Cancer Research Institute and RevImmune Announce Dosing of First Patient in New Phase 2 Study Assessing Therapeutic Benefit of Interleukin-7 in Patients with Cancer and COVID-19

Friend or Foe? Seeliger Probes the Mysteries of Mycobacteria

  • June 16, 2021

Newswise — From studies in her lab at Stony Brook University in New York to private-sector collaborations, Hertz Fellow Jessica Seeliger is accelerating the fight against multiple deadly diseases.  

Seeliger is an expert on mycobacteria—the “ducks of the microbial world,” so called for the thick, waxy outer coating that allows them to thrive in different environments and repel invaders.

Since her postdoc, she has focused on slowing or stopping tuberculosis (TB) caused by mycobacteria. She also is investigating mycobacteria that may be useful as an immunotherapy in cancer and as a vaccine platform for viruses like SARS-CoV-2, the virus that causes COVID-19. 

“I enjoy running my lab so much because I have the opportunity to work on so many different projects involving mycobacteria,” Seeliger said.

One of those projects is a collaboration with Dr. Boris Shor, founder and CEO of Manhattan BioSolutions, who proposed using mycobacteria to fight bladder cancer. 

“Scientific partnerships are largely about people,” Seeliger said. “I was fortunate that Boris is an excellent man in addition to being an excellent scientist. I agreed to test the waters, though I didn’t at first see this as a long-term partnership.” 

Four years later, the partnership is going strong.

The fight against cancer

Shor enlisted Seeliger to supercharge a weakened strain of Mycobacterium bovis — known as bacillus Calmette-Guérin (BCG) — for testing in a mouse model of bladder cancer. BCG is approved for the treatment of bladder cancer, the sixth most common form of cancer. BCG has a good safety profile (in addition to its use as a cancer treatment, it is administered as a vaccine to infants at high risk for tuberculosis). Shor hypothesized that an engineered BCG would be even more effective as an immunotherapy for bladder cancer.

To leverage the mouse’s own immune defenses against the cancer cells, Seeliger and Shor first identified tumor-associated proteins, which are very different from normal cell proteins. Shor and Seeliger engineered tumor neoantigen sequences and inserted the sequences into the BCG.  (A neoantigen is a protein that forms on cancer cells and triggers the body’s immune response.) The mouse immune system, they hoped, would recognize the neoantigens as non-self and kick into high gear. 

To test this idea, they injected bladder cancer cells under the animals’ skin. The researchers monitored and measured the resulting tumors, which they treated with BCG and Seeliger’s engineered BCG. The results were encouraging. 

The engineered BCG provoked an immune response to both the bacteria and to the cancer-associated protein that the bacteria was making. “The tumors resolved more quickly with our engineered strain of BCG than the original BCG. It’s very promising for future studies in other cancer models,” said Seeliger, noting that this was a preliminary study. In a February 23 press release, Shor said that the engineered BCG has the “potential to impact muscle-invasive, advanced and/or metastatic bladder cancer, a lethal disease with poor survival outcomes.” 

Seeliger and Shor are taking a similar approach to developing BCG as a vaccine platform for SARS-CoV-2 and for other types of viruses. “Instead of inserting cancer antigens, we have inserted viral proteins. It’s analogous to the mRNA vaccines for COVID that are out there right now, but just on a different platform,” Seeliger said.

They also will try a different mode of stimulating the immune system in a colon cancer model. “We’re engineering BCG to express a protein that is naturally part of the immune system, not a tumor-specific protein,” she said. “We’re trying to get the bacteria to load more of the protein into the animal to stimulate a stronger immune response.”

Seeliger credits the Hertz Foundation for encouraging her to step outside of her safety zone while earning a PhD in chemistry from Stanford University. 

“Throughout my fellowship, I was always in contact with a kind of fearlessness to just dive in. There’s always been community support for the idea that even though you were focusing in depth on one thing, you could continue to be engaged and curious about everything.”

Lipid membranes and tuberculosis

In her own lab, Seeliger is focused on identifying compounds that kill or prevent mycobacteriatuberculosis from growing. The need for such a compound is immense. In 2018, tuberculosis infected 1.7 billion people (roughly 23% of the world’s population). In fact, TB is the leading infectious disease killer in the world, claiming 1.5 million lives each year — and drug-resistant TB strains are on the rise.

