The 2018 Nobel Prize in Physiology or Medicine has had a very concrete, clinical application. Cancer patients around the world have been treated with James Allison’s and Tasuku Honjo’s immune checkpoint therapy, and during the Nobel week in December some of those patients gathered at the Grand Hotel in Stockholm to honor the two Laureates and show their gratitude. The most rewarding part of their research, both Laureates stated, as these patient’s cancers, if not treated with immunotherapy, would have taken their lives.

The activation of the immune system

Cancer diseases are characterized by uncontrolled proliferation of abnormal cells with the capacity for spread to healthy organs and tissues. Important progress has been made but advanced cancer remains difficult to treat and the need for better treatments is huge.

At the beginning of the 20th century the idea that activation of the immune system could be a strategy for attacking tumor cells emerged. Fundamental mechanisms regulating immunity were uncovered and it was shown how the immune system can recognize cancer cells. Scientists have also shown that T-cells (a type of white blood cells and key players in immune defense) have receptors that bind to structures recognized as non-self.

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Such interactions trigger the immune system to engage in defense, while additional proteins acting as T-cell accelerators are also required to trigger a full-blown immune response. Other proteins that function as brakes on the T-cells and inhibit immune activation have also been identified, and the balance between accelerators and brakes has been proven to be essential for tight control and a functioning immune system.

Disengaging the T-cell brake

In the 1990s James P. Allison at the University of California, Berkeley, studied this very thing. He was investigating the T-cell protein CTLA-4 and he observed that it functioned as a brake on T-cells. He had already developed an antibody that could bind to CTLA-4 and block its function and now he wanted to see if this blockade could disengage the T-cell brake and unleash the immune system to attack cancer cells.
The first experiment was performed and the results were amazing. Mice with cancer were cured through treatment with the antibody that inhibited the brake and unlocked anti-tumor T-cell activity. Allison and his co-workers developed this strategy into a therapy for humans and in 2010 a clinical study showed striking effects in patients with advanced melanoma. Actually, in several patients all signs of remaining cancer disappeared.

Another striking result

At almost the same time, in 1992, Tasuku Honjo at Kyoto University discovered PD-1, another protein expressed on the surface of T-cells. His results showed that, similarly to CTLA-4, PD-1 also acts as a T-cell brake, but is operated by a different mechanism. In animal models blocking of PD-1 was shown to be a promising strategy in cancer treatment. In 2012 a clinical study also demonstrated clear efficacy in the treatment of patients with different types of cancer.

A pardigm shift in cancer treatment

Since these clinical trials this new treatment strategy, known as immune checkpoint therapy, has fundamentally changed the outcome for certain patient groups with advanced cancer.

During the Nobel announcement in October, Klas Kärre, an immunologist at the Karolinska Institute, when describing the Laureates’ work said, “It represent a completely new principle, because unlike previous strategies it is not based on targeting the cancer cells but rather the brakes – the checkpoints – of the host immune system. The seminal discoveries constitute a paradigmatic shift and a landmark in the fight against cancer.” Others have likened it to the discovery of penicillin.

In 2011 the drug Yervoy (ipilimumab), an antibody that inhibits CTLA-4, won approval from the US FDA, and in 2014 the anti-PD-1 drug known as Keytruda (pembrolizumab) was approved. Since then the FDA has approved drugs that target PD-1 and PD-L1 to treat 13 different cancers. A large number of checkpoint therapy trials are currently underway against most types of cancer (according to the Cancer Research Institute, more than 1 500 trials), and new checkpoint proteins are also being tested as targets. New clinical studies also indicate that combination therapy, targeting both CTLA-4 and PD-1, can be even more effective, as demonstrated in patients with melanoma.

“The 2018 Nobel Prize in Medicine awards the work of James P Allison and Tasuku Honjo for their discoveries leading to cancer therapies by inhibiting the negative immune regulation. Removing the “brakes” from the immune system, as a treatment, has brought enormous value for many patients with cancer,” says Miguel Forte, CEO of the Norwegian company Zelluna Immunotherapies.

Future challenges

As with other cancer therapies, there is of course still need for improvement and in his Nobel announcement interview with Nobel Media Tasuku Honjo outlined the two most important problems. Still only 30 percent of patients are responding and biomarkers to predict whether the patient is responsive or not are needed. The efficacy of the treatment also needs to be improved. But Honjo said he believed that these problems will be solved in the future and that we are just at the beginning of this new treatment.

Another aspect is the cost. The use of checkpoint inhibitors in combination with other drugs will make the price of these therapies increase enormously.

Nordic progress

In the Nordic region there are also promising research findings and interesting new pharmaceuticals in the field of immune checkpoint therapy. AstraZeneca has for example been making headlines with its recent FDA approval of its checkpoint inhibitor Imfinzi (durvalumab) for the treatment of lung cancer. The approval was the first authorization of a treatment for lung cancer that has not progressed after chemoradiation and in which the tumors cannot be removed by surgery. The decision was based on Phase III trial data in which patients treated with Imfinzi showed an almost 50 percent reduction in the risk of disease progression compared to patients treated with a placebo.

Another company in the field of immunotherapy is Cantargia, specializing in antibody-based cancer therapy. Their patented treatment CAN04 fights cancer both through activation of the immune defense and through blockade of signals that drive tumor growth.

“To manipulate the immune system to treat cancer patients is probably the hottest research area today and this is where Cantargia also is contributing. We are therefore very happy that the Nobel Prize has been awarded to two scientists who have demonstrated the value of using the body’s own immune system to fight cancer. We continue to strive to make the future cancer therapies even better,” says Göran Forsberg, CEO of Cantargia.

Swedish Alligator Biosciences has also based its company on these Nobel discoveries. In particular its bispecific drug candidate, ATOR-1015, which is a next-generation CTLA-4 immuno-oncology agent, is born out of Allison’s pioneering discovery.

“We are thankful for the commitment of these two scientists and to the transformation they have brought to cancer research and to patients living with cancer. Their discovery has paved the way for improved therapies for this devastating disease,” says Per Norlén, CEO of Alligator.
Other examples of Nordic companies in the field of immuno-oncology are Hansa Medical, Targovax, Immunicum, Immunovia, Nuevolution and Zelluna Immunotherapy.

Genetically engineered

Zelluna, a biopharmaceutical company founded in 2016, focuses on the development of T-Cell Receptor (TCR) based immunotherapies. The company has several TCRs in different stages of development.

“We are developing cell therapies for solid tumors by genetically engineering the surface receptors of patient lymphocytes. We are also targeting cancer via the immune system, utilizing lymphocytes. However, Zelluna differentiates from the Nobel discoveries in approach by aiming at delivering a large number of activated targeted lymphocytes against the tumor rather than interfering with the “lymphocyte brake” of the immune system. This autologous adoptive cell therapy approach consists of the collection of blood from cancer patients, modified ex-vivo with the introduction of a TCR specific for cancer proteins, and returning activated lymphocytes back to the patient in large numbers to destroy the tumor. The TCRs used by Zelluna have been developed by scientists at the Oslo Radium Hospital from patients who had a long-term survival benefit after immunization with cancer-relevant peptides,” explains Miguel Forte, CEO of the company.

He and his colleagues aim at starting clinical trials using the TCRs in autologous adoptive cell therapy in 2020.

“Currently we are completing the preparation of the data necessary to request the authorizations to conduct those trials, as well as organizing the manufacturing capability with partners to produce the genetically modified cells from the patients to target their own tumor,” says Forte.