T Cell Therapies Offer a New Way to Treat Gynecologic Cancers

Source: Memorial Sloan Kettering - On Cancer
Date: 09/30/2020
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The American Cancer Society estimates that more than 113,000 people in the United States are diagnosed with a gynecologic cancer every year. Memorial Sloan Kettering is a leader in treating people with these cancers, which include tumors of the cervixovaries, and uterus.

Among the new treatments being developed for gynecologic cancers are a type of immunotherapy called T cell therapies. These are treatments in which a patient’s own immune cells are modified to recognize and attack cancer cells. MSK doctors and scientists were the first to develop these treatments for leukemia and lymphoma. Now, many researchers are focused on further advancing this approach to make it effective against solid tumors.

“For certain blood cancers, cellular therapy can be remarkably potent, perhaps even curative,” says physician-scientist Christopher Klebanoff, whose lab is focused on developing new cell therapy approaches. One challenge of immunotherapy is directing the immune cells only to tumors so they don’t cause injury to healthy tissues.

Treating Cancer with CARs and TRUCKs

The most well-known cell therapy is chimeric antigen receptor (CAR) T therapy, which has shown success in treating certain blood cancers. CAR T modifies a patient’s immune cells (T cells) so they can recognize a protein (called an antigen) on the outer surface of cancerous cells. These supercharged T cells then seek out and destroy the cancer. For many cancers, especially cancers originating from a solid organ, the antigen isn’t quite as easy for the T cell to find, making cell therapies more challenging to develop.

This has led to a related tactic called T cell receptor (TCR) therapy, in which T cells are engineered to detect antigens on the inside of the cancer cell. “The ability to do this is one of the greatest tricks in biology,” Dr. Klebanoff says. “That is, how can you allow an immune cell to look inside other cells to detect if the proteins inside are normal or abnormal?”

As it turns out, the way this “looking” works is actually indirect: As part of normal cellular operations, proteins eventually get broken down and recycled to make new proteins. One step in this recycling process displays protein fragments on the surface of cells — allowing them to be seen by engineered T cells. TCR therapies are designed to take advantage of this natural process that the immune system uses to survey tissues in the body.

Some of the newest cell therapies known as TRUCKs — T cells redirected for antigen‐unrestricted cytokine‐initiated killing — work by combining the antitumor abilities of CAR T or TCR therapy with a molecule called a cytokine. The cytokine recruits another wave of immune cells to the tumor.

A Personalized Approach to Cancer Care

Medical oncologist Roisin O’Cearbhaill is the research director for the Gynecologic Medical Oncology Service and a leader in studying new cell therapies and immunotherapy approaches for treating gynecologic cancers, including a treatment for cervical cancer and other tumors caused by the human papillomavirus (HPV). “We’re building up our clinical trial program at MSK so that we will be able to offer more cellular therapies for patients with gynecologic cancers,” she says.

“With cell therapies, we use our knowledge about specific molecular and genomic properties of the patient’s cancer,” Dr. O’Cearbhaill explains. “And we may also use certain markers on their blood cells in order to get the best possible match for a targeted therapy for that individual patient.”

“For each of our patients, we take a very personalized approach to match the best possible medicines, including experimental medicines offered in clinical trials, with the patient’s disease,” Dr. Klebanoff says. “I’m a big believer in the concept of partnership and shared purpose, and this is how we work in collaboration with our patients. We have a shared purpose to try to improve things both for them and for others with similar diseases in the future.”

Clinical Trials Offering Cell Therapies for Gynecologic Cancers

MSK currently has a number of clinical trials that are examining this approach.

  • Dr. O’Cearbhaill is co-leading a phase I study with Dr. Klebanoff that is assessing the safety and effectiveness of using a TCR therapy called KITE-439 to treat cancers caused by a strain of HPV called HPV 16. The majority of cervical cancers as well as many cancers of the mouth, throat, vagina, vulva, penis, and anus are associated with HPV 16. In this study, a patients’ immune cells are modified to recognize and attack tumor cells that contain HPV 16.
  • The doctors are also co-leading a phase I trial for a cell therapy called KITE-718, which targets cancers containing MAGE-A3/A6, a protein found in some ovarian and cervical cancers as well as other kinds of cancer.
  • To study another treatment for ovarian cancer and cancers of the fallopian tubes and the peritoneal cavity (the lower abdomen), Dr. O’Cearbhaill is leading a phase I trial for a CAR T therapy that targets a protein called MUC16, which is made by many of these tumors. MUC16, also called CA125, is best known as a biomarker used to monitor treatment for ovarian cancer.
  • Dr. O’Cearbhaill is also leading a phase I/II trial for a TRUCK drug called TC-210, which is being tested in combination with chemotherapy. This cell therapy targets tumors that make a protein called mesothelin, which is found in several cancers, including some ovarian tumors.

Working It Out: Does Exercise Boost the Effectiveness of Melanoma Treatment?

Source: Memorial Sloan Kettering - On Cancer
Date: 11/05/2020
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Exercise is not just an important part of life for Memorial Sloan Kettering physician-scientist Allison Betof Warner — it’s an important part of her research.

Dr. Betof Warner, a medical oncologist who specializes in treating people with melanoma, is also a member of MSK physician-scientist Jedd Wolchok’s lab. There, she studies the effects of exercise on melanoma and other cancers using mouse models. She hopes to eventually apply her findings to her patients.

