Chemotherapy Myths and Misconceptions


 

Chemotherapy has long been a mainstay of cancer treatment. But a lot has changed since Sidney Farber, MD, the founder of Dana-Farber Cancer Institute, achieved the first remissions for pediatric leukemia using chemotherapy in the 1940s.

Today, in the era of precision cancer medicine, there are newer treatments and chemotherapy that can more specifically target cancer cells. Researchers have also discovered the effectiveness of using chemotherapy drugs in conjunction with other drugs to pack a more powerful punch. To put it simply: Chemo is a lot better today than it used to be.

Still, there’s a lot of misinformation surrounding this kind of cancer treatment. In this episode, we explore some of the most common myths and misconceptions with Clare Sullivan, MPH, BSN, clinical program manager for Patient Education at Dana-Farber.

Transcript

MEGAN RIESZ: So, first, can you just kind of explain generally what chemotherapy is and how it’s commonly administered?

CLARE SULLIVAN, NPH, BSN: Sure. Think about what the body does. The body is made up of cells that normally divide and grow and are replaced. Think about how your fingernails grow. Chemotherapy (or chemo, for short) is a group of medicines or drugs that treat cancer and other diseases. Cancer also divides and replicates.

Different chemotherapy drugs act in various ways. Some chemotherapy drugs can kill the cancer as they divide at critical times during the cell cycle, something that we learned way back in high school. Some chemotherapy can target the cancer’s food supply and kill important hormones and other nutrients it needs to grow. And then some chemotherapies can target the cancer’s genes and prevent it from growing. Then, one of the other interesting areas is that some chemotherapy can prevent the tumor from growing new blood vessels that it needs to grow and spread.

There have been many new and exciting developments in the field of cancer care, and when I say this, I mean chemotherapy, whether you add different combinations or other treatments. So, chemotherapy is still a very important tool for treating many cancers today.

MEGAN: Just to be clear, how is chemotherapy different than immunotherapy, which is something that’s talked about a lot today?

SULLIVAN: Well, immunotherapy has received a lot of attention because of new medications discovered that help treat cancer, but immunotherapy is unlike chemotherapy because of the way that it fights cancer.

Let’s start at the beginning. The immune system is a very complex network of cells and organs that defend against foreign substances, like bacteria or viruses.

Think about when you get a cut. The body’s defenses go into action immediately scanning and will recognize any foreign bacteria and then send out the correct army or navy to wipe out that invader. The immune system is so sophisticated that it can remember that invader, and if it comes again, it will recognize it and protect you from that disease. This is very similar to the chicken pox.

MEGAN: And let’s talk about side effects, which can be big considerations for patients. What are some common side effects that patients experience during chemotherapy?

SULLIVAN: The most common side effects for chemotherapy depend on the drug, the manner it’s given, the dose, and how often you get it, but the number one side effect across the board is fatigue. Then there are a few others that I’ll mention: appetite changes, nausea. But again, remember, there’s a lot of anti-nausea medications that are very effective now. A weakened immune system where you might get bruising or bleeding, and this is because of the way the chemotherapy goes after the cell cycle—it decreases the red blood cell and the white blood cell. Constipation and diarrhea are also another side effect, but again, there are a lot of good medications that are very effective. Then, mouth care—mouth care is really important to prevent mouth sores.

I want to go back to my first symptom, which was fatigue. Fatigue is real. Think about it as tiredness that doesn’t go away with rest. If you take a nap and wake up, you should ordinarily feel refreshed, but fatigue is when you wake up and really feel just as tired as when you went to sleep. So, during your treatment, of course, there will be times that you need to rest, but when possible, the best way to offset a host of issues that can happen when you lay in bed all day is to stay active.

Here are some tips. First, I want to think about those days that you’re most tired, really struggling with fatigue and really just around the house. Every time that you get up to the bathroom, try to move around. Move from the bathroom to the couch for a few minutes to a chair, and then move back to bed and continue that cycle as you get up to the bathroom. Just keep moving. Keep walking, even if it’s around the dining room table and in the middle of the night. If you can carry something like a laundry basket, put some weight in it. If you can carry a carton of milk around the dining room table…something just to help you move. Do some arm or leg stretches when you’re in or out of bed. A tip is that if you’re watching TV, put the exercise channel on and follow along in bed.

On a good day, you’re going to want to put your coat on right over that bathrobe, walk around the block, get a good pair of slippers with some comfortable soles, and you don’t even need to change your shoes.

The tip here for you is that you will find your energy perks up a few days before your next chemotherapy treatment. Use this time wisely. This is when you can really get out of the house. Maybe you might work a half a day. Maybe someone would drive you to work. Maybe you could work around the house. Walk a little further than just around the block. Walk with a little bit of speed. Use your arms. Get off a stop earlier on the train. Take the stairs at work. Take the stairs during your hospital visit. Take the dog for a walk. On your way back, pull a few weeds in the lawn.

If you’re in the hospital and you’re getting your chemotherapy in the hospital, work with the nursing staff on the floor. Measure how many laps it would take around the unit to equal a mile. We have many units over at the Brigham with signs of encouragement for lap walking.

MEGAN: So, patients often wonder if they will lose their hair during chemotherapy. Can you talk about this as well?

SULLIVAN: Sure. There are many other side effects that are specific to the drugs, and the one that I have not mentioned, as you have brought up, is hair loss. Many people associate hair loss with chemotherapy from movies or TV, but this is not as common anymore. When you enter the infusion clinic, you might be surprised to see that many patients have hair. This is not to say that some chemotherapy still causes hair loss, but it is not as common as people think.

