hypothetical cases.

Overview of Immunotherapy

Immunotherapy is a novel approach in the field of precision onco-therapeutics. It employs stimulation of the body’s immune system using various techniques to boost immunity, such as Immune checkpoint inhibitors (ICI), Adoptive T-Cell therapy, Cancer vaccines and non-specific immune enhancers. Yet, the focus of this article is ICI which is more relevant for Precision Medicine – Immuno-oncology at the moment.

Despite the fact that the immune system is a body’s integral defense mechanism, what makes cancer cell escape immune attack and how the immune system can be harnessed to recognize and fight cancer cells is a complex question that needs insight of the tumour microenvironment (TME). Subsequently, cancer progression is not solely dependent on the characteristics acquired by tumour cells rather it is heavily influenced by its tumour biased microenvironment.

What is Tumour microenvironment (TME)?

TME is a multifaceted milieu comprising of a heterogenous cell population as depicted in the picture. Immune cells in the tumour vicinity possess tumour-killing and tumour-promoting functions. Although, tumour-killing cells (immune effectors) target and kill cancer cells in the early stages of tumour development, they eventually fail to recognise and eliminate them. Simply because the tumour killing function gets suppressed and tumour promoting function is favoured by TME. Understanding various mechanisms that cancer cells employ to escape immune attack, has led to the development of three immune hallmarks of cancer a) cancer cells can thrive in chronically inflamed environment b) it can mask itself from being recognised by immune cells and c) it can suppress immune responses (Federica Cavallo, et al., 2011) and TME plays a critical role in sustaining immune hallmarks. 

Abbreviations: M1, macrophage M1; M2, macrophage M2; MDSC, myeloid-derived-suppressor cells; NK - natural killer cell; Th - T helper; Treg - regulatory T cell; TC - lymphocyte T cytotoxic; B - B cell. (Image Credits: Hadi A. Goubran et al., 2014)

Importance of Immune checkpoints

Physiologically, there are certain immune checkpoints, such as PD1-PDL1 pathways, evolved to control the extent of inflammation at the location of antigen or foreign body invasion by protecting normal cells from immune attack. Cancer cells conveniently exploit such defense pathways to escape the battle with immune cells by over expressing certain molecules such as PD-L1 ligands. PD-L1 specifically binds to PD-1 receptors on the surface of activated T-cells and thereby inactivates it, called T-Cell Exhaustion. Some of the other checkpoints are CTLA4, TIM3, LAG3 and BTLA (Daqian Gu et al.), though, PD-L1 and CTLA4 have rapidly gained attention due to the development of monoclonal antibodies against PD-1/PDL1 and CTLA4.

Image credits: Anna Angelousi et al., 2018.

How immuno-oncology (IO) impacts precision medicine and vice versa?

In-depth understanding of immuno-oncology is a boon for precision medicine. Indeed, knowledge of patient’s genomics, immune profiles & immunogenomics altogether can provide greater insights on the strategy that cancer cells exercise to survive against the odds [It could be escaping immune surveillance or suppressing immune response itself]. Accordingly, when the reason for immune failure is understood, it is easier for physicians to adopt suitable therapy and precisely at this stage, precision medicine plays a key role in predicting immunotherapy outcomes.

Where does Immunotherapy stand in cancer therapeutics currently?

Despite good efficacy seen with Anti PD immunotherapy, its clinical use remains indefinite, since patient selection is a major challenge. Recently, randomized phase III clinical trials (KEYNOTE study) has demonstrated that patients who received pembrolizumab (Anti - PD1 antibody) with greater than 90% PD-L1 expression had an overall response rate (ORR) of 60% versus those between 50%-100% expression of PD-L1 had ORR of 32.7% (E.J. Aguilar et al., 2019). These results indicate that patient selection solely based on PD-LI biomarker show limited benefits and the underlying reason could be diverse. 

For example, consider a case where atezolizumab (Anti – PD-L1 antibody) did not prove beneficial in high PD-L1 condition, it could be simply because of low PD-1 levels, PD-1 being a receptor is the rate limiting step in the PD1-PDL1 pathway (Song JS et al., 2019). Therefore, having a high expression of PD-L1 in this case is irrelevant. In this scenario, immunogenomics (in addition to tumour genomics) of a patient might provide a broader perspective in understanding patient response to Immunotherapy.

