Personalizing Cancer Treatment

An exciting revolution is currently underway in cancer treatment. Immunotherapy is helping to unleash the power of the immune system against cancer, while new tools and technologies are providing ways to better understand individual cancers as well as predict which therapies might work best for particular patients. Together, these advancements are allowing doctors to develop novel strategies for patients with all types of cancer.

Though much progress has been made, we are still at the beginning of this revolution. There is still much work that needs to be done before we will be able to harness the full potential of personalized immunotherapy strategies and improve survival for more patients. To get a better sense of the current state of cancer care as well as how recent breakthroughs might impact the future of cancer care, we hosted a webinar for patients and caregivers with Patrick Hwu, MD, an oncologist and tumor immunology researcher who works at the University of Texas MD Anderson Cancer Center in Houston, TX.

In addition to serving as a member of the Cancer Research Institute (CRI) Scientific Advisory Council, Dr. Hwu is the head of the Division of Cancer Medicine, the chairman of the Departments of Melanoma and Sarcoma Oncology, and the co-director of the Center for Cancer Immunology Research at MD Anderson. Recently, Dr. Hwu also received the prestigious honor of being named a Fellow of the American Association for the Advancement of Science.

In this “Personalized Cancer Treatment” webinar, which you can watch in full on our website, Dr. Hwu covered the following topics:

What is Cancer?

While cancer comes in many different forms, all types of cancer are defined by cells growing uncontrollably. In general, cancers are classified according to the tissues from which they arise.

“The body is made of many different tissue types…and each of these tissues are a little bit different than the others,” Hwu explained. “So that's how we distinguish the cancers, usually from where they start. What organ did they start in? Because they're all different. And that's the first way we start to distinguish them to know what the best therapy is.”

Due to the differences in cancers that arise in different organs, some treatments work well in some cancer types but not in others, and vice versa, and immunotherapy is no exception.

Checkpoint Inhibitors

When it comes to current immunotherapies, the most successful class thus far are the checkpoint inhibitors that target the PD-1/PD-L1 checkpoint on immune cells called T cells.

These T cells are like “tanks circulating in the body,” according to Hwu. “And you can imagine, if we had a bunch of tanks protecting us on the streets, you wouldn't want those mortar shells to trigger automatically or [have] too many tanks in there. You'd have to put a brake on those tanks to make sure that they wouldn't harm anybody. And so when those immune cells get activated, our body typically shuts them down by putting brakes on the immune cells. And that's just normal. And that's good so that we don't get what's called autoimmunity.”

But in patients with cancer, doctors use these checkpoint inhibitors to block the brakes of the T cells—the PD-1/PD-L1 checkpoint—because they want these T cells to be unleashed against cancer. These immunotherapies work particularly well against cancers that have already been recognized by the immune system.

One good example is melanoma, which “starts in the pigment producing cells of the skin and spreads to many parts of the body.” In melanoma, “the UV (ultraviolet) light causes…changes in the DNA called mutations. And that makes those cells look very foreign, kind of like a virus to the immune system.” As Hwu noted, “[Checkpoint immunotherapies] have been very effective in some patients with melanoma.”

It hasn’t always been this way, as Hwu acknowledged.

“My melanoma clinic, for example, used to turn over every six months because the prognosis was so poor. Now so many of my patients, I would say the majority, are living many years, having great quality time with their families, because we've learned to take the brakes off the immune cells and allow the immune cells to kill the melanoma, sometimes which is spread everywhere. Some of these patients are free of disease for a very long time, because these immune cells can live for a very long time,” Hwu said.

“Another example is lung cancer, especially lung cancer that's caused by cigarette smoking, because the cigarette smoke also causes mutations or changes in the DNA that make the lung cancer look like a foreign body and a virus,” Hwu continued. “Not everybody responds to these…but some patients respond extremely well…and have really great responses when we take the brakes off the immune system.”

Overcoming Resistance

Due to their benefits, these checkpoint immunotherapies have been approved by the FDA, both alone and in combination, for cancers of the breast, bladder, cervix, colon and rectum, esophagus, head and neck, kidney, liver, lymph nodes (lymphoma), and skin, in addition to the lungs. However, in some cancer types, these checkpoint immunotherapies are especially ineffective by themselves.

“We know [long-term relief] can happen, but it doesn't happen in many kinds of cancers, like pancreatic cancer, ovarian cancer…we don't have enough immune cells that can recognize the cancer,” said Hwu.