MEGAN: So, chemotherapy can be used in a few different ways—curatively or palliative, for example. Can you talk about this?

SULLIVAN: Yes, Megan. What you’re referring to are the three goals of cancer treatment. There are actually three. You may see one of these terms on your initial chemotherapy consent, but most importantly, you may want to confirm with your cancer team what the strategy is for your treatment plan. Starting out on the same page with your team is very important. Remember, this can change as information about your cancer is understood over time by your team.

The three strategies to cancer treatment are cure, control, and palliation. Cure is when the cancer is completely removed, and the intent is that the cancer will not come back. Control would be the second strategy. That’s when disease cannot be fully removed from the body, but the team can keep it in check for long periods of time. Then the third strategy is what we call palliation. The disease here cannot be successfully removed and may not be controlled for long, but the team is confident that they can minimize any symptoms to help you feel more comfortable.

The word “palliation” can be confusing and even turn some people off from the medical specialty of palliative medicine. Palliative care is a specialized medical care for any cancer patient. It helps patients get relief from pain, symptoms, and the stress of having a serious illness. It can help improve their quality of life, no matter what treatment goal there is. Palliative care can help with fatigue, pain, nausea, shortness of breath, and a whole host of other symptoms that you may have during treatment, where the goal of palliative care is to help you feel more comfortable during your treatment, preserve your dignity, and better communicate with your family and caregivers.

Palliative care can be helpful through all stages of cancer care. Early on, it can help make the treatment more tolerable. Later, it can help you with daily life, can assist you in planning your care, and provide you with an additional layer of support. Think of it as a superhero. Think of it as the superheroes of cancer care.

Often, people mix up the word “palliative care” and “hospice care.” Palliative care is available to any patient with any stage of cancer at any age. Hospice care is for patients also receiving palliative care, but hospice care is typically only given during the final months of life.

MEGAN: Is there anything else you might like to convey to patients who are starting chemotherapy?

SULLIVAN: Sure. There are some tips here that I’d really like to share with you today. For those people who might be going to an infusion clinic or going even to a hospital, it’s OK to ask for a tour. Go and visit the infusion area, or even walk through the hospital ward, just to get familiar with the surroundings. Bring a friend and stay active.

If you don’t understand something that the doctor or nurse says, please ask them to repeat. It’s very important that you understand. Know who to call and when. Keep that information near you at all times, whether it be on your refrigerator, in your wallet, or type it right away in your phone contacts the minute that you get it. Make sure family members have it or close friends know where this information is kept.

Guardian of the Cell


Scientists unravel the structure, key features of a human immune-surveillance protein, setting the stage for more-precise immune therapies

protein structure
Scientists have identified the key structural and functional features of a critical immune protein in humans that guards against cancer, viral and bacterial infections.

 

The human body is built for survival. Each one of its cells is closely guarded by a set of immune proteins armed with nearly foolproof radars that detect foreign or damaged DNA.

One of the cells’ most critical sentinels is a “first responder” protein known as cGAS, which senses the presence of foreign and cancerous DNA and initiates a signaling cascade that triggers the body’s defenses.

The 2012 discovery of cGAS ignited a firestorm of scientific inquiry, resulting in more than 500 research publications, but the structure and key features of the human form of the protein continued to elude scientists.

Now, scientists at Harvard Medical School and Dana-Farber Cancer Institute have, for the first time, identified the structural and functional differences in human cGAS that set it apart from cGAS in other mammals and underlie its unique function in people.

A report on the team’s work, published July 12 in Cell, outlines the protein’s structural features that explain why and how human cGAS senses certain types of DNA, while ignoring others.

“The structure and mechanism of action of human cGAS have been critical missing pieces in immunology and cancer biology,” said senior investigator Philip Kranzusch, assistant professor of microbiology and immunobiology at Harvard Medical School and Dana-Farber Cancer Institute. “Our findings detailing the molecular makeup and function of human cGAS close this critical gap in our knowledge.” Importantly, the findings can inform the design of small-molecule drugs tailored to the unique structural features of the human protein—an advance that promises to boost the precision of cGAS-modulating drugs that are currently in development as cancer therapies. “Several promising experimental immune therapies currently in development are derived from the structure of mouse cGAS, which harbors key structural differences with human cGAS,” Kranzusch said. “Our discovery should help refine these experimental therapies and spark the design of new ones. It will pave the way toward structure-guided design of drugs that modulate the activity of this fundamental protein.”

The team’s findings explain a unique feature of the human protein—its capacity to be highly selective in detecting certain types of DNA and its propensity to get activated far more sparingly, compared with the cGAS protein in other animals.

Specifically, the research shows that human cGAS harbors mutations that make it exquisitely sensitive to long lengths of DNA but render it “blind” or “insensitive” to short DNA fragments.

“Human cGAS is a highly discriminating protein that has evolved enhanced specificity toward DNA,” said co-first author Aaron Whiteley, a postdoctoral researcher in the Department of Microbiology and Immunobiology at Harvard Medical School. “Our experiments reveal what underlies this capability.”

Location, location, location

In all mammals, cGAS works by detecting DNA that’s in the wrong place. Under normal conditions, DNA is tightly packed and protected in the cell’s nucleus—the cellular “safe”—where genetic information is stored. DNA has no business roaming freely around the cell. When DNA fragments do end up outside the nucleus and in the cell’s cytosol, the liquid that encases the cell’s organelles, it’s usually a sign that something ominous is afoot, such as damage coming from within the cell or foreign DNA from viruses or bacteria that has made its way into the cell.

