Jim Allison and the checkpoints bringing the house down at buddy guy's in Chicago at the American society of clinical oncology annual meeting 2018
At Kyoto University in Japan, clinician-scientist Tasuku Honjo discovered the second key immune checkpoint Programme Cell Death (PD)-1 in 1992, when studying dying mouse cells. It turned out PD1 was often expressed in activated T and B cells, and found to be another powerful brake to regulate the immune system. Honjo later showed that knocking out PD1 in mice causes various autoimmune conditions, but nothing as dramatically fatal from immune self destruction as knocking out CTLA4 in mice – where massive lymphoproliferation happened. Methodical understanding of the PD1-PDL1 axis central to peripheral immune tolerance followed in Honjo’s lab and in the labs of others. In the context of evasion of the immune system by the tumor, this is a “don’t kill me signal.” Imagine the cancer to be Darth Vader from Star Wars, and he pulls out a light sabre called PDL1, and the T cell is Luke Skywalker, and he pulls out his light sabre called PD1. The two ‘light sabres’ PDL1 and PD1 lock together and Darth Vader tells Luke Skywalker, “Don’t kill me, I am your father.” If this hypnotic spell can be broken by an immune checkpoint inhibitor, The T cell can unlock and unleash its light sabre to kill the cancer.
Honjo’s team published the anti-PD1 antibody in tumour-bearing mice studies in 2002. Clinical trials began in 2006. Just like for Allison, getting pharma financing partners interested was like climbing Mount Fuji – a steep, Sisyphean uphill. Finally Ono Pharmaceuticals agreed to step in. This anti-PD1 inhibitor development would be jointly shared with BMS in what would become the lead candidate drug Nivolumab. By 2018 in just under 5 years, PD1 inhibitors would receive FDA approvals in over a dozen indications and cancers – remarkable progress and truly a revolution in cancer treatment.
Both Allison and Honjo share the 2018 Nobel prize for Medicine and Physiology. This is the first time a Nobel prize has been awarded for a specific type of treatment for cancer, if one does not consider the 1990 Nobel Prize to Donnal E Thomas for pioneering bone marrow transplantation. In 2017, Harvard University’s prestigious Warren Alpert Foundation honoured James Allison, Tasuku Honjo, Gordon Freeman, Arlene Sharpe and Chen Lieping in their groundbreaking work in understanding how immune checkpoints are central to cancer evasion of the immune system. Chen Lieping, then at the Mayo Clinic, was first to clone the B7-H1 (now known as PDL1), and published his findings in Nature Medicine in 1999. By the early 2000s, Chen showed that PDL1 was expressed on many tumour types and that blocking the PD1-PDL1 axis could be a potent anti-cancer therapy. He was a major force in driving the PD1 inhibitor into first-in-human cancer clinical trials. Gordon Freeman discovered the natural binding molecules for PD1 – the B7 family. Husband and wife Freeman and Sharpe elucidated that T cell exhaustion was a result of PD1 overexpression and overstimulation of T cells, and that an antibody that blocked the PD1-PDL1 axis could reverse T cell exhaustion. Twelve years ago, I attended the cancer immunology Keystone Symposium in the snowy Colorado mountains. Longtime collaborator of Freeman and Sharpe – the eminent immunologist Rafi Ahmed of Emory University - presented exciting work on how anti-PD1 inhibitors could reverse T cell exhaustion in chronic viral infections which could be used to treat human immunodeficiency virus (HIV) patients with the Acquired Immunodeficiency Syndrome (AIDS). These studies in viral infections did not work out well. But, surprisingly, those in cancer worked beautifully.
Today, cancer immunotherapy is one of the hottest things in cancer therapy. But back in the 1990s, cancer immunology, immunotherapy and research on the tumour immune microenvironment (TIME) were about as hot as an ice cream in winter. When I was a clinical fellow in hematology-oncology at the Massachusetts General Hospital in Boston in the late 1990s, we witnessed the most amazing clinical trial in oncology – Imatinib (Gleevec) for the treatment of chronic myeloid leukemia (CML). Every CML patient responded to Gleevec miraculously and the FDA approved Gleevec in 2001 for CML – still the fastest approval of a cancer drug in FDA history. This started the revolutionary era of targeted therapy for cancer. Since then, the next 20 years would see huge efforts and investments in developing targeted therapy against many cancers. In 1998, transtuzumab (Herceptin) was approved for the treatment of HER2-expressing breast cancer. Getting funding for cancer immunology research in the 1990s was tough, then considered more science fiction and a waste of time. Instead, the world was excited by the immense potential of targeted therapy. However, “oncogene addiction” exists in less than 15% of all cancers and outside of this, precision medicine really only benefits a minority of cancer patients. From 2009 to 2013, the Europeans Medicines Agency reported that only 26 of 68 cancer drugs approved had proven overall survival benefit - of only a mere 2.7 months median survival. Moreover, outside of true oncogene drivers, finding predictive biomarkers for targeted therapies has proven difficult.
‘Precision medicine is not a panacea; it’s a tool. And like all tools, it needs to be used appropriately. If not, it will not work.’
George Sledge, Chief, Division of Oncology, Stanford University Medical Center
Meanwhile, back to the future of the 21st century. There has been unprecedented progress in defining biomarkers in immune-oncology (IO). Positive PDL1 expression, which, while not perfect, is predictive of immune checkpoint inhibitor benefit in some cancers. This has evolved to tumor proportion score (TPS) and combined positive score (CPS). Tumor mutational burden, microsatellite instable cancers also predict for benefit to IO therapy. New biomarkers to predict IO benefit continue to be validated : from simple ones like absolute lymphocyte count to much more complex ones such as the cancer immunogram comprising a collection of potential biomarkers.
The new revolution in cancer therapy from monoclonal antibodies against HER2, epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), CD20 and more, to the IO therapies would not be possible without two of this year’s winners of the Nobel Prize for Chemistry – George P Smith who founded phage display, and Sir Greg Winter who improved on it to engineer the humanization of the monoclonal antibody – pioneered by his own mentor Nobelist the late Cesar Milstein. He is the founder of three antibody companies. In the summer of 2018, over a dinner at Trinity College, Cambridge University - that included monkfish and macadamia nut tart with pear ice cream, I asked Sir Greg what the secret sauce was to translating science to impactful medicines. Sir Greg believes that basic science, blue sky research, asking fundamental questions, rigorous scientific culture and inspired mentoring are vital ingredients. And he added, “Dream big dreams !” Sir Greg was determined to move humanized monoclonal antibodies into patients when he met a lady with terminal cancer. She had thanked Sir Greg for giving her hope through receiving his experimental monoclonal antibody to potentially extend her life even by a few months. She said to him she needed just a few months more to look after her dying husband. Sir Greg was very moved.