From puzzle pieces to personalized medicine: how biomarkers tailor cancer therapy

By: Janniek Mors

A Personal Puzzle

Cancer is a scary and often unpredictable disease which can be different from person to person. We could imagine that every organ in the body is built from a large number of puzzle pieces. Just as the most complex puzzles come with many pieces in different shapes and colours, cells in our organs possess numerous properties that contribute to the organ’s overall function. However, sometimes cells acquire aberrant properties which might lead to the development of cancer. Additionally, within a tumour, there are differences in the genetic and molecular characteristics of the individual cells¹.

Each person’s cancer has a unique combination of pieces in their puzzle. Partly due to this complexity and heterogeneity, it is challenging to develop effective one-size-fits-all therapy that targets all the cells within the tumour. Therefore, it has been suggested that treatment should be tailored to individual patients based on the specific characteristics of their puzzle. This aspect of cancer treatment follows the idea of personalised medicine and has the potential to improve survival rates². By using personalised medicine, physicians can identify the most effective therapies for each patient and avoid treatments that are unlikely to work. In this article we will discuss how researcher’s decipher the pieces, use them for early detection or exploit them to personalise the treatment.

As illustrated below in Figure 1, it is as if some of the puzzle pieces have turned into a different shape or colour, making it harder to comprehend the puzzle as a whole. While these ‘wrong’ cancer puzzle pieces might still fit the puzzle, it is obvious that they are different from the healthy pieces in features at a molecular, or genetic level. Solid tumours, like those that form in the lungs are very heterogeneous between patients.

The Disguised Tumor

The original approaches that physicians use to fight cancer are described as ‘the pillars of cancer treatment’ and include surgery, radiation therapy, and chemotherapy. In recent years, a new pillar of cancer treatment has emerged: immunotherapy³. The notion that the immune system plays a key role in the natural defense against infections and malignancies was already established more than 50 years ago. During the past decades, research revealed that immune cells such as T-cells, B-cells, and natural killer cells, work together to recognize and destroy foreign substances in our body⁴. Think of your immune cells as protectors of the puzzle; they act as guards that are always on the lookout for invader pieces, like viruses, bacteria and cancer cells (Figure 2A, B). Once they recognize such invaders, the immune cells will rapidly replicate to be able to attack and neutralize the enemy as fast as possible. Additionally, our immune system has mechanisms to prevent it from attacking our own healthy cells. These mechanisms involve proteins on the outside of the cell called ‘checkpoints’ which can signal immune cells to stop the attack and prevent excessive damage to normal tissue⁵. Sometimes, cancer puzzle pieces trick the immune system by expressing these checkpoint proteins (Figure 2C). With this disguise, they avoid being recognized as an invader and may grow uncontrollably, leading to cancer. One form of immunotherapy, immune checkpoint inhibition (ICI), works by blocking the checkpoints with antibodies⁶. Due to these antibodies, the immune system’s ability to recognize and destroy cancer puzzle pieces is enhanced. In other words, they remove the ‘disguise’ that cancer cells use to hide from the immune system (Figure 2D). Unfortunately, the normal regulation of the immune system is disrupted by the checkpoint inhibitors. As a result, patients who do not respond to this therapy are potentially at risk for experiencing side effects like autoimmune reactions, where the immune system also attacks healthy tissue. Regardless, over the last decade, the introduction of ICI has had a revolutionary impact on the treatment of cancers and can induce durable responses in different cancer types and stages⁷.

Deciphering the Tumour

ICI functions by boosting the activity of immune system that target cancer puzzle pieces. With each patient and tumour being unique, gaining an understanding of the composition of the patient’s puzzle can help identify the individuals who will benefit from a certain therapy and those who will not⁸. The implementation of personalised medicine has the potential to achieve this goal, minimizing the negative side effects associated with ICI while enhancing outcomes. For such implementation, biomarkers can be used. Biomarkers are biological indicators (or puzzle features) that can help to accurately predict the composition of the patient’s own puzzle that leads to disease. By analysing a small tumour sample prior to treatment, scientists aim to decipher the tumour’s characteristics and its surroundings. Subsequently, these characteristics are assessed for their connection to the patient’s disease progression.