The cGAS protein works by recognizing such misplaced DNA. Normally, it lies dormant in cells. But as soon as it senses the presence of DNA outside the nucleus, cGAS springs into action. It makes another chemical—a second messenger—called cGAMP, thus setting in motion a molecular chain reaction that alerts the cell to the abnormal presence of DNA. At the end of this signaling reaction, the cell either gets repaired or, if damaged beyond repair, it self-destructs.

But the health and integrity of the cell are predicated on cGAS’ ability to distinguish harmless DNA from foreign DNA or self-DNA released during cell damage and stress. “It’s a fine balancing act that keeps the immune system in equilibrium. An overactive cGAS can spark autoimmunity, or self-attack, while cGAS that fails to detect foreign DNA can lead to tumor growth and cancer development,” said co-first author Wen Zhou, a postdoctoral researcher at Harvard Medical School and Dana-Farber Cancer Institute.

The current study reveals the evolutionary changes to the protein’s structure that allow human cGAS to ignore some DNA encounters while responding to others.

A foe, an accomplice

For their work, the team turned to an unlikely collaborator—Vibrio cholerae, the bacterium that causes cholera, one of humankind’s oldest scourges.

Taking advantage of a cholera enzyme that shares similarities with cGAS, the scientists were able to recreate the function of both human and mouse cGAS in the bacterium.

Teaming up with colleagues from the lab of Harvard Medical School bacteriologist John Mekalanos, the scientists designed a chimeric, or hybrid, form of cGAS that included genetic material from both the human and mouse forms of the protein. Then they compared the ability of the hybrid cGAS to recognize DNA against both the intact mouse and intact human versions of the protein.

In a series of experiments, the scientists observed activation patterns between the different types of cGAS, progressively narrowing down the key differences that accounted for differential DNA activation among the three.

The experiments revealed that out of the 116 amino acids that differ in human and mouse cGAS, only two accounted for the altered function of human cGAS. Indeed, human cGAS was capable of recognizing long DNA with great precision but it ignored short DNA fragments. The mouse version of the protein, by contrast, did not differentiate between long and short DNA fragments

“These two tiny amino acids make a world of difference,” Whiteley said. “They allow the human protein to be highly selective and respond only to long DNA, while ignoring short DNA, essentially rendering the human protein more tolerant of DNA presence in the cytosol of the cell.”

Plotting the genetic divergence on an evolutionary timescale, the scientists determined that the human and mouse cGAS genes parted ways sometime between 10 million and 15 million years ago.

The two amino acids responsible for sensing long DNA and tolerating short DNA are found solely in humans and nonhuman primates, such as gorillas, chimps and bonobos. The scientists hypothesize that the ability to ignore short DNA but recognize long DNA must have conferred some evolutionary benefits. “It could be a way to guard against an overactive immune system and chronic inflammation,” Kranzusch said. “Or it could be that the risk of certain human diseases is lowered by not recognizing short DNA.”

In a final set of experiments, the team determined the atomic structure of the human cGAS in its active form as it binds to DNA. To do so, they used a visualization technique known as X-ray crystallography, which reveals the molecular architecture of protein crystals based on a pattern of scattered X-ray beams.

Profiling the structure of cGAS “in action” revealed the precise molecular variations that allowed it to selectively bind to long DNA, while ignoring short DNA.

“Understanding what makes the structure and function of human cGAS different from those in other species was the missing piece,” Kranzusch said. “Now that we have it, we can really start designing drugs that work in humans, rather than mice.”

Other investigators included Carina de Oliveira Mann, Benjamin Morehouse, Radosław Nowak, Eric Fischer, and Nathanael Gray. The work was supported by the Claudia Adams Barr Program for Innovative Cancer Research, by the Richard and Susan Smith Family Foundation, by the Charles H. Hood Foundation, by a Cancer Research Institute CLIP Grant, by the National Institute of Allergy and Infectious Diseases grant AI-01845, by National Cancer Institute grant R01CA214608, by the Jane Coffin Childs Memorial Fund for Medical Research, by a Cancer Research Institute Eugene V. Weissman Fellow award, and by a National Institutes of Health T32 grant 5T32CA207021-02.

Relevant Disclosures: The Dana-Farber Cancer Institute and Harvard Medical School have patents pending for human cGAS technologies, on which the authors are inventors.

Harvard Medical School Harvard Medical School (http://hms.harvard.edu) has more than 11,000 faculty working in 10 academic departments located at the School’s Boston campus or in hospital-based clinical departments at 15 Harvard-affiliated teaching hospitals and research institutes: Beth Israel Deaconess Medical Center, Boston Children’s Hospital, Brigham and Women’s Hospital, Cambridge Health Alliance, Dana-Farber Cancer Institute, Harvard Pilgrim Health Care Institute, Hebrew SeniorLife, Joslin Diabetes Center, Judge Baker Children’s Center, Massachusetts Eye and Ear/Schepens Eye Research Institute, Massachusetts General Hospital, McLean Hospital, Mount Auburn Hospital, Spaulding Rehabilitation Network and VA Boston Healthcare System.