“I’ve been working on tuberculosis since I began my postdoc in 2007,” Seeliger said. “People thought that TB was a solved problem, but it surged with the AIDS epidemic. People who are HIV positive have suppressed immune systems, which make it difficult for them to fight off TB. TB is actually the leading killer of HIV-positive individuals.”

In Seeliger’s search for ways to fight TB, she has focused in part on the mycobacteria’s lipid membrane. “I trained as a chemist and thought the structure of mycobacteria lipids was just so wild,” she said. 

 

The lipid membrane has been described as a brick wall protecting the stuff inside the mycobacteria. Seeliger discovered that this brick wall is not only structural, but that the “bricks” are hurled out of the bacteria. “The lipid membrane becomes part of the way that the bacteria interacts with the host — that is, with us. These lipids don’t look like anything in our bodies, so the host sees them as something to attack.” 

Seeliger has explored the function and inhibition of lipid transport mechanisms, or pathways, in the TB mycobacteria, hypothesizing that inhibiting these pathways could sensitize it to drugs and host mechanisms. She is also investigating the very basic biology of how mycobacteria make proteins. 

“The protein carries out the functions in the cell,” she said. “We’re trying to understand more about how manipulating the DNA sequence actually leads to unexpected effects on the RNA and the resulting protein.”

The value of playing with others

It was almost inevitable that Seeliger would become interested in science. Her parents and sister are physicians, and her brother is a mathematician. “I was obviously always exposed to biology, biological processes and the practice of applying knowledge of the human body.” But she was also intensely curious about phenomena outside of biology. For a time, clouds fascinated her.

“We were learning about the weather, and I was totally obsessed by different forms of clouds,” Seeliger recalls. “I spent a lot of time in the car going to and from violin lessons, and I’d look out the car window at the clouds. I totally loved just looking up at the sky and saying, ‘Okay, that cloud is up high, and that means it’s icy. And that’s why it has that shape.’”

Seeliger continues to play the violin and viola, which she says provides both a counterbalance and metaphor for her work in the lab.

“I’m not a soloist. I’m no good at that,” Seeliger said. “When I was 9 or 10, I joined an orchestra and began to realize I could make something beautiful playing with others. The same thing is true about science. I have always loved research for the community aspect of it. So now I get to be partly a composer, but mostly a conductor of my own orchestra.”

Seeliger also loves being part of the Hertz Foundation “orchestra.” 

“Hertz Fellows aren’t just politely interested in what you do, they are deeply curious and engaged and really want to understand,” she said. “That level of engagement makes me fearless about saying, what is it that you’re really doing? How can I help you, and how can I understand what you’re doing? I’m always looking for that level of engagement in my science, thanks to the community that I was able to be a part of.” 

About the Fannie and John Hertz Foundation

The Fannie and John Hertz Foundation identifies the nation’s most promising innovators in science and technology and empowers them to pursue solutions to the world’s toughest challenges. Launched in 1963, the Hertz Fellowship is the most exclusive fellowship program in the United States, fueling more than 1,200 leaders, disruptors, and creators who apply their remarkable talent where it’s needed most—from improving human health to protecting the health of the planet. Hertz Fellows hold 3,000+ patents, have founded 200+ companies, and have received 200+ major national and international awards, including two Nobel Prizes, eight Breakthrough Prizes, the National Medal of Technology, the Fields Medal, and the Turing Award. Learn more at HertzFoundation.org.

Cancer Research Institute and RevImmune Announce Dosing of First Patient in New Phase 2 Study Assessing Therapeutic Benefit of Interleukin-7 in Patients with Cancer and COVID-19

Drug commonly used as antidepressant helps fight cancer in mice

  • June 16, 2021

Newswise — A class of drug called monoamine oxidase inhibitors is commonly prescribed to treat depression; the medications work by boosting levels of serotonin, the brain’s “happiness hormone.”

