Cancer Immunotherapy : 2018 Nobel Prize

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 [1]. 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 [2]. 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 [4]. 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 [56] (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% [7]. 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 [8]. 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 [9].

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 [10]. 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.’

What is Immunotherapy?

What is immunotherapy?

Immunotherapy refers to any treatment that uses the immune system to fight diseases, including cancer. Unlike chemotherapy, which kills cancer cells, immunotherapy acts on the immune system’s cells to help them attack cancer.

What are the types of immunotherapy?

Drugs called checkpoint inhibitors are the most widely used form of immunotherapy for cancer. They block a mechanism that cancer cells use to shut down the immune system. This frees killer T-cells — a critically important part of the immune system — to attack the tumor. Four checkpoint inhibitors have been approved by the Food and Drug Administration and are on the market. They are given intravenously.

Another form of immunotherapy, called cell therapy, involves removing immune cells from the patient, altering them genetically to help them fight cancer, then multiplying them in the laboratory and dripping them, like a transfusion, back into the patient. This type of treatment is manufactured individually for each patient and is still experimental.

Bispecific antibodies are an alternative to cell therapy, one that does not require individualizing treatment for each patient. These antibodies are proteins that can attach to both a cancer cell and a T-cell. That way, bringing them close together so the T-cell can attack cancer. One such drug, called Blincyto, has been approved to treat a rare type of leukemia.

Vaccines, another form of immunotherapy, have had considerably less success than the others. Unlike childhood vaccines aimed at preventing diseases like measles and mumps, cancer vaccines are aimed at treating the disease once the person has it. The idea is to prompt the immune system to attack cancer by presenting it with some piece of cancer.

The only vaccine approved specifically to treat cancer in the United States is Provenge for prostate cancer. Another vaccine, BCG developed to prevent tuberculosis, has long been used to treat bladder cancer. As a weakened TB bacterium, BCG appears to provoke a general immune system reaction that then works against cancer. Researchers hope that other vaccines may yet be made to work by combining them with checkpoint inhibitors.

Which types of cancer are treated with immunotherapy?

Checkpoint inhibitors have been approved to treat advanced melanoma, Hodgkin’s lymphoma, and cancers of the lung, kidney, bladder, and head and neck. The drugs are being tested in many other types of cancer.

So far, cell therapy has been used mostly for blood cancers like leukemia and lymphoma.

Which cancer drugs are checkpoint inhibitors?

The four on the market are Yervoy (ipilimumab) and Opdivo (nivolumab), made by Bristol-Myers Squibb; Keytruda (pembrolizumab), by Merck; and Tecentriq (atezolizumab), by Genentech.

How well does immunotherapy work?

Though immunotherapy has been stunningly successful in some cases, it still works in only a minority of patients. Generally, 20 percent to 40 percent of patients are helped by checkpoint inhibitors — although the rate can be higher among those with melanoma. Some patients with advanced disease have had remissions that have lasted for years. In some cases, combining two checkpoint inhibitors increases the effectiveness. But for some people, the drugs do not work at all, or they help just temporarily.

Cell therapy can produce complete remissions in 25 percent to 90 percent of patients with lymphoma or leukemia, depending on the type of cancer. In some cases, the remissions can last for years, but in others, relapses occur within a year.

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