The Truth About Melanoma and Skin Cancer: Facts and Common Myths


Often caused by excessive exposure to ultraviolet (UV) rays in sunlight, melanoma accounts for only 4 to 5 percent of skin cancer cases, but is responsible for most skin cancer-related deaths. As with many forms of cancer, melanoma is often misunderstood, and myths persist.

When detected and treated in its earliest stages, however, melanoma is often curable. The key is to avoid overexposure to UV rays – by limiting time outdoors during the peak hours of sunlight and wearing sun-protective clothing and sunscreen – and to be on the lookout for changes in moles and other blemishes that can be an early sign of the disease.

Jennifer Y. Lin, MD, of Dana-Farber Cancer Institute’s Melanoma Treatment Program, sets the record straight on five of the most common myths about melanoma.

Myth 1: A diagnosis of melanoma means that I have months to live.

There are four stages of melanoma — five if you include a form known as melanoma in situ, an early form of the disease that affects only the top layer of skin. Stage 1 melanomas, which are less than one millimeter thick and almost always have not spread beyond their original site, have an excellent prognosis and are generally cured by surgery. The depth of the original melanoma is critical to determining how it will be treated and how people with it are likely to fare. Although more melanomas are being diagnosed, the largest portion are made up of Stage 1 melanomas. Before worrying about the worst outcomes, speak with your doctor about what stage melanoma you have.

Myth 2: There is no difference between SPF 30 and SPF 100 sunscreen.

Although the baseline protection from SPF 30 and SPF 100 is not vastly different, the higher number provides longer coverage. (SPF stands for sun protection factor, or the amount of ultraviolet radiation the skin can absorb without burning while the sunscreen is on.)

If it normally takes you 10 minutes in the sun to burn, an SPF 30 sunscreen protects you for 300 minutes. An SPF 100 should, in theory, provide 1,000 minutes of coverage. If you are sweating and active, the sunscreen can rub off and should therefore be reapplied every two hours. When you are using a high SPF, there is a smaller likelihood of having a “missed spot.” A good way to know that you are applying enough sunscreen is to use the measurement of a shot glass of sunscreen for exposed sites.

Myth 3: If it is a cloudy day, I do not need to wear sunscreen.

About 80 percent of ultraviolet radiation reaches the earth even through clouds. Use a moisturizer with sunscreen daily, especially for areas that have high exposure, such as your face.

Myth 4: If I am low in vitamin D levels, I must get some sun exposure.

Although the skin is the most efficient site of vitamin D production, adequate amounts can be obtained from your diet and from supplements. Vitamin D helps you absorb calcium and build strong bones, so we frequently recommend supplements that include vitamin D and calcium.

Myth 5: If I have dark skin, I can’t burn and won’t get melanoma.

Even people with dark skin can burn if they’re exposed to the sun long enough. Although melanoma is much more rare in individuals of darker skin, it can occur. We recommend that darker-skinned individuals inspect their hands and feet once a month.

Source: Dana-Farber Cancer Institute.

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Breakthrough Therapies in Cancer: CAR T-Cell Therapies


With each passing day, we inch closer to curing cancer.

Until now, the cancer treatment universe was limited to 4 modalities, namely Surgery, Radiation, Chemotherapy and Targeted Drug Treatments. Recently, we have witnessed the addition of a fifth front in the battle against cancer, called Immunotherapy.

In Immunotherapy, scientists have been trying to develop ways to train the human immune system to fight and kill cancer-cells, just like they kill germs in trivial disorders such as the common cold. This technique of harnessing the immune system, is called “Adaptive Cell Transfer” or ACT.

CAR T-Cell Therapies have emerged as the most promising form of Immunotherapy.

What are CAR T-cell Therapies?

When we get sick with the common cold, our immune system attacks the infectious germs and kills them, effectively curing us. What is at work here are a type of cells present in our blood called T-cells. T-cells have the unique ability to identify affected cells, latch on to them and kill them.For a long time, cancer researchers have wondered if it’s possible to train our immune system to kill cancer cells the same way, and effectively become cancer-free. This field of study, titled ‘Immunotherapy’ has been widely researched, and Chimeric Antigen Receptor (CAR) T-Cell Therapies are one of the most exciting advancements in this field.

In a CAR T-cell therapy, a patient’s T-cells are genetically engineered, so that they attach themselves to cancer cells and kill them. More specifically, such T-cells are extracted from the patient’s own blood. These cells are then engineered in a lab to identify specific proteins (or antigens) present within cancer cells, and then these cells are injected back into the patient’s bloodstream.

Many scientists refer to CAR T-Cell Therapies as ‘Living Drugs’ because they constantly attach cancer cells, thereby reducing the rates of recurrence/relapse significantly.

The National Cancer Institute recently issued a simple graphical representation of such therapies on their Twitter feed:
Additionally, the Dana-Farber Cancer Institute has published a video explaining how CAR T-Cell Therapies work:

Current Status of Car T-Cell Therapies

The use of Car T-cell therapies has been limited to clinical trials so far. In these trials, many patients in advanced stages of cancer have experienced positive effects. Many such trials involved patients suffering from advanced ALL (Acute Lymphoblastic Leukemia) with limited treatment options. Most patients experienced 100% remission, and many of them remained in remission for prolonged periods of time.Similar promising results have been observed in the case of lymphoma patients. For patients with ALL, the first line of treatment is usually chemotherapy, followed by a bone marrow transplant. But if the cancer relapses, the treatment options get increasingly thin, close to none. CAR T-cell Therapies act as breakthrough treatments in such cases. So far, the clinical trials have shown positive results. In a trial conducted at the Children’s hospital of Philadelphia (CHOP), 27 out of 30 patients, showed all signs of cancer disappear completely.