A new study by UCLA researchers suggests that those drugs, commonly known as MAOIs, might have another health benefit: helping the immune system attack cancer. Their findings are reported in two papers, which are published in the journals Science Immunology and Nature Communications.

“MAOIs had not been linked to the immune system’s response to cancer before,” said Lili Yang, senior author of the study and a member of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA. “What’s especially exciting is that this is a very well-studied and safe class of drug, so repurposing it for cancer isn’t as challenging as developing a completely new drug would be.”

Recent advances in understanding how the human immune system naturally seeks out and destroys cancer cells, as well as how tumors try to evade that response, has led to new cancer immunotherapies — drugs that boost the immune system’s activity to try to fight cancer.

In an effort to develop new cancer immunotherapies, Yang and her colleagues compared immune cells from melanoma tumors in mice to immune cells from cancer-free animals. Immune cells that had infiltrated tumors had much higher activity of a gene called monoamine oxidase A, or MAOA. MAOA’s corresponding protein, called MAO-A, controls levels of serotonin and is targeted by MAOI drugs.

“For a long time, people have theorized about the cross-talk between the nervous system and the immune system and the similarities between the two,” said Yang, who is also a UCLA associate professor of microbiology, immunology and molecular genetics and a member of the UCLA Jonsson Comprehensive Cancer Center. “So it was exciting to find that MAOA was so active in these tumor-infiltrating immune cells.”

Next, the researchers studied mice that didn’t produce MAO-A protein in immune cells. The scientists found that those mice were better at controlling the growth of melanoma and colon tumors. They also found that normal mice became more capable of fighting those cancers when treated with MAOIs.

Digging in to the effects of MAO-A on the immune system, the researchers discovered that T cells — the immune cells that target cancer cells for destruction — produce MAO-A when they recognize tumors, which diminishes their ability to fight cancer.

That discovery places MAO-A among a growing list of molecules known as immune checkpoints, which are molecules produced as part of a normal immune response to prevent T cells from overreacting or attacking healthy tissue in the body. Cancer has been known to exploit the activity of other previously identified immune checkpoints to evade attack by the immune system.

In the Science Immunology paper, the scientists report that MAOIs help block the function of MAO-A, which helps T cells overcome the immune checkpoint and more effectively fight the cancer.

But the drugs also have a second role in the immune system, Yang found. Rogue immune cells known as tumor-associated macrophages often help tumors evade the immune system by preventing anti-tumor cells including T cells from mounting an effective attack. High levels of those immunosuppressive tumor-associated macrophages in a tumor have been associated with poorer prognoses for people with some types of cancer.

But the researchers discovered that MAOIs block immunosuppressive tumor-associated macrophages, effectively breaking down one line of defense that tumors have against the human immune system. That finding is reported in the Nature Communications paper.

“It turns out that MAOIs seem to both directly help T cells do their job, and stop tumor-associated macrophages from putting the brakes on T cells,” Yang said.

Combining MAOIs with existing immunotherapies

Yang said she suspects that MAOIs may work well in concert with a type of cancer immunotherapies called immune checkpoint blockade therapies, most of which work by targeting immune checkpoint molecules on the surface of immune cells. That’s because MAOIs work on MAO-A proteins, which are inside cells and function differently from other known immune checkpoint molecules.

Studies in mice showed that any of three existing MAOIs — phenelzine, clorgyline or mocolobemide — either on their own or in combination with a form of immune checkpoint blockade therapy known as PD-1 blockers, could stop or slow the growth of colon cancer and melanoma.

Although they haven’t tested the drugs in humans, the researchers analyzed clinical data from people with melanoma, colon, lung, cervical and pancreatic cancer; they found that people with higher levels of MAOA gene expression in their tumors had, on average, shorter survival times. That suggests that targeting MAOA with MAOIs could potentially help treat a broad range of cancers.

Yang and her collaborators are already planning additional studies to test the effectiveness of MAOIs in boosting human immune cells’ response to various cancers.

Yang said MAOIs could potentially act on both the brain and immune cells in patients with cancer, who are up to four times as likely as the general population to experience depression.   “We suspect that repurposing MAOIs for cancer immunotherapy may provide patients with dual antidepressant and antitumor benefits,” she said.

