Dr Vishva M Dixit is Vice President and Staff Scientist, Physiological Chemistry at Genentech, San Francisco, CA. After heading Molecular Oncology for 10 years, Dr Dixit has now turned his efforts to basic research to study the biochemistry of components of signaling pathways that often go awry in disease. Author of over 166 publications in various journals, he is the winner of several awards and honours including AHA Investigatorship Award – 1989-1994; Dawson Prize in Genetics – 2015 and Gutenberg Research Award – 2016, among others. “My mission is to further our knowledge of disease-related cellular signaling and to develop novel, high-impact therapeutics,” says Dr Dixit. Edited excerpts from his conversation with FM.
A discovery on cancer immunotherapy won this year’s Nobel Prize for medicine. How exactly does the discovery help in understanding malignancies?
Cancer immunotherapy has been in the doghouse for decades. The work of the two investigators, James P. Allison and Tasuku Honjo, resurrected it so that it plays a prominent role in the therapeutic armamentarium in future.
Immunotherapy held a lot of promise. But there weren’t any successes. The reason is that people were trying to activate the immune system. And a number of immune activators were tried and they invariably failed. The realization of Allison and Honjo was that the cells have a brake on them. You can put as much fuel in the system as you want, as much accelerator as you can press on: The car is not going to go. The cell is not going to proliferate or rejuvenate unless you remove the brakes. That was their realisation. They said, you have been trying to activate the immune system in a tumour without realising the fact that a brake has been put on it in the tumour environment. And the immune system is sitting there paralysed. It can’t do anything unless you remove the brakes. The molecules CTLA4 and CD-1 are essentially the brakes of the immune system. Now they have developed antibodies to neutralize the brakes and get the immune system work. Now the immune system is able to eradicate tumour cells in many cases.
In what way is immunotherapy going to change the treatment paradigms in cancer?
The potential of immunotherapy has already been validated in melanoma and NSCLC. Treatment with the immune activators — which activate the immune system against cancer cells — has proved to be immensely beneficial. In many cases, people who would have ordinarily been dead are still alive…
Does immunotherapy work for
No. There are many cancers that don’t respond to immunotherapy. That is an area of active research today. It works only for malignancies that have a very high mutational burden. NSCLC has the highest mutation because of smokers. Smoking generates a lot of mutagens.
What are the possible adverse effects?
There’s substantial toxicity, because when we remove the brakes, the immune system will also start to attack normal tissue. There is, especially with the anti-CTLA4 therapy, a tendency to get autoimmune diseases like thyroiditis and hypopituitarism. But that, fortunately, has been, largely managed now by dose alterations and other supportive care.
How do you compare the benefit of immunotherapy with other standard therapies?
These drugs are used in combination.In melanoma, metastatic melanoma, I never thought, in my lifetime, the
disease could be cured. Now, it has
been cured: Cured in 10% of the patients with twelve years out. There’s no relapse. It’s a small fraction. But still, it has been cured. I think it is an amazing step forward.
What is the potential of immunotherapy in lung cancer?
Trials are going on. NSCLC has been a heterogeneously aggressive disease. Maybe in the adjuvant setting, one may see a substantial benefit. We may get to a day when we have targeted biologics, or we have an inhibitor for an oncogene like the EGF receptor inhibitor. Then, we won’t need chemotherapy. We are not there yet.
The future of immunotherapy?
I think it is going to be bright. That’s why they gave the Nobel. It is going to be routinely used in melanoma, NSCLC, renal cancer and subsets of prominent malignancies. But it is not effective in colon cancer unless you have something called a mutated phenotype, which is found only in a small percent of colon cancers. But it is going to open the door for more immunotherapies.