Latest Developments

  • The United States FDA has recently approved CAR T-cell therapies for a subtype of ‘B’ cell Acute Leukemias in children (Kymriah) and another one for refractory ‘B’ cell Lymphomas in adults (Yescarta).
  • In another trial conducted on ALL patients at the Memorial Sloan Kettering Cancer center, 14 out of 16 patients demonstrated total recovery, some of them as early as 2 weeks into the treatment.

Potential Side Effects, Toxicity and Management

While the side-effects of such treatments can be life-threatening, the medical fraternity has developed sustainable safeguards against such effects, with supportive treatments. Some of these side effects are listed below:

  1. Cytokine Release Syndrome (CRS) – CRS may cause high fevers, low blood pressure or poor lung oxygenation. Some patients experience delirium, confusion and seizure while undergoing treatment. Such symptoms typically appear within the first week of treatment, and are usually reversible.
  2. Tumour Lysis Syndrome (TLS) – TLS includes a group of metabolic complications that can occur due to the breakdown of dying cells, usually at the onset of toxic cancer treatments. However, TLS can occur a month or more after CAR T-cell therapy. TLS can be a life-threatening complication arising from any treatment that causes cancer cells to break down, including CAR T-cells. This complication has been managed by standard supportive therapy.
  3. B-cell Aplasia – Since T-cells are targeted against surface receptors of B-cells, the normal B-cells also get dystroyed by them. However, no significant or long term side effects have been recorded.

In addition to these side effects, ScienceDirect.com has published a summary of various clinical trials conducted in the field, highlighting their effectiveness in hematologic disorders as compared to results in cases of solid tumors.

For solid tumours, there are a few challenges such as higher risk of major complications and a difficult tumour microenvironment for these cells to be effective. But these hurdles are surmountable, and we will eventually witness better results with this revolutionary approach.
-Dr Amit Jotwani (Co-founder, Onco.com and Senior Consultant Oncologist)

What’s Next in CAR T-cell Therapies?

CAR T-cell therapies seem to have a lot of potential, but further research is needed to make them mainstream and available to patients globally. Many labs around the world are currently testing these therapies, not just for blood cancer but also for solid tumors such as pancreatic and brain cancers. Given the amount of interest the field has generated among researchers worldwide, it is likely that the next decade will be transformative in defining the cancer treatment paradigm.

Watch the video. URL:https://youtu.be/OadAW99s4Ik

References:

1. LLS.org – Article on Chimeric Antigen Receptor T-Cell Therapies
2. ESMO.org – The Evolving Field Of CAR T-Cell Therapies
3. Nature.com – CAR T-Cell Therapies Journal
4. Cancer.gov – The National Cancer Institute’s take on CAR T-Cell Therapies
4. ScienceDirect.com – Toxicity & Management in CAR T-Cell Therapy

Cracking Tumor Defiance


Why does immunotherapy achieve dramatic results in some cancer patients but fail in others?

Scientists have elucidated the mechanism behind some tumor’s ability to escape immunotherapy drugs.

Why does immunotherapy achieve dramatic results in some cancer patients but doesn’t help others? It is an urgent and vexing question for many cancer specialists.

Now, two research groups from Harvard Medical School based at Dana-Farber Cancer Institute have independently discovered a genetic mechanism in cancer cells that influences whether they resist or respond to immunotherapy drugs known as checkpoint inhibitors.

The findings, the researchers say, reveal potential new drug targets and could aid efforts to extend the benefits of immunotherapy treatment to more patients and target additional types of cancer.

The discoveries are detailed in two articles published by the journal Science.

One report, focusing on clinical trial patients with advanced kidney cancer treated with checkpoint inhibitors, comes from scientists at Dana-Farber and the Broad Institute of MIT and Harvard led by Eliezer Van Allen, HMS assistant professor of medicine at Dana-Farber and an associate member at the Broad, and Toni Choueiri, the HMS Jerome and Nancy Kohlberg Associate Professor of Medicine and director of the Lank Center for Genitourinary Oncology at Dana-Farber.

The second report, which identifies the immunotherapy resistance mechanism in melanoma cells, is from a group led by Kai Wucherpfennig, HMS professor of neurology and director of Dana-Farber’s Center for Cancer Immunotherapy Research, and X. Shirley Liu of Dana-Farber.

The two groups converged on a discovery that resistance to immune checkpoint blockade is critically controlled by changes in a group of proteins that regulate how DNA is packaged in cells. The collection of proteins, called a chromatin remodeling complex, is known as SWI/SNF. Its components are encoded by different genes, among them ARID2PBRM1 and BRD7. SWI/SNF’s job is to open up stretches of tightly wound DNA so that its blueprints can be read by the cell to activate certain genes to make proteins.

Researchers led by Van Allen and Choueiri sought an explanation for why some patients with a form of metastatic kidney cancer called clear cell renal cell carcinoma (ccRCC) gain clinical benefit—sometimes durable—from treatment with immune checkpoint inhibitors that block the PD-1 checkpoint, while other patients don’t.

The scientists’ curiosity was piqued by the fact that ccRCC differs from other types of cancer that respond well to immunotherapy, such as melanoma, non-small cell lung cancer and a specific type of colorectal cancer. Cells of the latter cancer types contain many DNA mutations, which are thought to make distinctive tumor antigens called, neoantigens, which help the patient’s immune system recognize and attack tumors and make the cancer cells’ microenvironment hospitable to tumor-fighting T cells. By contrast, ccRCC kidney cancer cells contain few mutations, yet some patients even with advanced, metastatic disease respond well to immunotherapy.

