The Nobel Prize in medicine for 2018 was awarded to Prof James Allison of MD Anderson Cancer Center, USA, and Prof Tasuku Honjo of Kyoto University, Japan, to discover cancer therapy by inhibition of negative immune regulation. Previously in 2014, they both received the first Tang Prize for biopharmaceutical science for their work, Prof Allison won the Lasker prize in 2015, and Prof Honjo won the Kyoto Prize in basic sciences in 2016.
Immunologists have been trying to identify methods to activate the immune system and drive anti-tumor immune response for a long time. Prof Allison and Prof Honjo’s research helped in the development of successful strategies to enable the immune system and made tumor immunology a flourishing area of study. The Milestones in cancer immunotherapy are shown in Fig. 1a. Prof Allison is known for his work on cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), also known as cluster of differentiation 152 (CD152), a receptor expressed mainly on activated lymphocytes. CTLA-4 was first discovered in 1987 as a protein belonging to the immunoglobulin superfamily of proteins . Its structure is strikingly similar to the T-cell activating receptor, CD28. Both CTLA-4 and CD28 bind to the same ligands, CD80 and CD86.
Interestingly, CTLA-4 was initially thought to be a positive regulator of T-cells and to co-operate with CD28 in the activation of T-cells. Prof Allison’s research helped in clearly demonstrating the negative regulatory role of CTLA-4 and the opposing effects of CTLA-4 and CD28 in response to T-cell stimulation . His lab showed that CTLA-4 engagement resulted in inhibition of IL-2 accumulation and cell cycle progression in activated T-cells and further confirmed the inhibitory role of CTLA-4 by illustrating lymphoproliferative and lethal autoimmune phenotype in Ctla-4−/− mice (Fig. 1b). More importantly, his work also demonstrated the potential of blocking CTLA-4 in the treatment of cancer.
Prof Honjo is well-known for the discovery of Programmed cell death protein 1, also known as PD-1 and CD279 (cluster of differentiation 279), and for the elucidation of its functions. PD-1 gene was isolated using subtractive hybridization techniques while working on pathways of programmed cell death . PD-1 is a cell surface receptor belonging to the immunoglobulin superfamily proteins expressed on T cells, B cells, and natural killer (NK) cells. Prof Honjo worked extensively on PD-1 and demonstrated the immune inhibitory role of PD-1. His lab showed that a lack of PD-1 results in a comparatively milder autoimmune phenotype in mice that were dependent on the mice’s genetic background. He also collaborated with researchers across the world and contributed to the identification of ligands for PD-1 and showed the involvement of PD-1 ligands on tumor cells in the escape from immune response [5, 6] (Fig. 1b).
In the past decade, CTLA-4 and PD-1 have been found to be very reliable targets for the modulation of immune response and the treatment of cancer. CTLA-4 and PD-1 blockade were shown to stimulate immune response via T-cell priming, peripheral activation of immune cells, a reinvigoration of exhausted immune cells, and inhibition of immunosuppressor cells such as regulatory T cells (Tregs) (Fig. 1b). Drugs targeting CTLA-4 and PD-1, commonly known as immune checkpoint blockers, dramatically changed the treatment landscape for advanced cancers. Before the approval of anti-CTLA-4 monoclonal antibody, ipilimumab, metastatic melanoma patients had limited treatment options with durable response rates and had a poor prognosis with a 5-year survival rate of less than 20% . Long-term survival rates seen in ipilimumab-treated patients encouraged the development of anti-PD-1 antibodies, nivolumab, and pembrolizumab. Since their approval, immune checkpoint blockers have extended the survival of melanoma patients by years and wiped out all signs of disease in some patients. One among such patients is President Jimmy Carter, who had a remarkable recovery after being diagnosed with Stage IV melanoma that was metastasized to the brain.
Apart from metastatic melanoma, anti-PD-1 antibodies are approved as ‘first-line’ therapy for advanced non-small-cell lung cancer, chronic Hodgkin’s lymphoma, head and neck squamous cell carcinoma, gastric cancer, urothelial cancer, cervical cancer, renal cell carcinoma and hepatocellular carcinoma . They are also broadly approved for any solid tumor with microsatellite instability-high and mismatch repair deficiency. In addition to monotherapy, a combination of CTLA-4 and PD-1 targeting antibodies has also been approved for metastatic melanoma and other types of cancers. Most importantly, the adverse events seen with immune checkpoint blockers are milder and manageable compared to those seen with conventional cancer treatments such as chemotherapy. Adverse events seen with immune checkpoint blockers are also reversed upon cessation of the therapy .
The significance of targeting PD-1 and other immune checkpoints for cancer treatment can be seen by the interest of various pharmaceutical and biotech companies worldwide. Almost every pharmaceutical R&D has immunotherapy in its pipeline with at least one immune checkpoint blocker under development. More than 30 monoclonal antibodies targeting PD-1 or its ligand PD-L1 are in advanced stages of development. The success of immune checkpoint blockers also paved the way for other types of immunotherapy, such as chimeric antigen receptor engineered T-cells (CAR-T cells) and neoantigen based cancer vaccines, which were previously considered as ‘high-risk’ projects for drug developers . Three CAR-T cell-based therapies and one oncolytic virus-based therapy are approved for cancer treatment, and multiple new approaches are in clinical trials. Hundreds of new clinical trials have been initiated in the past five years to test new immune checkpoint blockers, new immunotherapeutic strategies, and combinations of approved PD-1 blockers. The success of CTLA-4 and PD-1 blockade for cancer treatment has had a significant impact on the fields of oncology as well as immunology and the Nobel prize for Prof Allison, and Prof Honjo is well deserved. It can be considered as recognition for the entire field of tumor immunology, which made surviving advanced stages of cancer ‘achievable.’