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Top cancer researcher to tout advances during Buffalo fundraiser

Some of the new drugs and practices saving lives from cancer today have their roots in research dating to the 1990s, Lee Greenberger says.

Roughly 40 percent of newly approved cancer drugs are being used to fight leukemia, lymphoma and myeloma, even though blood cancers make up about 10 percent of all malignancies.

That's a good thing, to hear Lee Greenberger tell it, because research that has taken place during the last six decades in this realm has helped find treatments for other cancers and conditions, including rheumatoid arthritis and cardiovascular disease.

"What typically has happened in the blood cancer space is that if you can demonstrate safety and efficacy in a small disease, it quite often happens that it can be applied more broadly," said Greenberger, chief scientific officer of the White Plains-based Leukemia & Lymphoma Society (LLS).

Greenberger is responsible for planning and executing the strategy for society research programs in eight countries around the world, work that has helped exponentially increase survival rates for several blood cancers. He will attend and speak Saturday evening at the LLS Western and Central New York chapter's annual Diamond Ball in Samuel’s Grand Manor in Clarence.

The Brooklyn native holds a bachelor's degree in psychology and biology from the University at Rochester and a doctorate in anatomy from Emory University, outside Atlanta. He worked for more than a quarter century in the pharmaceutical industry, focusing on cancer biology and drug discovery, before joining the LLS 3½ years ago.

Q. What do you plan to talk about during the Diamond Ball?

New therapies. Therapies for chronic lymphocytic leukemia and multiple myeloma have changed dramatically with approval of about four drugs in each of those tumor types in about the last three years. I'm going to talk about how the so-called CAR T therapy and applications for immunotherapy have changed the trajectory for some patients who have failed all therapies – and will be a major piece in terms of the future. I'll also talk a little bit about how we're approaching prevention.

We are one of the few cancer foundations that have been around long enough to see how cancer therapy has changed during the last 60 years. We've been around since the inception of chemotherapy. When Roswell Park Cancer Institute was beginning to work on cytotoxic therapy, we were there.

Q. Can you talk about the scope of LLS-supported research. How much does the nonprofit spend each year and how is that money spent?

We started funding academic research in 1953. We have funded about 4,000 academic grants since at institutions throughout the United States, Europe and Australia, all over the globe. The purpose of the work is to develop new therapies that ultimately will achieve a cure for all the blood cancers. Last fiscal year, we funded about $50 million worth of research and that's pretty typical. We have put about $1 billion into blood cancer research overall.

Obviously, we're looking to identify new therapeutics to treat blood cancer but this doesn't happen on its own. We fund a lot of basic research in laboratories that ultimately lead to identification of so-called drivers – proteins that drive cancer. You've got to develop the therapies that might hit those drivers and then you have to do clinical trials to prove that the therapies are safe and effective…

We're invested very early on. That has paid off because some of the newest drugs out there today started in our research portfolio where we can trace them back to 20, 25 years ago.

We also fund early stage careers. We have a career development program that has used up about $370 million out of that billion dollars spent. The idea is to fund investigators within 10 years of the start of a professional career … to attract them to the blood cancer area, to establish their footing. Many of these people have gone on to be well-established, prominent, internationally recognized cancer researchers.

Q. What are some of the most significant developments that have come to treatment of blood cancers in the years you’ve been in the research field?

When I started in about 1970, Roswell Park was heavily involved in this concept of using cytotoxic chemotherapy, which began in the 1950s. Those cytotoxic agents that caused bone marrow suppression also turned out to be able to control cancer. That made a difference for all kinds of cancers. Those with blood cancers probably benefited most. For example, children with acute lymphoblastic leukemia, ALL, went from about a 3 percent survival rate in 1950 or so to about 90 percent today. That's survival. That's cures. Most of that activity has come from combination cytotoxic chemotherapy.

What's happened in the last 25 years is that we have attempted to move away from the cytotoxic therapy and there's been a plethora of agents developed called targeted agents. In other words, the proteins that drive the cancer turn out to be mutated in one way or another and we've developed drugs – in some cases, oral drugs – that can be taken every day that can control the cancer long term.

For example, if you have chronic myeloid leukemia, or CML, you could take a drug called Gleevec  (LLS started helping with the research about 1995) – a little orange pill developed about 17 years ago. As long as they're on that drug, their CML is under control. Patients ultimately can live just about a normal life, in a normal lifespan.

Then there's antibody therapy that begins at about the late 1990s. Some people have heard about rituximab. It's also called Retuxan. That drug controls lymphoma. It also turns out to control arthritis – and in fact many of these blood cancer drugs, and the work we have done, have set the stage for the utility of these drugs in other cancers and other diseases. So there's a spillover from all this work in blood cancers to solid tumors and other diseases.

There's a couple new antibodies that have come out to control multiple myeloma. One that has had as dramatic effect is daratumumab. That antibody has prolonged survival of multiple myeloma patients in a dramatic way. That drug got approved about a year ago and is now being used in combination therapy … and we're doing these kinds of things in the hope of ultimately achieving cures.

A third thing that has come out, in about the last five years, is immunotherapy. It's been a very hot topic in solid tumors. There's a drug called Opdivo promoting life after lung cancer. You can activate the immune system by either pressing on the brakes or stepping on the gas. Opdivo was  developed to step on the brakes in solid tumors but it turns out it also has applications in blood cancers. It's had a very dramatic effect in treating Hodgkin's Lymphoma patients.