To search for other characteristics of ccRCC tumors that influence immunotherapy response or resistance, the researchers used whole exome DNA sequencing to analyze tumor samples from 35 patients treated in a clinical trial with the checkpoint blocker nivolumab (Opdivo). They also analyzed samples from another group of 63 patients with metastatic ccRCC treated with similar drugs.

When the data were sorted and refined, the scientists discovered that patients who benefited from the immunotherapy treatment with longer survival and progression-free survival were those whose tumors lacked a functioning PRBM1 gene. About 41 percent of patients with ccRCC kidney cancer have a nonfunctioning PBRM1 gene. That gene encodes a protein called BAF180, which is a subunit of the PBAF subtype of the SWI/SNF chromatin remodeling complex.

Loss of the PBRM1 gene function caused the cancer cells to have increased expression of other genes, including those in the gene pathway known as IL6/JAK-STAT3, which are involved in immune system stimulation.

The finding does not directly lead to a test for immunotherapy response yet, the scientists caution, but they carry a clear therapeutic promise.

“We intend to look at these specific genomic alterations in larger, randomized controlled trials, and we hope that one day these findings will be the impetus for prospective clinical trials based on these alterations,” Choueiri said.

In the second report, the scientists led by Wucherpfennig came at the issue from a different angle. They used the gene-editing CRISPR/Cas9 tool to sift the genomes of melanoma cells for changes that made tumors resistant to being killed by immune T cells, which are the main actors in the immune system response against infections and cancer cells.

The search turned up about 100 genes which appeared to govern melanoma cells’ resistance to being killed by T cells. Inactivating those genes rendered the cancer cells sensitive to T-cell killing. Narrowing down their search, the Wucherpfennig team identified the PBAF subtype of the SWI/SNF chromatin remodeling complex—the same group of proteins implicated by the Van Allen and Choueiri team in kidney cancer cells—as being involved in resistance to immune T cells.

When the PBRM1 gene was knocked out in experiments, the melanoma cells became more sensitive to interferon gamma produced by T cells and, in response, produced signaling molecules that recruited more tumor-fighting T cells into the tumor. The two other genes in the PBAF complex—ARID2 and BRD7—are also found mutated in some cancers, according to the researchers, and those cancers, like the melanoma lacking ARID2 function, may also respond better to checkpoint blockade. The protein products of these genes, the authors noted, “represent targets for immunotherapy, because inactivating mutations sensitize tumor cells to T-cell mediated attack.” Finding ways to alter those target molecules, they added, “will be important to extend the benefit of immunotherapy to larger patient populations, including cancers that thus far are refractory to immunotherapy.”

Research included in the report by Van Allen and Choueiri was supported by Bristol-Myers Squibb, American Association for Cancer Research Kure It Research Grant for Immunotherapy in Kidney Cancer, Kidney SPORE, and Cancer Immunologic Data Commons (National Institutes of Health grant U24CA224316).

Patient Turned Researcher Helps Advance Understanding of Brain Tumors


Interested in seeing images of his brain, Steven Keating, currently a graduate student at the MIT Media Lab, volunteered for a research study while attending school in Canada in 2007. When researchers returned his brain scans, they delivered some startling news.

“The researchers told me I had an abnormality near the smell center in my brain, but that lots of people have abnormalities and I shouldn’t be alarmed,” says Steven. However, as a precaution, researchers advised Steven to get his brain re-scanned in a few years.

Brain tumor patient turned researcher

 

 

 

 

 

 

 

 

 

Steven’s next set of brain scans, performed in 2010, showed no changes. But in July 2014, he started smelling a strange vinegar scent for about 30 seconds each day. He immediately had his brain scanned and learned that the strange smell was associated with small seizures due to the presence of a brain tumor called a glioma. Steven’s glioma had grown to the size of a baseball.

Steven met with E. Antonio Chiocca, MD, PhD, chair of the Department of Neurosurgery at Brigham and Women’s Hospital (BWH), who performed image-guided brain surgery on Steven last summer in BWH’s Advanced Multimodality Image Guided Operating (AMIGO) suite.

Since his surgery, Steven has gone through rounds of proton radiation and chemotherapy. He began another round of chemotherapy at Dana-Farber Cancer Institute in February 2015. Steven says he is extremely grateful for his care team, including Chiocca; Patrick Wen, MD, director of the Center for Neuro-Oncology at Dana-Farber/Brigham and Women’s Cancer Center; Keith Ligon, MD, PhD, a neuropathologist at Dana-Farber/Brigham and Women’s; and Helen Alice Shih, MD, associate medical director of the Francis H. Burr Proton Therapy Center at Massachusetts General Hospital.

Ever curious, Steven asked to have his surgery videotaped and his genome sequenced, and this information was used to print 3-D models of his brain and tumor. He also has been working with Chiocca and others on 3-D printing research and has given various talks and presentations about his work and his patient experience. Most recently, Steven was invited to the White House for discussions on the importance of allowing patients to have access to their health data.

Chiocca said it has been wonderful working with Steven, both as a patient and researcher. While it’s pretty rare that patients ask for their surgery to be filmed, he said it is valuable for them to participate in the research side of their care when possible.