In an interview, she talked about her work.

How did you get interested in studying the connection between exercise and cancer outcomes?

I’m a lifelong athlete. I was a competitive gymnast for many years, including as a Division 1 student-athlete in college. When I got to medical school [at Duke University School of Medicine], I became a marathon runner and CrossFit athlete. I competed in the CrossFit Games (the world championships of the sport) and have coached CrossFit since 2010.

I was also working on a PhD in cancer biology. I started out studying the structure of tumor blood vessels. Then I heard a talk from Lee Jones about exercise and cancer. [Dr. Jones, who was then at Duke, now leads MSK’s Exercise Oncology Service, which is studying how exercise affects cancer outcomes through both lab research and clinical trials.]

Lee was using mice to study whether exercise could help improve outcomes in breast cancer. He co-mentored me during my PhD, and we published a study that showed exercise improves the quality of the blood vessels going to a tumor, which, in turn, makes chemotherapy more effective.

How has the view of exercise and cancer changed?

When I started my PhD research about fifteen years ago, some people were concerned that if you improved the structure of the blood vessels in a tumor, it might help the tumor grow faster or make it easier to spread. Our research in mice showed that this is not a concern. We still haven’t shown that patients experience all the benefits we’ve seen in mice, but collectively the data suggest that exercise is not harmful — either in melanoma or any other kind of cancer.

Research has demonstrated that exercise has many benefits for people with cancer, including reducing cancer-related fatigue. It also provides psychological benefits by improving overall mood and sense of well-being.

What are you studying now?

My current research has been looking at mice running on a treadmill to see how it affects the immune system — both the immune cells coming into the tumor and those circulating in the body. We’re still learning, but early work has suggested that exercise slows the growth of melanoma tumors in mice and that it does so by acting on the immune system.

I first became interested in this topic when I was a medical resident, and immunotherapy was becoming an important form of cancer treatment. We’ve known for some time that exercise has effects on the immune system, so it raised interesting questions about the role exercise plays in the effectiveness of immunotherapy. After I came here as a fellow, I joined Jedd’s lab, where they were doing research on how to make immunotherapies more effective.

Does your research influence what you tell your patients?

Currently, we don’t have enough data to recommend one particular type of exercise over another. Several organizations, including the American College of Sports Medicine, have put out recommendations for people with cancer that recommend 150 minutes a week of moderate exercise or 75 minutes a week of more vigorous exercise. I share those guidelines with my patients.

If patients were exercising before their cancer diagnosis, I tell them to maintain what they were doing. For people who were completely sedentary, there is no magic number or exercise prescription for me to give them that’s data driven right now. But we know that getting up, moving around, and being active is good for people with cancer, and I tell them that.

What do you do to stay fit these days?

I exercise six days a week. It not only keeps me healthy, but it keeps me sane.

Before the COVID-19 pandemic, I was teaching CrossFit. I got a Peloton bike right before all the gyms closed, and I’ve become an avid user. My husband and I just bought a house in the suburbs, and I’m putting in a CrossFit gym in our garage. He’s very tolerant!

What are your plans for your research?

In addition to continuing my research in the lab, I’m working with Bill Tap [Chief of the Sarcoma Medical Oncology Service] and Julia Glade Bender [Vice Chair for Clinical Research in the Department of Pediatrics], who are leading the new Adolescent and Young Adult program at MSK. [This program aims to meet both the medical and psychosocial needs of people with cancer who are in their teens, 20s, and 30s.] I’m leading the development of an exercise component. It will focus on research as well as clinical care for patients in the program.

Because of the pandemic, the program will be remote at first, but our goal is to eventually hold in-person classes. One thing that’s important to emphasize about exercise is that it helps to create communities. For adolescent and young adult patients, we expect this program will become part of their support system.

Chemotherapy-Immunotherapy Combination Aims to Knock Out Melanoma with a One-Two Punch

Source: Memorial Sloan Kettering - On Cancer
Date: 02/02/2018
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For some people with cancer, drugs that help the immune system recognize and attack tumor cells have been a game changer. But for most, the outcomes from these immunotherapies are not effective, and other treatments are required.

Now a collaborative group of melanoma experts is testing a novel combination therapy for certain people with that aggressive form of skin cancer. They have combined immunotherapy drugs with chemotherapy that treats only the area affected by cancer. The results of lab research, as well as the first-ever clinical trial to explore this particular approach, are being reported in the journal Cancer Immunology Research.

“Immunotherapy has had great successes, but we’re looking for ways to make it effective for more people,” says Charlotte Ariyan, a Memorial Sloan Kettering surgeon who is the lead author of the new study. “Our work in the lab is focused on developing better treatments, which we can then bring to patients as part of clinical trials.”

Using Two Treatments Together for Better Results

The approach combines the relatively new immunotherapy drug ipilimumab (Yervoy®) with a treatment that’s been around much longer, called isolated limb infusion.

Limb infusion is used as a therapy for in-transit melanoma, which means the cancer has spread throughout an arm or leg. People with this form of the disease can have dozens of small tumors, making it difficult to treat them all with surgery or radiation. The infusion treatment is given by putting a very high dose of chemotherapy directly into the affected arm or leg. A tourniquet prevents the medication from going into the rest of the body.

