Introduction

Cancer has been a harsh enemy throughout human history, with evidence of its existence dating back to ancient times. This everlasting battle with cancer has led to the broadening of our understanding of this complex disease and our approaches to diagnosing and treating it have evolved significantly over the centuries. Immune checkpoint therapy has revolutionised cancer treatment in recent years, offering new hope for patients with various types of malignancies. This innovative approach harnesses the power of the body's immune system to fight cancer cells more effectively.¹

Early Understanding and Diagnosis

In ancient times, cancer was poorly understood and often attributed to supernatural causes. The earliest recorded description of cancer dates back to around 3000 BCE in an Egyptian papyrus. Hippocrates, the Greek physician, later coined the term "karkinos" (crab) to describe tumours, due to their crab-like appearance. Early diagnosis relied primarily on physical examination and limited surgical procedures. It wasn't until the 19th century, with the invention of microscopy, that cellular pathology began to shed light on the nature of cancer at a microscopic level.

The Role of Biomarkers in Modern Oncology

The concept of biomarkers emerged in the mid-20th century, revolutionising cancer diagnosis and management. Biomarkers are biological molecules that indicate the presence or characteristics of cancer. Some key milestones in biomarker discovery include:

• 1948: Discovery of cell-free DNA
• 1960s-1970s: Identification of "cancer antigens" like CEA and AFP
• 1990s: Discovery of genetic mutations such as BRCA1 and BRCA2
• 2000s onwards: Development of multi-gene signatures and molecular profiling

Modern Diagnostic Techniques

As our understanding of cancer biology grew, so did our diagnostic capabilities. Some key developments include:

• Imaging technologies: X-rays, CT scans, MRI, PET scans
• Molecular diagnostics: PCR, next-generation sequencing²
• Liquid biopsies: Analysis of circulating tumour cells and cell-free DNA²
• Immunohistochemistry: Detection of specific proteins in tissue samples²

Evolution of Cancer Treatments

Cancer treatment has undergone a remarkable transformation over time:

• Surgery: The oldest form of cancer treatment, refined over centuries
• Radiation therapy: Introduced in the early 20th century
• Chemotherapy: Developed in the 1940s, with significant advancements in subsequent decades
• Hormone therapy: First used in the 1970s for breast and prostate cancers²
• Targeted therapies: Emerged in the late 1990s, focusing on specific molecular targets
• Immunotherapy: Gained prominence in the 2010s, developing the body's immune system

How Immune Checkpoint Therapy works

Immune checkpoint therapy targets specific proteins/peptides that act as "brakes" on the immune system. Under normal circumstances, these checkpoints prevent the immune system from attacking healthy cells. However, cancer cells can exploit these checkpoints to evade detection and destruction by immune cells, generally natural killer cells(NK) and adaptive immune cells.¹ In the past immunotherapy was not that prevalent due to

• i)  targeting of non-specific molecules that boost immune cells such as IL-12(An Interleukin which are messengers that trigger the body to mass produces T-helper cells) and
• ii) neoantigen(foreign) vaccine which caused many patients' bodies to have toxicity(over-reaction) due to over-reaction by immune cells. 

The breakthrough which re-focussed Immunotherapy’s potential received the Nobel Prize in 2018 when they recognised Immune checkpoint blockade (ICBs) of the immune cell. Cancer cells exploited ICBs to escape detection and re-engineering thischeckpoint could make cancer cells vulnerable to immune cells 

The two main types of checkpoint proteins targeted in current therapies are:

• Immune checkpoint blockade immunotherapy, CTLA-4 (Cytotoxic T-lymphocyte-associated protein 4)³ which was the to be first established
• PD-1 (Programmed cell death protein 1) and its ligand PD-L1³, which is most used by ICB clinics

By blocking these checkpoint proteins, the therapy "releases the brakes" on the immune system, allowing T cells to recognise and attack cancer cells more effectively.³

FDA-Approved Checkpoint Inhibitors

Several checkpoint inhibitors have been approved by the Food and Drug Administration (FDA) for cancer treatment mainly using monoclonal antibodies:

PD-1 Inhibitors:

• Nivolumab
• Pembrolizumab
• Cemiplimab

PD-L1 Inhibitors:

• Atezolizumab
• Durvalumab
• Avelumab

CTLA-4 Inhibitor:

• Ipilimumab

These drugs have shown remarkable efficacy in treating various types of cancer, including melanoma, lung cancer, and renal cell carcinoma.³

Efficacy and Response Rates

The success of immune checkpoint therapy varies depending on several factors, including

• Cancer type
• Patient characteristics
• The specific inhibitor used 

Response rates can range from 15% to 100%.¹ Some patients experience long-term remission, even after discontinuing treatment, raising hopes for potential cures in certain cases.³

Challenges and Limitations

Despite its success, immune checkpoint therapy faces several challenges:

Limited response: 

Not all patients respond to the treatment, with response rates varying widely across different cancer types.

Resistance mechanisms:

Tumours can develop resistance through various mechanisms, such as neoantigen (foreign particle) depletion or genetic alterations that disrupt interferon signalling.¹

Side effects:

Immune-related adverse events can occur due to the enhanced immune response, affecting various organs and systems.

Biomarker identification:

There is an ongoing need to develop reliable biomarkers to predict treatment response and guide patient selection.³

Combination Therapies and Future Directions

To improve efficacy and overcome resistance, researchers are exploring combination approaches:

Radiation and chemotherapy:

Combining checkpoint inhibitors with these traditional treatments has shown promise in enhancing antitumour immunity and improving survival rates.¹

Adoptive cell therapies:

Combining checkpoint inhibitors with CAR-T cell or tumor-infiltrating lymphocyte (TIL) therapy has demonstrated potential in challenging solid tumours.¹

Neoantigen-based vaccines:

These personalised vaccines, combined with checkpoint inhibitors, have improved response rates and overall survival, particularly in cancers with high mutational burdens.¹

Novel checkpoint targets:

Researchers are investigating inhibitors targeting other checkpoint molecules, such as LAG-3, TIM-3, and TIGIT.¹

Next-generation antibodies:

Bispecific antibodies and antibody-drug conjugates are being explored to enhance anti-tumour responses.¹

As research progresses, the field of immune checkpoint therapy continues to evolve, offering hope for improved outcomes and expanded treatment options for cancer patients.

Emerging Therapies and Future Directions

The field of oncology continues to evolve rapidly. Some promising areas of research include:

• Precision medicine: Tailoring treatments based on individual genetic profiles
• CAR-T cell therapy: Engineering patients' immune cells to fight cancer
• Cancer vaccines: Both preventive and therapeutic approaches
• Combination therapies: Synergistic use of multiple treatment modalities
• CRISPR gene editing: Potential for correcting cancer-causing genetic mutations

The Role of Biomarkers in Modern Oncology

Biomarkers play a crucial role in various aspects of cancer management:

• Early detection and screening
• Diagnosis and disease classification
• Prognosis and risk stratification
• Prediction of treatment response
• Monitoring disease progression and recurrence

For instance, prostate-specific antigen (PSA) has been widely used for prostate cancer screening, while HER2 expression guides treatment decisions in breast cancer.²

Challenges and Future Perspectives

Despite significant progress, challenges remain in cancer diagnosis and treatment. These include:

• Tumour heterogeneity and evolution⁴
• Development of drug resistance⁴
• Early detection of aggressive cancers⁴
• Minimising treatment side effects⁴
• Accessibility and affordability of advanced therapies⁴

Ongoing research focuses on addressing these challenges through innovative approaches such as artificial intelligence in diagnostics, novel drug delivery systems, and personalised treatment strategies.⁴

Summary

In conclusion, Oncology has made remarkable strides in understanding, diagnosing, and treating cancer. Integrating biomarkers, advanced diagnostics, and targeted therapies has paved the way for more personalised and effective cancer care. As research uncovers the complexities of cancer biology, we can anticipate further breakthroughs that will improve outcomes for cancer patients worldwide.