“It is very easy for a patient to become depressed by their disease,” says Chiocca. “But Steven’s approach of being actively involved to raise consciousness and funding for more research for this type of tumor is remarkable. I’m just so proud to have been involved in his care.”

Survival Among Patients With Pancreatic Cancer and Long-Standing or Recent-Onset Diabetes Mellitus


Abstract

Purpose Long-standing diabetes is a risk factor for pancreatic cancer, and recent-onset diabetes in the several years before diagnosis is a consequence of subclinical pancreatic malignancy. However, the impact of diabetes on survival is largely unknown.

Patients and Methods We analyzed survival by diabetes status among 1,006 patients diagnosed from 1986 to 2010 from two prospective cohort studies: the Nurses’ Health Study (NHS) and Health Professionals Follow-Up Study (HPFS). We validated our results among 386 patients diagnosed from 2004 to 2013 from a clinic-based case series at Dana-Farber Cancer Institute (DFCI). We estimated hazard ratios (HRs) for death using Cox proportional hazards models, with adjustment for age, sex, race/ethnicity, smoking, diagnosis year, and cancer stage.

Results In NHS and HPFS, HR for death was 1.40 (95% CI, 1.15 to 1.69) for patients with long-term diabetes (> 4 years) compared with those without diabetes (P< .001), with median survival times of 3 months for long-term diabetics and 5 months for nondiabetics. Adjustment for a propensity score to reduce confounding by comorbidities did not change the results. Among DFCI patient cases, HR for death was 1.53 (95% CI, 1.07 to 2.20) for those with long-term diabetes compared with those without diabetes (P = .02), with median survival times of 9 months for long-term diabetics and 13 months for nondiabetics. Compared with nondiabetics, survival times were shorter for long-term diabetics who used oral hypoglycemics or insulin. We observed no statistically significant association of recent-onset diabetes (< 4 years) with survival.

Conclusion Long-standing diabetes was associated with statistically significantly decreased survival among patients with pancreatic cancer enrolled onto three longitudinal studies.

Unveiling the effects of an important class of diabetes drugs


A research team led by Dana-Farber Cancer Institute and Brigham and Women’s Hospital has uncovered surprising new findings that underscore the role of an important signaling pathway, already known to be critical in cancer, in the development of type 2 diabetes. Their results, published in the November 17, 2014 online issue of the journal Nature, shed additional light on how a longstanding class of diabetes drugs, known as thiazolidinediones (TZDs), work to improve glucose metabolism and suggest that inhibitors of the signaling pathway — known as the MEK/ERK pathway — may also hold promise in the treatment of type 2 diabetes.

“It’s been recognized that thiazolidinediones have tremendous benefits in the treatment of type 2 diabetes, but they also have significant risks,” said Alexander S. Banks, PhD, lead author and a researcher in the Division of Endocrinology, Diabetes and Hypertension at BWH. “The question is, can we minimize these adverse effects by modifying the drugs slightly or by approaching the pathway from a different direction?”

This hypothesis led Banks and Bruce Spiegelman, PhD, a researcher in the Department of Cancer Biology at Dana-Farber, to focus on a critical molecular player known as CDK5. A type of enzyme known as a kinase, CDK5 modifies a key site on the molecule targeted by TZDs (known as PPARγ). To further understand CDK5’s role, Banks and his colleagues created a special strain of mice lacking CDK5 in adipose tissues —where PPARγ is most highly active and TZDs are thought to act.

Instead of confirming their initial suspicions about CDK5, the team’s results pointed them in a very different direction: their findings suggested that another key kinase was involved. In collaboration with researchers at Harvard Medical School, Banks, Spiegelman and their colleagues conducted a wide, unbiased search to determine its identity. That search ultimately led them to the kinase known as ERK.

After a detailed biochemical study of ERK function, the team set out to test its role in glucose metabolism, and found that MEK inhibitors, which block ERK function, significantly improve insulin resistance in mouse models of diabetes.

“A new class of drugs, aimed primarily at cancer, has been developed that inhibits ERK’s action. These drugs, known as MEK inhibitors, help to extend the lives of patients with advanced cases of melanoma,” said Banks.  “One of the most exciting aspects of this paper is the concept that you could inhibit the abnormal activation of ERK seen in diabetes using these MEK inhibitors designed for treating cancer, but at lower, safer doses.”

“All attempts to develop new therapeutics will carry risks, but the opportunities here certainly seem worth exploring in the clinic,” said Spiegelman.

While much more work must be done to determine if MEK inhibitors will be a safe and effective treatment for type 2 diabetes, the Nature study offers an important window on the molecular underpinnings of TZD action. In addition, it suggests that MEK/ERK inhibition may offer a viable route toward minimizing the drugs’ undesired effects.

Discovery of new gene regulator could precisely target sickle cell disease.


A research team from Dana-Farber/Boston Children’s Cancer and Blood Disorders Center and other institutions has discovered a new genetic target for potential therapy of sickle cell disease (SCD). The target, called an enhancer, controls a molecular switch in red blood cells called BCL11A that, in turn, regulates hemoglobin production.

The researchers — led by Daniel Bauer, MD, PhD, and Stuart Orkin, MD, of Dana-Farber/Boston Children’s — reported their findings today in Science.

Prior work by Orkin and others has shown that when flipped off, BCL11A causes red blood cells to produce fetal hemoglobin that, in SCD patients, is unaffected by the sickle cell mutation and counteracts the deleterious effects of sickle hemoglobin. BCL11A is thus an attractive target for treating SCD.