“Limb infusion is an interdisciplinary treatment that requires a lot of expertise,” Dr. Ariyan explains. “At MSK we have a dedicated team for limb infusion that includes an anesthesiologist, an interventional radiologist, nurses, and medical oncologists. This allows us to offer this specialized treatment to our patients in a very efficient way.”

But limb infusion often doesn’t have long-lasting results. Most of those who respond see their disease come back within a year. This is where the immunotherapy comes in.

Making Cancer Visible to Immune Cells

In research conducted in the lab, Dr. Ariyan and her colleagues, including Sloan Kettering Institute Immunology Program Chair and Director of the Ludwig Center for Cancer Immunotherapy (LCCI) Alexander Rudensky, found that when mice were given chemotherapy before ipilimumab, the responses to the immunotherapy were much better.

“The idea behind immunotherapy is that you’re trying to get the body to recognize the tumor, but a lot of times the tumor stays silent,” says Dr. Ariyan, who is also a member of LCCI. “Because chemotherapy causes some of the cancer cells to die, it leads to inflammation in the area around the tumor. This is an opportune time to give immunotherapy because the tumor is easier for the immune system to find.”

In the mice, the researchers found that combining the treatments resulted in an increase in the number of immune cells that were able to get into the tumor. This ultimately led to improved survival in the animals.

A few previous studies done in people with lung cancer have looked at combining immunotherapy with systemic chemotherapy. That’s when chemotherapy is delivered throughout the body. The results of that combination treatment have been mixed. “Because systemic chemotherapy can wipe out a person’s immune cells, it’s usually not the best approach,” she says. “However, if you can give chemotherapy in a way that the immune system is still intact, it appears to show benefits.”

Taking the Treatment Approach to People

The discoveries made in mice led to the idea to test this treatment in people. Money from Cycle for Survival — MSK’s indoor team-cycling fundraiser, which supports research on rare cancers — as well as from other foundations helped move the research into a clinical trial.

The phase II trial included 26 people who had advanced melanoma in an arm or leg. Participants were given limb infusion with chemotherapy followed by ipilimumab. After three months, 85% had their tumors shrink as a result of the treatment. Of those who responded, more than half had a complete response, meaning that their tumors disappeared. Today, 58% of them remain disease free, even after they stopped receiving ipilimumab.

Dr. Ariyan says that the team will continue to explore this approach in people with in-transit melanoma who are not responding to immunotherapy alone. In addition, they are considering it to treat other types of cancer, such as sarcoma, which frequently occurs in the muscles, bones, and connective tissues in the arms or legs and usually doesn’t respond to immunotherapy.

Immunotherapy Combination Is Better than Chemotherapy for Non-Small Cell Lung Cancer

Source: Memorial Sloan Kettering - On Cancer
Date: 04/16/2018
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A treatment that combines two specific immunotherapy drugs has already had success in some people with advanced melanoma and kidney cancer. A phase III study has now shown that the same combination was also effective for people with lung cancer. The international research team that conducted the trial was led by Memorial Sloan Kettering medical oncologist Matthew Hellmann. The findings are being presented at the 2018 American Association for Cancer Research (AACR) annual meeting. They are being published online in the New England Journal of Medicine as well.

The clinical trial was called CheckMate -227. It looked at combining nivolumab (Opdivo®) and ipilimumab (Yervoy®) to treat people with advanced non-small cell lung cancer, the most common type of lung cancer. The analysis being presented focused on people with a molecular marker indicating that there were many mutations in their tumors. Previous studies from MSK have suggested that tumors with many mutations are likely to respond to immunotherapy. After a minimum follow-up of nearly a year, those whose tumors had many mutations who received the immunotherapy combination were 42% less likely to have their cancer progress compared with those in the control group, who got standard-of-care chemotherapy.

“This trial had two important findings,” says Dr. Hellmann, who is a member of the Parker Institute for Cancer Immunotherapy at MSK. “First, it showed us that the combination of these immunotherapies together control lung cancer better than chemotherapy. Second, it showed that molecular markers are effective in helping to predict which people will benefit from immunotherapy.

“The results of this study highlight the importance of molecular profiling to identify the best treatment options for each patient,” he adds. “We are already doing this type of testing routinely for people with lung cancer, for example, with MSK-IMPACT™.”

Leading the Way in Clinical Trials

Ipilimumab and nivolumab are both in the class of drugs called immune checkpoint inhibitors. These drugs help control cancer by taking the brakes off the immune system. This allows the white blood cells called T cells to attack tumors. MSK physician-scientist Jedd Wolchok led the clinical research that resulted in the approval of ipilimumab in 2011 by the US Food and Drug Administration for the treatment of advanced melanoma.

Dr. Wolchok also led the pivotal clinical trial that resulted in FDA approval for the combination of ipilimumab and nivolumab in melanoma in 2015. Because that combination has worked well for melanoma, researchers decided to evaluate it for other cancers as well, including non-small cell lung cancer. Nivolumab on its own is already approved for this type of lung cancer, as well as for a number of other cancers.

Importance of Mutational Burden

Despite the striking success of checkpoint inhibitors at stopping cancer growth and even eliminating tumors in some people, these drugs don’t work for everyone. Research at MSK has focused on why that’s the case and looked for ways to predict beforehand who is most likely to benefit.