There are two types of biomarkers used to predict therapy responses: cancer-specific biomarkers and immunological biomarkers. For cancer-specific biomarkers, scientists look for information about the tumour’s characteristics, like its genes, protein expression and cellular processes. For instance, patients whose tumour express the checkpoint proteins that are targeted by the ICI, have a better chance of benefiting from therapy than patients whose tumour does not⁹. In clinical practice, this means that physicians make decisions on whether a particular patient should receive ICI or not based on the expression levels of the checkpoint proteins. While these cancer-specific biomarkers are very helpful, it is crucial to recognize that immune puzzle pieces play a significant role in anti-tumour responses during ICI treatment, too. As a result, it is equally, if not more, important to consider immunological biomarkers to help choose the best treatment for each patient.

Immunological biomarkers assess the presence of immune cells in and around the tumour. Studies have reported that higher levels of immune infiltration in the tumour often correlate with improved treatment outcomes, suggesting potential benefits from ICI¹⁰. Therefore, assessment of pre-existing immune puzzle pieces provides valuable information regarding the suitability of ICI for the individual patient. In conclusion, both cancer-specific and immunological biomarkers assist physicians in implementing personalised medicine and making informed decisions regarding the administration of ICI.

Missing Pieces

Assessment of cancer-specific and immunological biomarkers currently relies on invasive tumour tissue biopsies. Moreover, despite the current implementation of these biomarkers to identify patients who are likely to benefit from therapy, they fail to consistently predict clinical outcomes⁸. The inconsistent results could potentially be explained by the biopsied tissue only containing a selection of the puzzle pieces present in the tumour. Considering the heterogeneity within the tumour there is a risk that one singular biopsy may not be representative for the complexity of the puzzle. This may lead to inaccurate predictions of response to treatment. This goes hand in hand with the importance of the timing of the biopsy as the infiltration of immune puzzle pieces may change over time. This means that the condition of the tumour before treatment may not accurately reflect its condition during treatment, making the accuracy of pre-treatment tissue biopsies inconsistent. This creates difficulties in identifying the best treatment for each patient and switching therapies if needed.

Instead of only analysing a small piece of the tumour before treatment, it has been proposed to fill in the missing pieces by monitoring the patient’s tumour throughout treatment^11,12. Unfortunately, obtaining tumour tissue biopsies is an invasive process, making repeated monitoring undesirable. A more consistent and less invasive way to predict treatment success is needed. Luckily, recent advances in technologies have enabled the detection of biomarkers in blood samples¹².

Putting the Pieces Together

Multiple innovative technologies have enabled the identification and quantification of different types of puzzle pieces in a tissue sample or blood sample. Using these techniques, researchers have tried to determine whether immune cells that can specifically recognize tumour cells are also detectable in the blood. Looking back at the big puzzle in Figure 2A, they compared the colours and shapes of the immune puzzle pieces that were infiltrating the tumour to immune puzzle pieces that were circulating in the blood¹³. Their findings suggest that throughout the course of immunotherapy, the immune cells that recognized and may kill the tumour are detectable in the blood as well¹⁴. All this highlights the potential of monitoring immune cells in the blood to predict ongoing anti-tumour responses. Ideally, this allows for the collection of blood samples prior and during anti-cancer treatment followed by the evaluation of specific immune cells in the blood. This data could then be used to distinguish the patients who are responding to the treatment from those who are not (Figure 3).

Although much remains to be elucidated, it is clear that each patient’s puzzle is distinct and undergoes changes over time. While cancer treatment is progressing – there is a need for both repetitive biomarker measurements and personalised medicine. The utilization of blood-based biomarkers presents a highly promising approach towards achieving the goal of personalized medicine, while considering the unique puzzles.

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Further Reading

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