The disease affects roughly 90,000 to 100,000 people in the United States and millions worldwide.

However, BCL11A plays important roles in other cell types, including the immune system’s antibody-producing B cells, which raises concerns that targeting it directly in sickle cell patients could have unwanted consequences.

The discovery of this enhancer — which regulates BCL11A only in red blood cells — opens the door to targeting BCL11A in a more precise manner. Approaches that disable the enhancer would have the same end result of turning on fetal hemoglobin in red blood cells due to loss of BCL11A, but without off-target effects in other cell types.

The findings were spurred by the observation that some patients with SCD spontaneously produce higher levels of fetal hemoglobin and enjoy an improved prognosis. The researchers found that these individuals possess naturally occurring beneficial mutations that function to weaken the enhancer, turning BCL11A’s activity down and allowing red blood cells to manufacture some fetal hemoglobin.

“This finding gives us a very specific target for sickle cell disease therapies,” said Orkin, a leader of Dana-Farber/Boston Children’s who serves as chairman of pediatric oncology at Dana-Farber Cancer Institute and associate chief of hematology/oncology at Boston Children’s Hospital. “Coupled with recent advances in technologies for gene engineering in intact cells, it could lead to powerful ways of manipulating hemoglobin production and new treatment options for hemoglobin diseases.”

“This is a very exciting study,” said Feng Zhang, PhD, a molecular biologist and specialist in genome engineering at the McGovern Institute for Brain Research at the Massachusetts Institute of Technology (MIT) and the Broad Institute of MIT and Harvard, who was not involved in the study. “The findings suggest a potential new approach to treating sickle cell disease and related diseases, one that relies on nucleases to remove this regulatory region, rather than adding an exogenous gene as in classic gene therapy.”

Source:DFCI

 

 

 

Vaccine stirs immune activity against advanced, hard-to-treat leukemia.


Novel treatment boosted selective immune attack on leukemia cells in post-transplant patients

Patients with advanced chronic lymphocytic leukemia (CLL) often receive donor transplants that effectively “reboot” their own immune defenses, which then attack and potentially cure the hard-to-treat disease. However, there is a high rate of relapse in these patients, and the transplanted immune cells may also harm normal tissues, causing graft-versus-host disease (GVHD).

Now, scientists at Dana-Farber Cancer Institute report in the
 Journal of Clinical Investigation that they observed a strong and selective immune response in some patients who received, shortly after the transplant, several doses of a “personalized” tumor vaccine composed of their own inactivated leukemia cells combined with an immune stimulant, GM-CSF. Thus the vaccine boosted the power of the transplanted immune system’s ability to attack the cancer – known as the graft-versus-leukemia (GvL) effect.

“Our studies suggest that autologous tumor cell vaccination is an effective strategy to advance long-term leukemia control” following transplants from donors, saidCatherine Wu, MD, senior author. “Although this was a phase 1 study and not powered to look at questions of clinical efficacy, we did see promising clinical activity.”

There are few treatment options for advanced CLL. Standard transplants, which involve powerful doses of pre-transplant chemotherapy to wipe out as much of the leukemia as possible, have proven too toxic for older patients and those with co-existing diseases. Over the past decade, researchers have developed reduced-intensity conditioning (RIC) regimens, using lower chemotherapy doses that are more tolerable but which rely entirely on the activity of the transplanted immune cells to battle the leukemia. Usually this is insufficient to keep the cancer at bay long-term and the disease progresses.

Furthermore, research has shown that the identifying antigens on the surface of CLL cells in individual patients may differ – that is, they have “personal tumor antigens,” the scientists said. “Based on these principles, vaccination with autologous [the patient’s own stored leukemia cells] irradiated leukemia cells is an attractive approach to expand leukemia-reactive T cells, since this vaccine formulation reliably includes personal tumor antigens.”

To make the vaccine, the researchers mixed the patients’ irradiated leukemia cells with cells that produce GM-CSF (granulocyte-macrophage colony-stimulating factor) and then injected them back into the patient. The combination stirs up a strong response by immune T cells, and the distinctive antigens on the injected leukemia cells direct the T cells to attack similar leukemia cells wherever they are present in the body.

In the phase 1 trial, the vaccine was administered between 30 and 100 days after the transplant, with some patients receiving as many as six vaccine doses. The study enrolled 22 patients with advanced, aggressive CLL. Thirteen of the patients had evidence of the leukemia in their bone marrow at the time of transplant.

Four patients did not receive the vaccine because they developed GVHD following the transplant. The remaining 18 received at least one vaccine dose; seven patients stopped receiving the vaccine after they developed GVHD.

When examined six months post-transplant, the majority of patients showed evidence of clinical response: 10 had complete remissions and six had partial remissions. After a median follow-up of 2.9 years, 13 patients (72 percent) had remained in continuous complete remission; one patient had stable disease, three patients developed progressive disease and two of those patients died.

The results support the safety and biological activity of whole tumor-cell vaccination in hematological malignancies, said the authors, and that giving the vaccine shortly after transplant may have been critical in its effectiveness. In addition, they said a key to the vaccine’s potency was the development by Dana-Farber scientists of GM-CSF-secreting “bystander” cells that can be used against lymphoid malignancies – which was not possible previously.

However, the authors noted that further randomized studies in larger patient groups will be necessary to determine if this strategy “will translate into a true clinical benefit for patients with advanced CLL.”

Source:DFCI