The experimental combination therapy in the study was used in preclinical tests only and has not been studied in humans or approved by the Food and Drug Administration as safe and effective for use in humans. The newly identified therapeutic strategy is covered by a patent application filed by the UCLA Technology Development Group on behalf of the Regents of the University of California, with Yang, Xi Wang and Yu-Chen Wang as co-inventors.

The research was supported by Stop Cancer, the Broad Stem Cell Research Center Rose Hills Foundation Innovator Grant and Stem Cell Training Program, the UCLA Jonsson Comprehensive Cancer Center and Broad Stem Cell Research Center Ablon Scholars Program, the Magnolia Council of the Tower Cancer Research Foundation and the National Institutes of Health, including a Ruth L. Kirschstein National Research Service Award.

Intralesional Therapies Help Bridge the Gap Between Improved Results and Less Toxicity

Intralesional Therapies Help Bridge the Gap Between Improved Results and Less Toxicity

  • June 15, 2021

In 2011, when Harry Clark was 60 years old, he noticed a mole on his right shin. Even though he grew up under the hot Tucson, Arizona, sun and jokes that he lost his dark bronze tan every November, Clark didn’t think much about the dime-sized, dark red spot — and he’d never seen a dermatologist.

“It wasn’t causing any discomfort and it didn’t grow or change shape,” he says. “When I asked my primary care doctor to take a look, he said it was nothing to worry about.” Two years later, his new primary care provider saw the mole and immediately sent him for a biopsy.

A talented musician, Clark soon discovered he had melanoma, a disease that strikes over 100,000 Americans each year. Surgeons cut out the diseased skin on his shin. But his stage of melanoma required additional treatment. Clark endured 32 radiation treatments. Then he went through isolated limb infusion, in which doctors isolate the limb from the rest of the body with a tourniquet and then flood the area with heated blood and high-dose chemotherapy. “The treatment is so toxic, you have to be hospitalized,” Clark says.

Throughout Clark’s treatment for advanced stage 3 melanoma, new lesions continued forming. Clark’s wife, fellow musician Sanda Schuldmann, thought there might be a solution. A fan of the pianist Martha Argerich, Schuldmann knew that Argerich had received a diagnosis of stage 4 melanoma that had spread to her lungs decades before. She also knew that doctors at John Wayne Cancer Institute in Santa Monica, California, had treated Argerich with something called intralesional therapy.

With intralesional therapies, doctors administer treatment by needle injection directly to the tumor to jump-start the immune system and possibly obliterate cancerous tumors throughout the body. The late Dr. Donald Morton was among the first to repurpose the anti-tuberculosis drug bacillus Calmette-Guerin (BCG) as a first-line intralesional therapy for late-stage melanoma, publishing astonishing results in Annals of Surgery in 1974. In the study of 151 patients, Morton and his colleagues found that directly injecting BCG into metastatic melanoma lesions limited to the skin produced a 90% regression of injected lesions and a 17% regression of lesions that were left untouched. What’s more, one-quarter of these patients remained disease free for one to six years. Since BCG is still not Food and Drug Administration (FDA)-approved for the treatment of melanoma, it can be difficult to find physicians who are familiar with using it in this way.

Schuldmann reached out to John Wayne Cancer Institute, where she connected with Dr. Mark Faries, who is now a professor of surgery and co-director of the melanoma program at Cedars-Sinai The Angeles Clinic and Research Institute. Faries, who trained under Morton at the National Institutes of Health, agreed to review Clark’s medical records. Within days, Clark learned he was a candidate for BCG intralesional therapy and began traveling to California weekly to receive the experimental treatments. After 15 to 20 BCG injections, Clark’s lesions were gone.

Once considered an incurable disease in its advanced form, melanoma has emerged as one of the cancers most responsive to immunotherapy. Immune checkpoint inhibitors have dramatically improved outcomes for patients with late-stage melanoma, with more than half of patients on combination Yervoy (ipilimumab)/Opdivo (nivolumab) still alive years after treatment. Unfortunately, the remaining half don’t respond to treatment, and some experience debilitating side effects that force them to discontinue immunotherapy.

