Discorsi di ringraziamento – Berna, 17.11.2017 (video + testo – inglese)

USA

James P. Allison e Robert D. Schreiber

Premio Balzan 2017 per gli approcci immunologici nella terapia del cancro

I professori Schreiber e Allison sono stati artefici di un cambiamento di paradigma nel campo dell'immunologia tumorale. Il primo, per aver dimostrato che il sistema immunitario ricopre un ruolo fondamentale nella lotta e nella caratterizzazione dei tumori e aver introdotto il concetto di immunoediting soprattutto con riferimento alla fuga immunitaria (immuno-escape). Il secondo, per aver svelato le basi molecolari di questa fuga ed essere riuscito a bloccarla attraverso una terapia con anticorpi monoclonali, aumentando per la prima volta la sopravvivenza in pazienti affetti da melanoma metastatico. Entrambi hanno collaborato di recente, insieme ad altri scienziati, all'identificazione di neoantigeni tumore-specifici, un approccio che potrebbe portare allo sviluppo di efficaci vaccini anticancro personalizzati.

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James P. Allison 

President of the Swiss Confederation,
Members of the Balzan Foundation,
Ladies and Gentlemen,

I am so glad to be here and very honored to be selected for the Balzan Prize, especially because the Balzan Foundation’s goal is the betterment of mankind. I am also pleased to share the prize with my long-time friend and colleague Robert Schreiber.
As a basic scientist, I have been blessed to see my research findings translate into a powerful new strategy for cancer therapy. In 2006 I met a patient named Sharon, a 24-year old who had recently graduated from college and gotten married. More than a year earlier, her doctors told her that she had only a few months to live. Sharon had stage 4 metastatic melanoma, with tumors in her brain, lungs, and liver. She had received multiple prior therapies but her cancer continued to grow and weaken her body.
As a last ditch effort, she participated in a clinical trial of a then experimental drug called anti-CTLA-4 therapy. Within three months of starting treatment, her tumors shrank and then disappeared. When I met her a year later she hugged me and cried. She had just been told by her doctor that she showed no evidence of recurrent cancer. I was moved and cried with her.
Sharon and I have become good friends. When her first child was born a few years later, she sent me pictures. Then pictures of her second child. She is now eleven years out from her battle with cancer and enjoying life with a vibrant family. I can’t help but cry whenever I tell this story. My meeting with Sharon was my first experience of how years of research as a basic scientist could have an impact on patients.
When I began my career in the late 1970s, cellular immunology was still in its infancy. T cells are a critical part of the immune system, circulating throughout the body to find foreign antigens related to bacteria, viruses, and potentially cancer cells, and remove them. Little more was known about T cells, and in the 1970s I joined a growing cadre of scientists trying to solve their mysteries. In the early 1980s my lab identified and worked out the structure of the receptor that T cells used to identify foreign antigens. But it wasn’t that simple. The T cell receptor can be compared to a car’s ignition switch. It is needed to turn the car on and start the T cell activation process but isn’t enough to get it going. It seemed that another signal was needed. We showed that another molecule, CD28, was the accelerator that enabled T cells to take off, proliferating into an army of cells to do their jobs and attack.
But that’s not the end of the story. There had to be a mechanism to stop the rapid proliferation of T cells. Many thought that T cells just died, but in 1994 my lab and Jeff Bluestone’s identified another signal, called CTLA-4, that acted as a brake, stopping T cell responses before they caused damage. Then I had one of those rare Aha! moments in science when you recognize that you may have learned something with important implications. Numerous attempts had been made to mobilize T cells to treat cancer, but with disappointing results. It oc- curred to me that if we could block the brakes, we would allow T cells to keep going for sufficient periods of time so as to destroy large tumors.
We tested this idea in mice with an antibody we made to CTLA-4. This worked beautifully to destroy tumors in mice. We couldn’t believe it! Many tu- mors melted away, and the mice were permanently immune to rechallenge.
We eventually teamed up with a small biotech company to move CTLA-4 blockade therapy into clinical trials.
And, as they say, the rest is history! We now know that the therapy is effective against many types cancer, and many patients are alive a decade or more after treatment and can be considered cured.
I’ve had the privilege of meeting many patients who had benefitted from anti-CTLA-4 therapy. It’s always overwhelming and my emotions often get the best of me as they tell their stories.
Additional CTLA-4-like brakes have been identified and antibodies to these show remarkable benefit in patients. Because these drugs, now known as check- point blockade therapy, treat the immune system, not the cancer, they are effective against many kinds of cancer. Checkpoint blockade agents are now approved for melanoma, kidney cancer, bladder cancer, Hodgkin’s lymphoma, lung cancer and others.
Of course, we still have a lot of work to do. We have not been able to successfully treat cancers such as pancreatic cancers and glioblastoma. We’re continuing our efforts and hope to make progress in the near future.
I am truly honored to have been selected for this prize. I owe this success to a large number of students and fellows who worked in my lab, and plan to use the grant funds to support the training of physician/scientists to bring the benefits of immunotherapy to patients. And I owe special thanks to my wonderful partner in science, and life, my wife Pam Sharma.

