January 2016 Edition Vol.11, Issue 1

2016 Forecast Series – On Curing Cancer with Vincent T DeVita Jr MD

2016 Forecast Series—On "Curing" Cancer with Vincent T. DeVita, Jr., MD, Professor of Medicine and Professor of Epidemiology and Public Health, Yale Cancer Center, Yale School of Medicine

Dr. Vincent T. DeVita, Jr., is a former director of the National Cancer Institute, and co-author of the book "The Death of Cancer."

OBR: Congratulations on the publication of your book, titled “The Death of Cancer," last year.  It is a very bold title, and yet of anyone who can title a book like that, you are in a position to do so. Please tell us what you mean by the “death of cancer”.

VD: I think we are approaching a time when we will be able to either cure or control most cancers. Those we don't cure will be converted into an easily controllable chronic disease. This will be accomplished by controlling the 8 hallmarks of cancer I outline in the book. That will be the death of cancer.

OBR: The reviews have been pretty terrific, which has got to be very rewarding for you, and you’re a very outspoken person. Does that affect how you’re perceived?

VD: (laughs) I mean, who’s going to do anything to me? If you don’t like me, you don’t like me. You can’t be director of the cancer institute and only make friends. I’m used to people being upset with me. I’ve always been outspoken, and I’m too old to change. It was the right time to write this book, and I think it came out as well as we could have hoped.

OBR: Cancer treatment has changed enormously over time, but what practice changing advances have you seen in your time working in cancer research that have been most impressive?

VD: There have been three paradigm changing discoveries in the treatment field. The first was the work we did which provided proof of principle that combination chemotherapy can cure advanced metastatic cancers. It not only cured the cancers we studied, but led to the use of combination chemotherapy as an adjunct to surgery in common tumors, like breast and colorectal, with subsequent sharp declines in national mortality rates. 

The second was Brian Druker's work showing that targeted therapy aimed at a specific driver mutation in a cancer (in this case the BCR/Able translocation in chronic myelocytic leukemia) could convert a fatal disease into a chronic disease with a near normal life span. This approach has now been extended to every cancer with specific identifiable driver mutations, with very good outcomes. 

The third was the discovery of checkpoints on lymphocytes that control their reaction to foreign elements like cancer cells. The use of checkpoint inhibitors now approved for melanoma and lung cancer and being tested in most other tumors has revolutionized the immunotherapy of cancer. Another subset of immunotherapy using chimeric antigen receptor modified T cells to attack specific antigens on the surface of tumors is also rapidly gaining acceptance. 

These three approaches have revolutionized cancer treatment. 

OBR: Now that we’re seeing such great clinical responses to the new immunotherapy drugs, do you think harnessing a patient’s immune system to fight cancer is the ultimate weapon?

VD: Not by itself no. Like most of these approaches they work better when combined with other ways to treat cancer. But it gives us a very powerful tool in the therapy toolbox. 

OBR: You don’t see checkpoint inhibitors being used as a solo weapon?

VD: I think they’re probably better when they’re combined. Data in melanoma are already showing that if you combine two different checkpoint inhibitors, you get a much more robust immune response and improved outcomes. Then, of course, there’s combining immunotherapy with chemotherapy. I think that’s going to be useful as well. It’s only a question of exact timing – do you lead with the immunotherapy first and then give chemotherapy or vice-versa? Those are the kinds of studies we’re going to have to do.

OBR: There’s a lot of enthusiasm for doing those kinds of studies right now. Is your medical center actively accruing to trials in the field of checkpoint inhibitors and immuno-oncology?

VD: The problem is the FDA. Right now the FDA is in the business of approving combination chemotherapies, which they have never done in the past, and shouldn’t be doing now. If they’d had to have approved the steps in MOPP, for example, a therapy we developed for Hodgkin’s disease, it would have taken 15 years to develop, instead of 3 or 4 years. I think the same thing’s going to happen here.

OBR: You believe the FDA should only be approving individual products?