One important discovery that’s been made in many types of cancer is that tumors with a greater number of mutations tend to respond better to checkpoint inhibitor drugs than those with fewer mutations. This characteristic is called a high tumor mutation burden (TMB). In a related study, published online April 12, 2018, in the journal Cancer Cell, Dr. Hellmann and colleagues at MSK and elsewhere focused on the role of TMB in people with non-small cell lung cancer who were treated with nivolumab plus ipilimumab. The goal of study was to examine was to link the molecular features of the tumors to the patients’ outcomes after treatment with nivolumab plus ipilimumab in a phase I trial called CheckMate-012.

Based on their analysis, the researchers found that a high TMB was a good way to predict the effectiveness of combination immunotherapy in people with non-small cell lung cancer. The findings were used to guide the testing that was later done in the CheckMate -227 trial. TMB is already part of the results obtained from the MSK-IMPACT test.

A New Treatment Option for Non-Small Cell Lung Cancer

In CheckMate -227, among people whose tumors had a high TMB, the response rate was much better for those who got immunotherapy rather than chemotherapy. After getting the combination, 45% had their tumors shrink compared with 27% of those who got chemotherapy. And responses were distinctly durable with immunotherapy, where 68% were still responding to the immunotherapy combination one year after treatment started compared with only one-quarter of those who got chemotherapy.

The researchers say that immunotherapy is an important addition to the roster of treatment options for people with advanced non-small cell lung cancer. “This drug combination shows that some people can be spared treatment with chemotherapy,” Dr. Hellmann says. “And if a person stops responding to immunotherapy, they can still be given chemotherapy for additional benefit.”

Putting the STING in Immunotherapy: Research Focuses on Ways to Improve Cancer Treatments

Source: Memorial Sloan Kettering - On Cancer
Date: 09/19/2018
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Drugs called immune checkpoint inhibitors have made a significant difference for some people with cancer. They work by taking the brakes off the immune system, allowing white blood cells called T cells to attack a tumor.

For this approach to work, however, the T cells need to be able to see the tumor and recognize it as something that doesn’t belong in the body. Often, they cannot. That explains why, for most people, these drugs are not effective. Finding new tactics for making tumors more noticeable to the immune system is an important area of research.

Tumors are sometimes described as “hot” if they show signs of inflammation, with lots of immune activity around them. “We’re looking for ways to turn a cold tumor into a hot tumor,” says Memorial Sloan Kettering physician-scientist Liang Deng. “If you can bring the tumor out of hiding and make it more visible, it will help to really ramp up the immune response.”

Finding Ways to Trick Cancer Cells

One approach that many investigators around the world are studying is the potential to harness the cGAS/STING pathway. (The abbreviation cGAS/STING is a much shorter way of saying “cyclic GMP-AMP synthase/stimulator of interferon genes.”)  

In particular, cGAS/STING works by detecting bits of DNA from bacteria or viruses that have infected a cell. The detection fires up the innate immune pathway, the system of immune defenses that are present from birth and are always active. Innate immune cells produce chemicals that alert other parts of the immune system to the presence of the intruders. In 2013, Sloan Kettering Institute structural biologist Dinshaw Patel published two papers in Cellshowing some of these complex structures for the first time.

Now, some pharmaceutical companies are starting to develop drugs called STING agonists. These are small molecules designed to activate the STING pathway after being injected into a tumor, which sends out a beacon for immune cells to follow. The idea is to use these new drugs in combination with checkpoint inhibitors.

“STING agonists are based on the hypothesis that you can trick immune cells into thinking that the tumor cells are infected with a virus,” says MSK physician-scientist Samuel Bakhoum. “Then the immune cells will come in and basically clear the cancer away.”

Seeing the Full Immune Picture

More recently, however, investigators have learned that in some cases the STING pathway plays a role in helping cancers thrive, making this approach more complicated. “It turns out that many cancer cells also have DNA where it doesn’t belong. Rather than being only inside the nucleus where it normally resides, it’s also floating around inside the cytosol [fluid] of the cell. This is caused by a phenomenon called chromosomal instability — a widespread feature of human cancer,” Dr. Bakhoum says.

“Chromosomally unstable cancer cells have found ways to adapt to that floating DNA. They avoid the harmful consequences of cGAS/STING activation while using this pathway to their advantage,” he adds. “Alternatively, a small number of tumors lose cGAS and STING altogether. This adaptation to DNA in the cytosol may actually help them spread to other parts of the body.” In January 2018, Dr. Bakhoum was the first author of a paper in Naturethat reported this phenomenon.

Along with researcher Lewis Cantley of Weill Cornell Medicine, Dr. Bakhoum recently published a review article in Cell on the ways that cells with unstable chromosomes use STING to their advantage to evolve and become more aggressive. It turns out that chronic activation of this pathway might suppress the immune system rather than trigger it to fight the cancer. “It suggests that we need to be very careful in determining which people could benefit from treatment with STING agonists,” Dr. Bakhoum says. “Patient selection will be a critical contributor toward the success of this therapy.”

Another Approach to Heating Up Tumors

Dr. Deng’s lab is taking a different tack for activating innate immunity in tumors: injecting them with a virus. This is another way to flag tumors and make them more visible to the immune system.

She’s working with modified vaccinia virus Ankara (MVA). This engineered virus has been safely used as a vaccine against smallpox. In 2017, her laboratory published a paper in Science Immunology demonstrating that injecting inactivated MVA into tumors in mice stimulates the immune response against the tumors. The findings showed that the response was boosted by checkpoint inhibitor drugs.