“Intralesional therapies can help bridge this gap by modifying the tumor microenvironment in such a way that the immune system can recognize it as foreign and attack, but without the toxicities of systemic treatment,” says Dr. Lynn Schuchter, chief of the division of hematology/oncology at the Abramson Cancer Center at the University of Pennsylvania in Philadelphia. The hope is that injecting these therapies at the tumor site will train the immune system to identify cancerous cells and launch a systemic and sustainable attack. For patients like Clark with late-stage disease that hasn’t metastasized to distant sites, intralesional therapy can produce durable remission.

INTRALESIONAL THERAPY EXPLAINED

Intralesional therapy is the oldest form of immunotherapy and dates back to the 1890s. In its early stages, intralesional therapy was made with neutralized, non-live bacteria and other stimulatory proteins without a clear understanding of the immune system. “More recently, we’ve learned why the immune system shuts down closer to the level of the tumor, and now we have drugs that can make the tumor visible to the immune system,” says Dr. Genevieve Boland, surgical director of the therapeutic intralesional program at Massachusetts General Hospital in Boston.

The goal of intralesional therapies is to attract the body’s killer T cells and draw them toward the tumor. In fact, one of the first approved immunotherapies for melanoma was the inflammatory cytokine interleukin-2 (IL-2) because cytokines attract T cells to tumors. Unfortunately, agents like IL-2 and BCG fell from favor because of systemic side effects and inconsistent results. Patients experienced significant toxicities ranging from anaphylaxis to changes in blood pressure and heart rate with IL-2.

“We’ve now learned that the immune system doesn’t work the same way that other drugs work,” Faries says. “There’s a sweet spot for how much stimulation you need to induce the desired effect.” And you can get there by using the tumor as a weapon against itself.

The idea behind intralesional therapy is to activate both innate and adaptive immunity to transform the patient’s tumor into a personalized vaccine. The innate immune system is ready to roll when faced with a threat. It automatically kicks in when a person cuts a finger, develops strep throat or needs to fight off the common cold. Adaptive immune cells need to be trained and activated to fight disease.

“These adaptive immune cells help create the right microenvironment for the fighter T cells to come in and do their job,” Boland says. And since doctors inject therapies directly into the tumor, they can deliver drugs safely and at a much higher dose than systemic drugs like checkpoint inhibitors.

USING VIRUSES TO ACTIVATE THE IMMUNE SYSTEM

Denis McGlynn of Camden-Wyoming, Delaware, received his first melanoma diagnosis in 2011 at 65 years of age. After multiple surgeries to treat the aggressive skin cancer, the married father of two and grandfather of five had his first experience with immunotherapy in June 2019. Within days of completing 13 months on Opdivo, McGlynn experienced debilitating side effects.

“I was lying on my back for five days because every joint in my body ached,” recalls McGlynn. The steroid medication prednisone instantly quieted his pain temporarily. Today, he still takes 6 milligrams of prednisone daily for the autoimmune effects.

To make matters more complicated, McGlynn continued to develop cancerous lesions on his scalp. That’s when his doctor suggested he visit Penn Medicine for intralesional treatments with an agent called T-VEC (talimogene laherparepvec). “I had multiple lesions, and the T-VEC injections took only five or six seconds each,” McGlynn says. “When I came back two weeks later, all of the lesions were either healing or gone.”

T-VEC is a genetically engineered herpes virus that obtained FDA approval in 2015 to treat patients with stage 3 or stage 4 melanoma who have injectable lesions but who are not eligible for surgery. Intralesional T-VEC works in these cases because it’s a modified virus, and research suggests viruses are among the best agents to reactivate a tumor’s microenvironment.

“The immune booster is attached to the virus and the virus has the ability to enter cells. When you inject this conjugate of the herpes virus with the immune booster into a melanoma nodule, it’s like raising a red flag and saying, ‘hey, immune system, here I am — attack me,’” Schuchter says.

Called an “oncolytic virus” because of its ability to selectively target, infect and annihilate tumor cells, T-VEC essentially trains the immune system to identify and attack the cancer not only in the injected tumor but also all tumors susceptible to the immune response — and in some cases, it produces complete responses.