Robert D. Schreiber

President of the Swiss Confederation,
Members of the Balzan Foundation,
Ladies and Gentlemen,

I am extremely honored to have been chosen as a co-recipient of the 2017 Balzan Award. This wonderful award is particularly meaningful because it is shared with Dr. James Allison, who has been a close friend and respected colleague for over 40 years.
The achievements forming the basis of this award have been possible because I have had a core of dedicated and extraordinary individuals who have been the backbone of my lab for nearly thirty years, and more than 50 talented predoctoral and postdoctoral trainees who have worked in the lab. One of my greatest joys has been to see the trainees mature into very accomplished, independent scientists. I also deeply appreciate my colleagues at Washington University and elsewhere for their collaboration, insights, and support that helped advance our research efforts.
For the past 25 years, my lab has explored whether the immune system is capable of interacting with developing or established cancers. This was a controversial topic when we first began, since the argument had been raging for nearly 100 years. In fact, the prevailing view was that immunity and cancer represented two non-intersecting processes. In actuality, there was very little experimental evidence to support this conclusion. We felt that with advancing technologies and a deeper understanding of immune mechanisms, the time was right to pursue an in-depth investigation about the role of the immune system in cancer development.
I am here today because our work showed that the immune system not only protected individuals against cancer, but also reduced a tumor’s susceptibility to immune control. These paradoxical host-protective and tumor-promoting actions of the immune system constitute the framework for a process we named “cancer immunoediting”. As expected, we initially met with strong resistance to this idea. The concept gradually gained acceptance as we further characterized the process and other groups independently obtained confirmatory results. Today we have a very high-resolution understanding of cancer immunoediting and this idea has achieved nearly universal acceptance as one mechanism leading to tumor escape from immune control. The cancer immunoediting concept now serves as a strong conceptual foundation upon which modern approaches to cancer immunotherapy have been built.
This work led to our current studies aimed at using mutant proteins uniquely expressed in a patient’s cancer to generate a personalized tumor-specific vaccine for that patient. We were one of the first to use an immunogenomics approach to identify mutant proteins in a tumor that can target that tumor for immune destruction.Three years ago, we obtained proof-of-principle results using therapeutic personalized cancer vaccines in preclinical tumor models and have since expanded on these studies to show that personalized vaccines can be used with other immunotherapies or standard-of-care therapies to produce effective anti-tumor responses. We also showed that personalized cancer vaccines can effectively treat human cancer patients without inducing serious side-effects sometimes caused by other immunotherapies. I am very excited to see our work contributing to the development of new cancer immunotherapy approaches and hope that personalized vaccines will make human cancer immunotherapy more specific, more effective and safer than the cancer immunotherapies available today.
I want to again thank the Balzan Foundation for this great honor. I am very much looking forward to continuing our research program in cancer immunotherapy and working with trainees who will be supported by the research component of the Balzan Award.