Now her laboratory is working on engineering MVA to make it more potent for immunotherapy. Dr. Deng explains that using the engineered MVA has several potential advantages over drugs designed only to fire up STING. For one thing, the virus is larger than a drug molecule, allowing it to remain in the tumor tissue for a longer time. In addition, the virus can be engineered to do much more than draw attention to the tumor.

The engineered MVA activates STING not only in tumors but T cells too. It also carries a growth factor for immune cells called dendritic cells. “We know based on previous work that dendritic cells are an important part of the immune response to cancer,” she says. “Injecting engineered MVA into tumors creates an in situ vaccination effect, which teaches T cells to recognize tumors.”

Dr. Deng and her MSK colleagues Jedd WolchokTaha Merghoub, and Stewart Shuman recently co-founded a start-up company called IMVAQ Therapeutics. The company is developing the virus so that an application can be submitted to the US Food and Drug Administration to begin clinical trials. IMVAQ is planning tests in a number of solid tumors, either alone or in combination with checkpoint inhibitors. “We hope this approach will be particularly successful in tumors that don’t usually respond to checkpoint inhibitor drugs, like breast and prostate cancers,” she notes. “We also believe this virus will be very safe because it doesn’t replicate in human cells.”

MVA is not the only virus being studied for this purpose. MSK already has other trials underway that use this immunotherapy approach as well. A phase III trial using a virus called T-VEC (talimogene laherparepvec) is being studied in combination with the checkpoint inhibitor pembrolizumab (Keytruda®) for advanced melanoma, for example.

“All of the research that’s been done over the past 20 years on the basic science of the innate immune system, including a lot of work done at MSK, has made these kinds of studies possible today,” Dr. Deng concludes.

New Study Shows Immunotherapy and Chemo Combination Extends Survival for People with Hard-to-Treat Breast Cancer

Source: Memorial Sloan Kettering - On Cancer
Date: 10/20/2018
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Today at the annual meeting of the European Society for Medical Oncology, an international team of breast cancer experts reported findings from a large clinical trial. They had tested a combination of immunotherapy and chemotherapy in people with advanced triple-negative breast cancer. The investigators found that many people in the study who had the immunotherapy combination therapy lived longer compared with chemotherapy alone.

Memorial Sloan Kettering medical oncologists Elizabeth Comen and Christopher Klebanoff, both experts in breast cancer immunotherapy, offer their perspective about these findings and the potential impact on the field. Neither Dr. Comen nor Dr. Klebanoff were part of the study, which is being published in the New England Journal of Medicine.

“Immunotherapy works best on solid tumors that have large numbers of mutations because mutations put up flags that make the tumors visible to the immune system,” explained Dr. Comen. “It’s long been thought that triple-negative breast cancers might be susceptible to immunotherapy because they tend to have a lot more mutations that the immune system can recognize.”

The trial included 902 people who were treated at 246 hospitals in 41 countries. All of them had locally advanced or metastatic triple-negative breast cancer. The people in this study were given either a standard chemotherapy drug for this type of breast cancer called nab-paclitaxel (Abraxane®); an immunotherapy drug already approved for other cancers called atezolizumab (Tecentriq®), which works against the protein PD-L1; or a combination of the two.

The researchers reported that people with tumors that expressed the PD-L1 protein who received the combination therapy lived 9.5 months longer. About 41% of people in the trial had this protein on their tumors. “This is not a cure, and at every step of the way we’re always looking for that,” Dr. Comen says. “But any incremental benefit to patients’ lives can be significant, and this is a significant benefit.”

“There is a tremendous unmet medical need in this breast cancer subtype,” Dr. Klebanoff says. “We’ve made great progress in recent years in treating other types of breast cancer, but triple-negative breast cancer has not benefitted from many advances. This study dispels the myth that immunotherapy cannot work for breast cancer. As we learn more about this approach, we expect to see more and better treatment options for many breast cancer patients.”

Tumor Mutational Burden Can Help Predict Response to Immunotherapy in Many Different Cancers

Source: Memorial Sloan Kettering - On Cancer
Date: 01/17/2019
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Very early on in the development of the immunotherapy drugs called checkpoint inhibitors doctors realized that melanoma and lung cancer have something important in common. These cancers were the first shown to respond to checkpoint inhibitors. Both tend to have a lot of DNA mutations. Tumors with an elevated number of mutations are referred to as having a high tumor mutational burden (TMB).

Researchers from Memorial Sloan Kettering have conducted a wide-ranging study to find out if the relationship between high TMB and a positive response to checkpoint inhibitor drugs holds across other cancers. Their findings were recently published in Nature Genetics.

“Based on observations in lung cancer and melanoma, experts in the field have made the assumption that the association between mutation burden and immunotherapy response is true for all cancers,” says surgeon-scientist Luc Morris, one of the three senior authors on the paper. “Until now, however, it hasn’t been well studied. Our study asked if TMB has value as a predictive biomarker across all cancers.”

The investigators confirmed that TMB is predictive across many cancer types. They also noted that people with high-TMB tumors who were treated with immunotherapy lived longer compared with those who had high-TMB tumors and got other kinds of treatment. And importantly, they determined that what is considered a high level of TMB varies depending on the type of tumor. This is a critical question that needed to be answered before using this information when caring for patients.