Additionally, Tumour mutation burden (TMB), appears to be a promising biomarker and it has been hypothesized that tumour with higher TMB have more neoantigens that can be recognized by immune cells and thus respond better to checkpoint inhibitors. On the contrary, tumour with lower TMB have lesser neoantigens and fail to elicit T-cell infiltration into TME due to lack of immunogenicity. Furthermore, consider a patient with lower TMB and high PD-L1 expression and atezolizumab is advised. In this case, what could possibly happen is that T-cell infiltration being inadequate due to insufficient neoantigens and PD1 – PD-L1 pathway itself may be irrelevant in this context and atezolizumab therapy could remain unsuccessful. While TMB is an evolving biomarker for immunotherapy, its clinical evaluation considering variation across platforms such NGS/WES & definition of its optimum threshold is underway (Conor E. Steuer and Suresh S. Ramalingam, 2018). 

Other approaches such as immune profiling have also proven beneficial in cases where TMB and molecular biomarker fails to provide right insights on therapy outcomes. For example, in a case where high TMB and high PDL1 expression cannot explain atezolizumab therapy failure, immune profile may be used to understand immune strength of the patient (Lyons YA et al., 2017). 

On a concluding note, it is prudent to stimulate body’s immune system strategically to ensure success of immunotherapy and precision medicine is evolving with novel approaches to ensure accuracy.

One other approach, gut microbiomics, is being experimented currently to understand the biology of cancer and its application in the field of precision medicine. In the next article, I will focus on the role of the Gut microbiome in cancer and therapeutics.

Additional information

Immunogenomics: study of gene expression signature in different immune cell types in tumour microenvironment.

Immune profile: is immunohistochemistry-based study of immune strength of a patient using biopsy samples.

Abbreviations

PD-1: Programmed death-1 receptor

PD-L1: Programmed death Ligand 1

CTLA4: cytotoxic T-lymphocyte-associated protein 4

TIM3: T-cell immunoglobulin mucin-3

LAG3: Lymphocyte Activation Gene-3

BTLA: B And T Lymphocyte Associated protein

NGS: Next Generation Sequencing

WGS: Whole exome sequencing

References

Lyons YA, Wu SY, Overwijk WW, Baggerly KA, Sood AK. Immune cell profiling in cancer: molecular approaches to cell-specific identification. NPJ Precis Oncol. 2017 Aug 15;1(1):26.

Song JS, Kim D, Kwon JH, Kim HR, Choi CM, Jang SJ. Clinicopathologic Significance and Immunogenomic Analysis of Programmed Death-Ligand 1 (PD-L1) and Programmed Death 1 (PD-1) Expression in Thymic Epithelial Tumors. Front Oncol. 2019 Oct 15; 9:1055.

Conor E. Steuer and Suresh S. Ramalingam. Tumor Mutation Burden: Leading Immunotherapy to the Era of Precision Medicine? J Clin Oncol 2018;36(7):631–632.

Aguilar EJ, Ricciuti B, Gainor JF, Kehl KL, Kravets S, Dahlberg S, Nishino M, Sholl LM, Adeni A, Subegdjo S, Khosrowjerdi S, Peterson RM, Digumarthy S, Liu C, Sauter J, Rizvi H, Arbour KC, Carter BW, Heymach JV, Altan M, Hellmann MD, Awad MM. Outcomes to first-line pembrolizumab in patients with non-small-cell lung cancer and very high PD-L1 expression. Ann Oncol. 2019 Oct 1;30(10):1653-1659.

Cavallo F, De Giovanni C, Nanni P, Forni G, Lollini PL. 2011: the immune hallmarks of cancer. Cancer Immunol Immunother. 2011 Mar;60(3):319-26.

Hadi A Goubran, Rami R Kotb, Julie Stakiw, Mohamed E Emara, Thierry Burnouf. Regulation of tumor growth and metastasis: the role of tumor microenvironment. Cancer Growth Metastasis. 2014 Jun 2; 7:9-18.

Anna Angelousi 1, Eleftherios Chatzellis, Gregory Kaltsas. New Molecular, Biological, and Immunological Agents Inducing Hypophysitis. Neuroendocrinology. Epub 2017 Aug 8 2018;106(1):89-100.

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