“These oncolytic viruses rupture the tumor and kill cancerous cells while simultaneously stimulating the immune system,” Boland says. “We can create this superactive immune response locally, at the site of the tumor, while limiting or even eliminating the toxicities associated with traditional immunotherapy.”

In McGlynn’s case, the treatment was wildly successful. He hasn’t seen a lesion reappear since his last treatment in October 2020. Researchers are investigating other potential targets for melanoma, including other viral vectors, such as coxsackieviruses, HF-10, adenovirus, reovirus, echovirus and Newcastle disease virus. They’re also exploring another class of drugs to boost “innate immunity” — the immune system’s first responder cells that trigger T cells to kill tumors. Like viruses, these therapies activate the warning signs required for the immune system to launch an effective attack against a foreign invader. “Ideally, this sets off a strong reaction within the body that can turn an immunologically ‘cold’ tumor into a ‘hot’ one,” Boland says.

No matter which agents doctors choose, side effects of intralesional therapies tend to be minimal, particularly compared with systemic treatments. The most common complaints relate to soreness at the injection site and mild fatigue. However, a small subgroup of patients may develop inflammatory syndromes like those doctors see with checkpoint inhibitor therapy.

INTRALESIONAL THERAPY BEYOND THE SKIN

Down the line, combination treatment with intralesional therapy and checkpoint inhibitors may even play a role in the treatment of complicated tumors, such as stomach and pancreatic cancer. “The tumor microenvironment of pancreatic cancer has a lot of fibrous tissue, so the local tumor environment acts like a shield hiding the cancer from the immune system,” Schuchter says. “Using ultrasound guidance and other techniques, doctors can inject therapy directly into the tumor to help the immune system recognize cancerous cells and destroy them.”

Unfortunately, scientists don’t know yet who is most likely to respond to treatment. They don’t know whether it’s best to use intralesional therapies as a first-line approach or a last-ditch effort.

“Even though we inject T-VEC directly into tumors, it’s still a weakened form of the herpesvirus, and that makes it potentially dangerous,” Schuchter says. “Patients also have to cover the lesions for a week, and staff have to implement a variety of safe handling practices.”

Some clinics reserve a specific room for intralesional therapies and perform the procedure only at the end of the day. Others have strict preparation and cleaning requirements. And all intralesional therapies require consistent refrigeration. This level of preparation, time, training and logistics can be challenging or even impossible for community clinics.

“It’s important not to overhype intralesional therapy since it’s relevant for only a small subset of patients,” Schuchter says. But when it works — and sometimes it does work — patients reclaim their lives and enjoy decades-long survival. Innovations to this type of therapy with newer drugs are entering clinical trials.

“My one wish is that more people knew that intralesional therapy is an option,” Clark says. He is so indebted to BCG — he credits the drug with saving his life — that he partnered with a musicologist friend from his Peabody Institute days to develop a musical composition using notes B, C and G for Faries. “It’s probably the first fugue for a drug,” he says. Now that’s something to sing about.

For more news on cancer updates, research and education, don’t forget to subscribe to CURE®’s newsletters here.

Immunotherapy for non-small cell lung cancer: A guide

Immunotherapy for non-small cell lung cancer: A guide

  • June 15, 2021

Immunotherapy is one of several treatment options for non-small cell lung cancer (NSCLC). A type of immunotherapeutic medication called immune checkpoint inhibitors teaches the body’s immune system to recognize and destroy cancer cells. It can have longer-lasting effects than other treatment options for NSCLC and can improve the outlook for people with the disease.

Immunotherapy is a new and emerging treatment option for cancer. Many of the first clinical trials on its effectiveness were initially published in 2015 or later.

Several studies have shown that immunotherapy can enhance overall survival for people with NSCLC. So the Food and Drug Administration (FDA) has approved several immune checkpoint inhibitors to help treat this condition.

This article will describe how doctors use immune checkpoint inhibitors to treat NSCLC. It will compare this treatment with chemotherapy and radiation therapy and explain what a person taking this medication can expect before and during treatment.

If a person is having immunotherapy, it means they are receiving medications that help their own immune system to find and destroy cancer cells.