The stepping on the gas is this so-called cellular therapy. CAR T. What it is – and we started funding this work in the mid-1990s – has shown that it can control tumor growth in a major way.

The patient's own T cells are taken out of the patient and genetically engineered such that you put a homing device on the T cells, and you put them back in the patient. The T cell now homes on the tumor cell and the T cell is programmed when it does that to kill the tumor cell and increase the number of T cells.That CAR T therapy turns out to be astonishingly effective with these kids who have acute lymphoblastic leukemia … and ultimately fail cytoxic therapy. The first kid who had this problem failed everything – cytotoxic therapy, radiation therapy, transplants. She went on to this CAR T therapy and the disease cannot be detected today, four years out.

The other arm of immunotherapy is this so-called vaccine therapy. The concept is what if I can use a vaccine to activate the immune system to kill tumor cells.

Q. As point person for promising new treatments, what do you see on the horizon?

One thing is precision medicine. Now that we can sequence all the known proteins, all the genes, in a person, we know that are about 200 really bad actors that get mutated and drive cancers. That's interesting but the next question is, "So what?" I could tell a patient, "You've got a mutation. It's a really bad one. The prognosis is bad." Do we have any therapies for this? What we've done during the last 20 years with some of these therapies, including Kinase inhibitors, is to develop an arsenal of drugs that target these mutated, or driver, proteins…

We have a large clinical trial underway in which LLS is the (sponsor). It's quite unusual for a nonprofit to be one. This will run nationwide in about 10 clinical sites to sort out all these patients and use new agents that are coming to pharmaceutical companies to apply in this fashion. It's called the Beat AML Master Trial.

Q. How costly is it to research and develop these treatments?

When I say we've spent a billion dollars, there's a reason why a lot of money gets spent. We're just on the research and early clinical development end. The clinical trials take place in three phases. Trials get progressively bigger. A Phase 1 trial might start with 20 to 50 patients. By the time you're in a Phase 3 trial, you could be talking about over 500 people. The drug discovery work can take place over five, 10, 15 years, with a lot of misfires. You have to develop all sorts of systems and maybe a new therapeutic to maybe even put something in the clinic.

The reason there's such a funnel is because the clinical trials are very expensive. Cost per patient could run $100,000. When you start running the numbers, it can get pretty large.

Beyond that, any company that takes on these large trials is recognizing that there's going to be a failure rate, which can be very significant. Better than half the amount clinical work could ultimately fail and not lead to a clinical drug that gets approved by the FDA.

Q. Are some of the leading drugs used to treat leukemia, lymphoma and myeloma very expensive?

These new drugs are expensive. There's no doubt about it. They can run $100,000 a year for therapy. Beyond that, the patients who we treat for cancer in general tend to be older. Over 65, they're Medicare age, which means the government is going to have a huge bill to pay. These are life-extending drugs with very dramatic effects in terms of controlling disease. We've seen people with lymph node masses the size of a baseball on their necks go to zero. Zero. That's how powerful some of these drugs are. But they're costly. How all of this gets resolved is unclear because the drugs are expensive. They're paying for the innovation and research that's required to develop these drugs, yet we have a dilemma of patients who have bills, governments that have big bills. The more of these drugs come out – and remain on patent, where you can charge a high rate – the bills are going to mount up. And it gets worse. … The cost is going to be over $200,000 a year for combination therapy. If we know these drugs are going to be used in combination, it's a challenge.

Q. There seems a conundrum with people donating money out of pocket to help develop drugs that go on patent.

It is a dilemma. LLS spends a billion dollars. The government spends a huge amount of money funding all this work and then you can say the pharmaceutical companies benefit from it. They do, but the benefit is to society. When you put it down to the level of a person, what's the benefit of changing the trajectory of a child who has ALL, and taking him back from that cliff, and saying "Here's your life back"? That is a really tough equation. I will say that Pharma has spent a lot of money in drug development, with a lot of risk. Most of the projects I worked on in Pharma failed. We couldn't find a drug. It wasn't safe enough. It failed in toxicology studies. It failed in the clinic. There are so many ways to derail a drug. But if you take away the incentive for Pharma companies, the price you pay is innovation. How do you innovate and motivate companies to produce new drugs at risk if you take that footing away? That's a real challenge.

That's where the future lies. Can we develop safe, and highly effective strategies, to get rid of those cells that have the mutations and keep the ones that have only the good cells. If that can be accomplished, we will have made a major, major advance. Some of that work we are now funding. It's looks very promising.

Q. What are the key challenges that remain when it comes to finding even more effective treatments to blood cancers and other cancers?

Tumor cells are really sneaky. You can get a response to a therapy and then they develop resistance. They're constantly changing, and develop other mutations and get around the therapies. That evolution is a major problem, and being able to detect and do something about it before it happens is a major goal…

That's where the future lies. Can we develop safe, and highly effective strategies, to get rid of those cells that have the mutations and keep the ones that have only the good cells. If that can be accomplished, we will have made a major, major advance. Some of that work we are now funding. It's looks very promising.

email: refresh@buffnews.com

Twitter: @BNrefresh, @ScottBScanlon

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