“So how do we get more immune cells recognizing the cancer? One way we're doing that is to try to take the few that are there, growing them up to large numbers, and then giving them back. We call that T cell therapy. We can also take blood cells from patients, put in receptor genes to allow them to recognize and hone in on the cancer.”

This latter approach can involve either supplying T cells with a new cancer-targeting T cell receptor, or a synthetic receptor known as a CAR (chimeric antigen receptor) that can enhance their ability to target and eliminate cancer cells. These CAR T cells have been especially helpful against blood cancers, including in children, and have already been approved by the FDA for subsets of patients with leukemia and lymphoma.

Another immunotherapy strategy Hwu mentioned is vaccines, which he compared to “training the soldiers in the body to proliferate to large numbers to raise an army that can then go in and attack the cancer.”

Better Understanding of Individual Cancers

For a long time, cancer was treated in a one-size-fits-all manner, mainly because we lacked the tools to precisely characterize the activity of tumors and their interactions with the immune system at the molecular level. “The traditional way that we've done [analysis] is just to look. You take a piece of the tumor and you put it under a microscope,” said Hwu. ”That's the traditional way that we can figure out what kind of cancer it is, [or] are there immune cells in there. But there are other really exciting ways to understand cancers.”

“One is to look at the genes, the genes that are mutated and change that cause the cancers, and that can tell us what therapies we can use. Now, that's traditionally also done by a biopsy. But biopsies often require interventional radiology to scan the tumor and then stick a needle in. Normally, that's very safe…but it'd be much easier to just get blood drawn,” a reference to non-invasive blood-based biopsies currently in development. 

“As these tests improve, it's going to be remarkable what kind of information you're going to get just by going to the doctor and getting your blood drawn. It's possible one day we'll get our blood drawn, I'll say, ‘hey, you got a little colon cancer starting. We can't see anything yet, but you're going to need a colon cancer vaccine to try to get rid of this colon cancer that you don't even know about.’”

The Bacterial Microbiome

One of the most surprising discoveries of the last few years is just how important bacteria are when it comes to treating cancer. The collection of these bacteria, along with viruses and other entities, make up the body’s microbiome.

“We're made of human cells, but we're mostly made of bacteria. There's so much bacteria in our mouths, in our colons, GI (gastrointestinal) tract. There's different kinds of bacteria in all of our bodies, and it turns out certain kinds of bacteria in the body will help the body respond to these immunotherapies and [cause] the cancers to shrink.”

Right now, Hwu noted that the challenge is “trying to figure out which kinds of bacteria are necessary. And we're starting to get some hints, but with trillions of different types of bacteria, it's quite complicated.”

But for all those rushing to go out and grab a probiotic supplement, Hwu suggested that that might not be the best course of action. “We shouldn't just go to the grocery store and take a probiotic, because that's probably not the right bacteria, and that will potentially crowd out the good bacteria. So I wouldn't recommend that.”

“One thing we're starting to look at is what we call prebiotics.” This, Hwu explained, is the concept that “what you eat changes the bacteria in your gut.”

“It turns out, if you consume a lot of fiber, such as you have in beans, that may feed the right kind of bacteria in our gut so that it helps us have an immune response against the cancer. It sounds crazy. But we do think that if you have the right diet, you may have better response to immunotherapy because of changing the microbiome. It's extremely exciting research, but it's just at the beginning. There's a lot that we don't understand yet.”

Cancer Vaccines

For many decades, vaccines have been used to help protect against diseases caused by viruses and bacteria. However, it’s been more challenging—and taken longer—to develop vaccines against cancer.

“As you know, every year, we make a different flu vaccine. Why do we do that? Because the virus is different every year, so we have to make a different kind of vaccine. And every person's cancer is different from every other person’s.”

Fortunately, cancer vaccines, which Hwu called “a very exciting area,” have shown promise recently. Certain vaccines might also be capable of triggering the immune system to attack cancer cells while leaving healthy cells alone.

“The key to having a non-toxic therapy is to kill the cancer cells without hurting the normal cells,” said Hwu, “and the best way to do that is to target the changes in the cancer that are unique to that cancer but not on normal cells. That's where we have personalized vaccines.”