The immune system protects the body against certain dangers, such as bacteria and fungi. But it does not always identify cancer cells as a danger. Immunotherapy teaches the body this difference, as well as how to fight these cancer cells. Scientists sometimes achieve this by introducing cells to the body that they have made or modified in a laboratory setting.

Sometimes, cancer cellscontain “messengers” that essentially shut down the immune system. Immunotherapy may also target these messengers, which keeps the immune system working at its best.

Some people visualize cancer cells as putting the “brakes” on immune system cells. Medications, such as immune checkpoint inhibitors that treat NSCLC, work to take the brakes off so the immune system can work better.

Immune checkpoint inhibitors are not effective in all people who have NSCLC. Some people are treatment-resistant, meaning the medications do not seem to help at all. Other people develop acquired treatment resistance. This means the medications work for a while, then stop working. A person should ask their doctor about how well they perceive the medication to be working.

There are several key similarities and differences between immunotherapy and other NSCLC treatments, such as chemotherapy and radiation therapy. These include their:

  • Function: Immunotherapy focuses on the entire immune response, teaching it to react more effectively to the presence of cancer cells. Chemotherapy kills cancercells directly but affects the whole body, too. Radiation therapy works by being directed to specific areas in the body to destroy cancerous cells.
  • Location: Immunotherapy is a systemic treatment for cancer. This means the approach affects the entire body instead of a specific tumor area. Chemotherapy is also systemic. Systemic cancer treatments are different from regional options such as radiation, which doctors aim directly at a specific area of cancer cells.
  • Effectiveness: Taking immunotherapy alone or in combination with other therapies, such as chemotherapy or radiation therapy, can significantly improve outcomes in people with lung cancer. Immunotherapy can provide long-term benefits because instead of attacking the cancer only while the treatment is in a person’s body, it teaches the body to fight the cancer. The body can remember this even once treatment has finished.
  • Side effects: Chemotherapy can attack healthy cells as well as cancerous ones, so a person can experience hair loss and nausea due to cell damage. Side effects from immunotherapy happen when the body overreacts to the treatment, or it receives it in the wrong place. Symptoms can range from mild to life threatening.

A doctor may prescribe immunotherapy treatments in combination with chemotherapy. As well as combining different immune checkpoint inhibitor types, this combination may help a person with NSCLC live longer, according to a 2019 article in the journal Clinical Cancer Research.

For example, a study published in the New England Journal of Medicine compared people with metastatic NSCLC receiving chemotherapy with people who received chemotherapy plus the immunotherapy pembrolizumab. After 12 months, the estimated overall rate of survival for the group who received both medications was 69.2% compared with 49.4% who took only chemotherapy.

Learn about the 10 most common side effects of chemotherapy here.

Doctors prescribe three main types of immune checkpoint inhibitors to treat NSCLC. These are:

  • PD-1 inhibitors: Programmed-death 1 (PD-1) is a protein naturally present in the body. The protein is on the surface of immune system cells known as T cells. These cells work to protect the body from infection and may have cancer-fighting properties. PD-1 inhibitors include the medications pembrolizumab and nivolumab.
  • PD-L1 inhibitors: Programed-death ligand-1 (PD-L1) is another protein type that some cancer cells commonly have. If PD-1 attaches to PD-L1, the PD-1 protein signals the PD-L1 cell to stop killing the cancer cell. PD-L1 inhibitors include the medications atezolizumab and durvalumab.
  • CTLA-4 inhibitors: Cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) inhibitors boost the immune response by blocking the CTLA-4 proteins that exist on T cells. One example is ipilimumab. It can work alongside nivolumab and does not necessarily require chemotherapy.

Doctors prescribe PD-1 and PD-L1 inhibitors as immunotherapy fighters to enhance a person’s immune system. Doctors call these types immune checkpoint inhibitors. These medications help to ensure the immune system kills cancerous cells.

If a doctor thinks immunotherapy will work, a person will usually take the medications until their cancer progresses or the disease becomes too toxic. If they have an unanticipated side effect, they may also discontinue the medication.