VD: They should approve products that are going to be used as a tool in the clinician’s toolkit, but leave the product’s use to the doctors who are doing the research. The people at the FDA don’t have that kind of experience. The doctors in the cancer centers, where these things are being done, are far more experienced than the panels at the FDA. Doctors shouldn't have to go to the FDA for approval every time a combination is put together. It’s ridiculous. It’s a retrogressive step.

OBR: With melanoma, NSCLC, and other tumor types being investigated, it feels like we’ve only scratched the surface of checkpoint inhibitors. Do you see a broad application for these products?

VD: I haven’t seen a tumor yet that hasn’t responded to some degree to the checkpoint inhibitors. The data in breast cancer are not terribly impressive, but they’re there. So we don’t know what the optimal circumstances are for using checkpoint inhibitors in something like breast cancer, but it looks like they might be useful for virtually every kind of cancer. We have a lot of testing to do to see if that’s true, but certainly they’re working in hard-to-treat cancers like lung cancer, which develops after being exposed to thousands of chemicals by smokers over a long period of time. When the lung cancer cell is born, it’s trained to be very resistant to chemotherapy. It’s a very difficult tumor to treat for that reason. That’s why chemotherapy doesn't work very well in lung cancer. But lung cancer tumors are just like any other tumor when it comes to checkpoint inhibitors. The tumors are responding in a very robust way for some people who are living with metastatic disease, much more so than any type of chemo that we’ve had. I think it’s a way of overcoming tumors that are highly resistant to chemotherapy.

OBR: In other words, we’ve got a lot of trials left to do.

VD: I think so… The other thing I think we’ll see a lot more of is the use of engineered T cells to attack specific antigens. You don’t need to worry about checkpoints in that case because you’re arming the lymphocytes to attack a specific antigen. That is the ultimate in personalized therapy. A person comes in, you sequence their genome, you find a receptor mutation that’s unique to that person, and you engineer the T cells to attack that particular receptor. I think that some of these very resistant tumors are going to start responding to engineered T cells.

OBR: Is there really a scalability that can be attained there? It’s one thing to do it on one cholangiocarcinoma patient, but do you see this field as growing and becoming the ultimate weapon?

VD: I can see it being done. It’s not that difficult to do. You obviously need a good lab to engineer the T cells, which take about a week to engineer and grow to a level where you can reinfuse them, and sequencing the genome is no longer cost prohibitive. Generally speaking, most cancer patients will give you a week before they start treatment, so I think it could be more widely applicable. However, cancer centers need to be equipped so they have the skills to do these things. This is nothing you’re going to see at a physician’s office.

OBR: What are your thoughts on the potential of precision medicine to change the way cancer is treated in the future?

VD: There is no question in my mind that identifying specific targets on cancer cells and developing drugs to attack those targets is the way to go in cancer treatment. But we need to convince the FDA that the way to approve new targeted drugs should be based on their safety profile and their ability to hit the target in question alone. And leave the therapeutic application of these new approaches to doctors who specialize in doing this. 

I suggest in my book that we delegate responsibility away from the cancer institute and away from the FDA for phase 1 and phase 2 clinical trials and give it to the cancer centers. The FDA and the NCI can keep their right to come in and audit anytime they want, but the cancer centers are very developed to the point where they can do these trials now themselves. It would speed up clinical trials tenfold, and it would cost less money. It’s one of these unique things that could be done without having to get a bigger appropriation.

OBR: There was some controversy over Keytruda being approved with a companion diagnostic. Is the companion diagnostic accurate in identifying the right patients? What do you do with a patient who says, “I didn’t test positive, but I still want to try this exciting new drug”?

VD: We don’t know enough about the value of a PD-1 marker or the levels of PD-1 ligand to know which one predicts what kind of therapy. There are certainly patients who respond that don’t have very high levels of PD-L1 on their tumor, so to put a guideline out that says “only people with elevated levels should use Keytruda” is backward. It stops people from investigating how to use the drug and finding out which patients that don’t have high PD-1 levels respond. The guideline also denies patients access to a therapy before we know the answers. It’s very typical of the FDA. It’s easy for them to approve an assay and then pat themselves on the back, but I think, with rare exceptions, they shouldn’t do that.

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