Bringing Tumors Out of Hiding

The relationship between a high TMB and response to immunotherapy was first demonstrated in two groundbreaking studies from MSK researchers. One, published in 2014 by physician-scientists Timothy Chan and Jedd Wolchok, reported the connection in melanoma. Another study the following year from Dr. Chan and then MSK researcher Naiyer Rizvi reported the same relationship between immunotherapy response and high TMB in non-small cell lung cancer.

The connection made sense. DNA mutations lead to the production of altered proteins that the immune system is able to recognize as foreign. The more mutated proteins a tumor has, the more likely it is that the immune system will attack the cancer, and that drugs that promote an immune response, such as checkpoint inhibitors, will be successful in eliminating it.

For melanoma, the high number of mutations results from exposure to the sun’s damaging UV rays. For some lung cancers, bladder cancers, and head and neck cancers — for which immunotherapy drugs often work well — the high TMB may be due to carcinogens in tobacco.

Using Data to Confirm a Long-Standing Assumption

Other cancers also have high TMBs, but these elevated mutation rates tend to appear with less frequency and at varied levels. “The assumption that TMB is a useful predictor of response to checkpoint inhibitors for all types of cancer has not been proven,” Dr. Morris explains. “Until now, we also haven’t known whether this testing is valuable for people who are treated as part of routine care, as opposed to those who were carefully selected for clinical trials.”

The current study used data from more than 1,600 people who were treated with checkpoint inhibitor drugs at MSK and about 5,300 people who received nonimmune-based treatments. All of the patients had their tumors analyzed with MSK-IMPACT. The US Food and Drug Administration has authorized this targeted tumor-sequencing assay, which is offered to MSK patients. The test looks for mutations in tumors that can be targeted with drugs and also reports TMB. Results from MSK-IMPACT were anonymously linked with clinical records, allowing researchers to tease out connections between different levels of TMB and drug response.

“The bottom line is that we confirmed that TMB does have predictive value across a range of cancer types,” Dr. Morris says. “We also showed that the predictive value of TMB is dose dependent. This means that the higher the TMB in a person’s cancer, the more likely they are to respond to the drugs.”

But the researchers found that there is not one universal definition for what it means to have a high TMB. For example, having six mutations was considered high in breast cancer and glioblastoma, compared with 31 in melanoma and 52 in colorectal cancer.

A Collaborative Project Focusing on Many Cancer Types

The team was able to conduct such a large, multifaceted project thanks to contributions from 57 researchers from a number of Disease Management Teams. MSK’s Immunogenomics and Precision Oncology Platform (IPOP) and the Marie-Josée and Henry R. Kravis Center for Molecular Oncology (CMO) helped bring together the collaborators and analyze the data.

To further advance this important and growing field of research, all of the data from the study are being made available to other scientists through MSK’s cBioPortal for Cancer Genomics. This will allow scientists at other institutions to use the data to design future trials.

“We are still optimizing the use of TMB as a way to predict response to therapy,” Dr. Morris notes. “We need more research to determine the optimal number of mutations that we should use for each cancer type. We hope that based on our data, researchers will move forward with more clinical studies that will ultimately result in the ability to select the best treatments for people with cancer and allow them to avoid treatments that are unlikely to help them.”

The first author of the Nature Genetics paper is Robert Samstein, a fellow in radiation oncology at MSK. In addition to Dr. Morris, the other senior authors are Dr. Chan, Director of IPOP, and physician-scientist David Solit, Director of the CMO.

CAR T Cells Get an Invisibility Cloak

Source: Memorial Sloan Kettering - On Cancer
Date: 01/29/2019
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Genetically engineered immune cells have shown tremendous promise in treating blood cancers. Indeed, the US Food and Drug Administration approved two such cell therapy treatments for these diseases in 2017. Some people with blood cancer do not have a lasting response from this therapy, however. For solid tumors, results have been comparatively modest so far.

Emerging clinical trial results suggest that one of the most important factors in determining the success of immune cell treatments is how long the cells persist in the body after being infused. This observation led a team of investigators from Memorial Sloan Kettering and other institutions to focus on helping cancer-fighting immune cells stick around longer. Findings from their latest research were published January 29 in the Journal of Clinical Investigation.

“Once the genetically engineered white blood cells are reinfused into a patient’s body, they begin receiving signals that cause them to self-destruct,” says MSK physician-scientist Christopher Klebanoff, the senior author of the paper. “We’ve developed a cloaking technique that wraps the cells in a protective barrier, making them impervious to the signals telling them to die. This enables the immune cells to wage a sustained attack against cancer cells in the body.”

Hiding from Death in Plain Sight

Chimeric antigen receptor (CAR) therapy involves isolating the white blood cells called T cells from people with cancer and inserting a gene so that the cells recognize cancer. After the gene is transferred into the cells, they’re infused back into the patient, where they seek out and attack the cancer.

The body has a natural way to make sure that individual T cells don’t overstay their welcome. A molecular trigger induces them to self-destruct through a process called programmed cell death, or apoptosis. In most situations, this system is an advantage. It prevents immune cells from sticking around too long and causing prolonged inflammation after an infection or from bringing on an autoimmune response. But with specially engineered CAR T cells, it’s useful for them to persevere.

