The Nobel intersection of immunology and oncology


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A Nobel Prize for foundational work in immuno-oncology highlights the potential for further advances in cancer care today. From discovery, to preclinical tests, to clinical results, the story behind this year’s prize involves translating basic research into significant medical outcomes for patients.

 

On Monday October 1st 2018, the Nobel Prize in Physiology or Medicine was awarded jointly to James P. Allison and Tasuku Honjo “for their discovery of cancer therapy by inhibition of negative immune regulation”. This is the first mention of “cancer” in a Nobel committee announcement since the 2008 prize awarding Harald zur Hausen’s discovery of the link between HPV and cervical cancer. The research of this year’s winners is based on the larger role of immune system dysfunction in multiple pathologies. Dr Allison and Dr Honjo demonstrated the potential of unlocking the immune system to limit tumour growth. The resulting translation of their work into direct clinical applications and drug approvals make this year’s prize highly relevant to the field of oncology.

 

The role of the immune system has been established in multiple pathologies, including auto-immune diseases, transplant rejection and even common allergies. The link between infection and tumour disappearance has been observed for centuries and, in the past 150 years, multiple clinicians have tried to treat cancer with induced infection. Despite some success, such trials produced inconsistent results.

 

In recent decades, various T cell regulatory factors have been identified. One class of surface receptors functions as a brake to limit T cell function when activated. Certain tumour cells take advantage of these immune checkpoints by expressing ligands to inhibit T cell activation and escape their regulatory function. By combining the logic behind activating the immune system and these specific T cell target receptors, the newest Nobel laureates uncovered an entirely new way to treat cancer, immune checkpoint inhibition.

 

Between 1994 and 1996, James P. Allison experimented with antibodies directed against cytotoxic T lymphocyte antigen 4 (CTLA-4), a negative regulator of T cell function. In experiments where mice were injected with tumour cells, anti-CTLA-4 antibodies completely stopped tumour growth. When tested in patients with advanced melanoma, similar antibodies caused unprecedented success in reducing or eliminating this difficult-to-treat cancer. In 2011, the first anti-CTLA-4 antibody, ipilimumab was approved for the treatment of advanced melanoma. This was the first approved immunotherapy for cancer taking advantage of immune checkpoint inhibition.

 

Tasuku Honjo’s research followed a similar trajectory, but with the Programmed Cell Death 1 (PD-1) molecule and its ligand PD-L1. Honjo discovered PD-1 in the early 1990s and PD-L1 in 2000 as part of a collaborative study. This research also noted that tumour cells may express PD-L1, helping block T cell activation to escape immune system regulation. From mouse studies in the early 2000s to initial clinical studies in several types of cancer, antibodies against PD-1 or PD-L1 showed striking anti-tumour results. The first anti-PD-1 antibodies, pembrolizumab and nivolumab, were approved for treatment of melanoma in 2014.

 

In addition to currently approved single immunotherapies, several types of combinations are proving effective. Both the FDA and EMA have approved the combination of ipilimumab and nivolumab for treatment of melanoma. Positive Phase III results have been reported for the combination of pembrolizumab and standard chemotherapy for both squamous and non-squamous non-small cell lung cancer. And trials of the various checkpoint inhibitors with standard radiotherapy are ongoing in thoracic and other cancers.

 

Additional developments are advancing rapidly with over 2000 new agents being tested in a mix of clinical and preclinical trials. Some near-term goals are uncovering which types of combinations are most effective, validating diagnostic methods for predicting treatment success, and expanding the use of immunotherapy to additional cancer types. The awarding of the 2018 Nobel Prize in Physiology or Medicine to two researchers whose findings form part of the foundation of this field speaks to the importance and potential of such work.

 

 

EMA approved anti-CTLA-4 and anti-PD-1 or PD-L1 antibodies and their indications as of 1 October 2018

Approved antibody

Indications

Anti-CTLA-4 ipilimumab

advanced (unresectable or metastatic) melanoma

Anti-PD-1 pembrolizumab

advanced (unresectable or metastatic) melanoma, locally-advanced or metastatic non-small cell carcinoma, relapsed or refractory classical Hodgkin lymphoma, and locally advanced or metastatic urothelial carcinoma

Anti-PD-1 nivolumab

advanced (unresectable or metastatic) melanoma, locally-advanced or metastatic non-small cell carcinoma, advanced renal cell carcinoma, relapsed or refractory classical Hodgkin lymphoma, recurrent or metastatic squamous cell carcinoma of the head and neck, and locally advanced unresectable or metastatic urothelial carcinoma

Anti-PD-L1 atezolizumab

locally advanced or metastatic urothelial carcinoma and locally advanced non-small cell lung cancer

Anti-PD-L1 avelumab

metastatic Merkel cell carcinoma