In addition to personalized vaccines that are developed to target the unique mutations possessed by an individual’s tumor, Hwu also discussed efforts to develop vaccines that could be used to target proteins that are commonly shared across many different patients. As a result, these vaccines could be made in advance so that they’re ready and available for patients as soon as they need them.

“Now, there's a number of mutations that can happen [in cancer]. And they interact very differently with different kinds of tissue types. But still, it's finite, the number of potential…vaccine products that we can have on the shelf. And so then if we have what I call a warehouse of antigens or vaccines…we can then do [treatments] fairly rapidly in patients.”

“Ultimately, we'd hope that someone could come to the office, we check their tissue, we check the characteristics of the mutations, of the expression levels of the tumor. And then we pull the right things out of the warehouse, and we either give a vaccine or a T cell therapy fairly rapidly, within a couple of weeks.”

“That's the goal, because whatever we come up with has to be scalable to the masses. Just in the US alone, 500,000 people a year die of cancer. So we've got to be able to, once we come up with these therapies, scale it to the population in an affordable way.”

Clinical Trials

Hwu also discussed the importance of clinical trials when it comes to advancing the field, including evaluating novel immunotherapy strategies as well as answering crucial questions that might help doctors better understand why certain patients respond and others don’t.

“Clinical trials are essential. All of the progress we've talked about today wouldn't have been possible without clinical trials. Also, clinical trials will give patients the best chance at the best outcome, because it's always the new stuff. The old stuff's been around for a few years, but the new stuff's always present in a clinical trial.”

“I can't tell you how many patients I have that are doing great after years, but the only reason they were cured was because they got on the cutting edge clinical trial at the right time. And so the right clinical trial will save many, many lives and also help us give the best therapies. I always say, each patient that we see, we want to give the best therapy today that we can possibly give.”

“That's where biomarkers come in. We really want to be able to figure out, for this patient, we should give this drug. For this patient, we should give a combination of drugs. And that's where we are working on biomarkers, to try to understand what it is about the patient as well as their cancer to allow us to give the right drug combination that will be the least toxic and the most effective against their cancer.”

“And we want to develop, at the same time, better therapies for patients that come tomorrow,” Hwu added. “So that's what clinical trials allow us to do.”

In addition evaluating the newer, potentially better therapies of tomorrow, clinical trials are also helping to reveal the benefits of treating patients with immunotherapy earlier in the course of their disease. “If at that early time point you give immunotherapy, you can greatly decrease the chances of the melanoma coming back and increase how long patients live. And so if you get them earlier, it's much better, the immune system is healthier… We really want to start these wonderful clinical trials early as the first therapy if possible.”

In particular, treating patients with checkpoint immunotherapy prior to surgery—known as the neoadjuvant setting— “has been working quite well,” according to Hwu.

The Future

Hwu capped off his webinar with his vision and hope for the future when it comes to immunotherapy and the promise of personalized cancer strategies.

“How do we get everybody to respond? It's our dream, and I think a very realistic one, that a few decades from now, people just shouldn't be dying of cancer. That we know so much, the science is going so rapidly, that we should be able to detect through blood tests and other things someone's cancer very early and intervene early and prevent it so that people don't even get cancer.”

“We should be able to figure out what we should do for our diet and the environment and exercise and other things to try to prevent cancer from coming on in the first place. So there's going to be many ways that, hopefully, in a few decades, we're not going to have patients dying of cancer. It'll be unusual.”

“The Cancer Research Institute and other groups have really been strong supporters of cancer research. And it's extremely important, because that way, we can make that dream a reality sooner.”

Patrick Hwu, MD, is the head of the Division of Cancer Medicine, the co-director of the Center for Cancer Immunology Research, and the Sheikh Mohammed Bin Zayed Al Nahyan Distinguished University Chair at the University of Texas MD Anderson Cancer Center in Houston, TX.

As both a practicing oncologist and a tumor immunology researcher, Dr. Hwu’s goal is to translate basic immunological concepts into treatments that can benefit patients in the clinic. In pursuit of that goal, his work has provided important insights into our understanding of the relationship between tumors and the immune system, many of which have helped to advance clinical immunotherapy strategies, especially adoptive cell-based approaches. Most recently, he has focused on combining cellular and checkpoint immunotherapies, in addition to rational combinations involving other agents, in order to improve patient survival.

This webinar, the second in the 2019 Cancer Immunotherapy and You webinar series, is made possible with generous support from Bristol Myers-Squibb as well as Cellectis.