In the current study, the investigators hypothesized that the trigger causing the immune cells to self-destruct was located in the tumor microenvironment. This includes the immune cells and other tissues that are not cancer but help make up a tumor. Using sequencing data from more than 9,000 tumors and 26 kinds of cancer, they identified a likely candidate for that molecular trigger: a gene called FASLG. This gene is enriched in more than three-quarters of both solid tumors and blood cancers. Further analysis revealed that the target of FASLG is found at high levels on the surface of CAR T cells. This explains why the death-inducing trigger would be so effective against them.

Helping Immune Cells Get Where They’re Going

Once the team identified the likely culprit, they set about making a genetic modification that would provide a protective cloak to help the immune cells hide from the kill signal. They tested these modified cells in mouse models of cancer as well as in cell cultures of human cancer. They found that the cloaked T cells persisted longer and were more effective at destroying tumor cells for a longer time period. “In multiple animal models, including models of leukemia as well as solid cancers, this approach led to much stronger cancer regression,” Dr. Klebanoff says.

One of the biggest complications of CAR therapy is a reaction called cytokine release syndrome. It involves a rush of immune activity that can overwhelm the body. Dr. Klebanoff says that the tests in mice indicated that using more persistent T cells for therapy would not increase the severity of this side effect. But to be cautious, the team plans to engineer the cells with a kill switch in case they need to be turned off quickly.

“We are so excited by these preclinical data that we’re already moving ahead and making preparations to do a first-in-human clinical trial,” Dr. Klebanoff says, adding that he hopes the trial will start sometime in 2020. “We envision that this is a potentially generalizable strategy that needn’t be constrained to one type of cancer or one type of CAR T cell. We could apply this cloak to any kind of immune cell therapy to make it work better.”

The MSK researchers collaborated with scientists from the National Cancer Institute at the National Institutes of Health, the University of Pennsylvania, Oregon Health and Science University, the University of Colorado in Denver, and the Medical University of South Carolina.

An Old Protein Gets a New Look: Researchers Target TGF-ß to Make Immunotherapy More Effective

Source: Memorial Sloan Kettering - On Cancer
Date: 04/05/2019
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The immunotherapy drugs called checkpoint inhibitors have transformed treatment for some people with cancer. Currently, a major focus in cancer research is looking for ways to make these drugs effective for a greater number of people and more types of cancer.

One of the many approaches that scientists are now studying is combining immunotherapies with drugs that block the actions of a molecule called transforming growth factor-beta (TGF-ß). The importance of TGF-ß was uncovered more than 30 years ago by Sloan Kettering Institute Director Joan Massagué.

“There has been tremendous interest in this new avenue of treatment,” Dr. Massagué says. “Right now, we have a serious opportunity to leverage the robust knowledge that we’ve built about TGF-ß and use it to make immunotherapy more effective. TGF-ß is actually a hormone that is released by cells. This means it is quite accessible to drugs that can block its activity.”

A Fundamental Molecule with Many Roles

TGF-ß is critical for regulating how cells function. It works by sending signals from a cell’s membrane to its nucleus, telling it which genes to make into proteins. Among the most important jobs of TGF-ß are directing embryonic development and regulating the immune system. It also plays a role in whether cancer spreads.

It is the effect of TGF-ß on the immune system that many researchers are now most interested in studying.

A study published in February 2018 in Nature reported that, in people being treated with the immunotherapy drug atezolizumab (Tecentriq®), levels of TGF-ß in tumors correlated with how well people responded. In short, the more TGF-ß that tumors had, the less likely it was that atezolizumab worked. This is because TGF-ß can prevent the immune cells called T cells from infiltrating and attacking tumors. Checkpoint inhibitors boost the activity of T cells, but if the immune cells can’t get into the tumor, they will not be effective.

Another study in the same issue of Nature reported that combining a TGF-ß-blocker called galunisertib with immunotherapy allowed the immune system in mouse models of colon cancer to attack tumors that it had previously not been able to go after.

“This research showed that TGF-ß prevents the incoming T cells from penetrating and infiltrating the tumor,” Dr. Massagué says. “If you block TGF-ß, however, T cells infiltrate and kill the tumor cells.”

Combining Approaches in the Clinic for Many Cancer Types

Several clinical trials now under way are looking at how to combine immunotherapy with drugs that block TGF-ß. MSK medical oncologist Anna Varghese is the co-principal investigator of one such trial for pancreatic cancer.

“Immunotherapy alone is not effective against pancreatic cancer for most patients,” Dr. Varghese explains. “This is because pancreatic tumors have an immunosuppressive microenvironment.” That means the cells and tissue around the tumor prevent immune cells from getting in and attacking the cancer.

Dr. Varghese’s trial combines the immunotherapy drug durvalumab (Imfinzi®) with galunisertib. The study is still ongoing, and it’s too early to know how effective the combination will be or what side effects it will have, but Dr. Varghese hopes to report preliminary findings soon.

Research on TGF-ß blockers goes beyond immunotherapy to look at their effectiveness when combined with other kinds of drugs. Recently, MSK medical oncologist James Harding was an investigator in a trial that looked at galunisertib, either alone or in combination with other drugs, for the treatment of liver cancer.

Early analysis of the study showed that when galunisertib was combined with the targeted therapy sorafenib (Nexavar®), people had more favorable outcomes compared with other treatments. However, Dr. Harding comments that “the design of this early study makes it difficult to say how impactful this combination strategy will ultimately be for liver cancer.

“Furthermore,” he adds, “with the advent of effective immunotherapy, the focus of the investigation has shifted to pairing galunisertib and other TGF-ß blockers with immune checkpoint inhibitors.”

Clinical trials focusing on TGF-ß blockers are ongoing at other cancer centers as well as at MSK.

Taking a New Look at a Familiar Target

“For a long time, drug companies have been interested in harnessing the power of TGF-ß blockers, not only for cancer but for other diseases as well,” Dr. Massagué says. “Until now, there’s been concern about doing that because we know that TGF-ß has so many different functions in cells.” Long-term use of these drugs, he explains, would have too many harmful side effects.

“However, combining a TGF-ß blocker with checkpoint immunotherapy and using it as temporary way to boost the effectiveness of these other drugs may be possible,” he concludes.

One Patient’s Exceptional Response Leads to a Surprising Discovery about Immunotherapy

Source: Memorial Sloan Kettering - On Cancer
Date: 04/30/2019
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Findings from a single person with cancer can kick-start a major scientific breakthrough. When one person benefits from treatment in an uncommon way, doctors call it an exceptional response. In this era of personalized medicine, exceptional responses offer clues about how a drug or class of drugs works.

In a study published online on April 22 by Nature Medicine, a group of Memorial Sloan Kettering doctors and scientists describes one such exceptional response. The research suggests that in some cancers, genetic changes called gene fusions can occasionally send signals that the immune system can recognize. These signals can boost the effectiveness of immunotherapy drugs called checkpoint inhibitors. Checkpoint inhibitors take the brakes off the immune system and allow it to attack tumor cells.

“This is a great reminder that despite what we know about how immunotherapy and other cancer drugs work, we’re far from understanding all the rules,” says physician-scientist Timothy Chan, one of the paper’s two senior authors.

“What we’ve learned from this one patient has opened a new door,” adds surgeon-scientist Luc Morris, the paper’s other senior author. “Our findings suggest a new way that the immune system can recognize and attack certain types of tumors. But we’re really just at the beginning of knowing how to apply this discovery and target these alterations. We are working on the next steps in the laboratory.”

An Unexpected Outcome

The exceptional response described in the paper was in a teenage girl with a head and neck cancer that had spread to her lungs. She initially saw Dr. Morris, a head and neck cancer surgeon, who began tests to genetically profile the tumor, saving samples in the hopes of learning more about her cancer in the future. She was then treated by MSK pediatric oncologist Leonard Wexler with chemotherapy, which kept the disease stable. When the cancer started growing again, Dr. Wexler decided to try the immunotherapy drug pembrolizumab (Keytruda®).

“Further chemotherapy was unappealing because of the side effects and the limited chance that it would be effective,” Dr. Wexler says. “We also knew that the tumor had some unusual features for a head and neck cancer. We decided to think outside the box about how to treat the patient.”

Only about 12 to 15% of head and neck cancers respond to drugs like pembrolizumab. An initial analysis of this patient’s tumor suggested that she was not likely to be one of them.

There were two reasons for this belief. For one, her tumor had very few mutations. It’s known that the more mutations a tumor has, the more likely it is to respond to checkpoint inhibitors. That’s because having a lot of mutations means a tumor is more likely to produce proteins called neoantigens, which the immune system recognizes as foreign. This discovery was first reported in 2014 by Dr. Chan and his colleagues.

Additionally, her tumor was “cold,” meaning it had little immune activity around the tumor cells. By contrast, tumors described as “hot” — with many immune cells interspersed among the tumor cells — are more susceptible to checkpoint inhibitors. Immune cells can more easily find and attack a cancer when they’re already in the vicinity.

Despite these factors, the girl’s cancer had begun to shrink within five months. After three more months, it had completely disappeared. The MSK team decided to take a deeper dive, studying the tumor in greater detail to figure out why.

A Focus on Neoantigens

After sequencing the entire genome of the patient’s tumor, the MSK team discovered it had a kind of alteration called a gene fusion. Gene fusions occur when a gene from one chromosome breaks off during cell division and attaches to a gene on another chromosome. This new combined gene can make a protein that drives cancer growth.

“The fusion that this patient had was totally unheard of, something that has not been seen before,” Dr. Morris says. “But this gene fusion is probably what caused her cancer.”

The researchers discovered that the protein created by the gene was a neoantigen. “Neoantigens are seen as foreign by the immune system. They’re something that doesn’t belong in the body,” says Dr. Chan, who is Director of MSK’s Immunogenomics and Precision Oncology Platform. “In this case, the neoantigen resulting from the gene fusion made the patient’s cancer susceptible to immunotherapy.”

Looking for Potential Benefit in More Cancer Types

Although this patient’s particular gene fusion was rare, other fusions are more common in certain cancer types. The investigators analyzed tumors from other people treated at MSK for a type of head and neck cancer with common fusions. They found that immune cells in these people were able to recognize tumor cells with these gene fusions.

“One of the things that our team is doing now is systematically going through every single gene fusion across human cancers and predicting which ones may result in neoantigens that can be seen by the immune system,” Dr. Chan says. “We expect these findings are going to apply broadly to many different types of cancer.”

The original patient completed treatment with pembrolizumab and has remained free of cancer. It has been more than 30 months from when she started immunotherapy.