Other types of immunotherapy for NSCLC include immune system modulators and therapeutic vaccines.

Learn more about these different types of immunotherapy for lung cancer here.

A doctor may perform biomarker testing before prescribing immunotherapy. This testing measures the likelihood of response to immunotherapy. Some tumors do not express PD-L1 proteins. When this is the case, prescribing the medications would likely be ineffective. Because these tests are not perfect predictors, some doctors may not use them.

A doctor will describe a person’s overall treatment plan to them. This should include:

  • an explanation of recommended medications
  • their anticipated side effects
  • how they will help to treat a person’s cancer

Learn about possible complications of lung cancer here.

The processes and side effects of immune checkpoint inhibitors for NSCLC will depend on which type of treatment a person receives.

Immunotherapy is a cancer treatment that may extend the life of those with NSCLC. The medication works to keep cancer cells from preventing immune system cells from killing them.

Because not all people are a good fit for immunotherapy and the medications may cause severe side effects, doctors will carefully evaluate if immunotherapy could benefit a person with NSCLC.

Children's immune response more effective against COVID-19 -- ScienceDaily

Researchers discover how cowpea mosaic plant virus activates immune system against cancer — ScienceDaily

  • June 14, 2021

Previous work by a team of researchers led by Steven N. Fiering, PhD, Immunology and Cancer Immunotherapy researcher at Dartmouth’s and Dartmouth-Hitchcock’s Norris Cotton Cancer Center and Nicole Steinmetz, PhD, Jacobs School of Engineering and Moores Cancer Center, University of California San Diego, showed that a plant virus that does not infect mammals, cowpea mosaic plant virus (CPMV), when injected into cancerous tumors, strongly stimulated the immune system to attack and often eliminate the tumor. However, very little was understood about immune recognition of plant viruses and how and why CPMV is exceptionally immuno-stimulating. In a new study, the team identifies just how CPMV is recognized by the immune system, opening the door for CPMV to be pursued as a new biological drug for treatment of cancer.

CPMV is recognized by the immune system as a pathogen — any infectious agent that can cause disease — through a family of receptors on immune cells called toll-like receptors. Toll-like receptors recognize molecules that signal the invasion of a pathogen and send a warning signal to the immune cells to mobilize to attack the pathogen. When tumors are injected with CPMV, the immune system activates and attacks the tumors by way of this pathogen pattern recognition. “The recognition of CPMV by toll-like receptors illustrates how these receptors are quite flexible and recognize many more molecular patterns than immunologists previously knew,” says Fiering.

During the immune stimulation process, the immune cells release proteins that signal and activate other immune cells, known as cytokines. The team’s study, “Cowpea mosaic virus stimulates antitumor immunity through recognition by multiple MYD88-dependent toll-like receptors,” newly published in Biomaterials, identifies the three toll-like receptors that recognize CPMV. The paper also highlights the importance of a particular cytokine, “interferon alpha,” for strong anti-tumor impact when used as an in situ vaccine to treat cancer.

In situ vaccination, in which tumors are directly treated with immune stimulating reagents, have powerful potential to improve cancer immunotherapy in a safe and inexpensive manner. “In situ vaccination has made contributions already to cancer treatment. CPMV is an excellent reagent that may soon be used to help patients in the same manner,” says Fiering. “The in situ vaccination treatment of a tumor by CPMV can stimulate the immune system to also attack distant metastatic tumors that have not been treated.”

Commercial development of CPMV as a biological drug for the treatment of cancer in the form of in situ vaccination is in progress by Mosaic ImmunoEngineering Inc., a biotech company co-founded by Steinmetz and Fiering with a team of scientists and entrepreneurs. The company has licensed the rights to this technology and is actively pursuing bringing it to the clinic for the direct benefit of patients.

Phase I trials of CPMV in situ vaccination in humans are planned to start in late 2021 or early 2022.

Steven N. Fiering, PhD, is a Professor of Microbiology and Immunology at the Geisel School of Medicine at Dartmouth, and a member of the Immunology and Cancer Immunotherapy Research Program at Dartmouth’s and Dartmouth-Hitchcock’s Norris Cotton Cancer Center. His research interests include developing clinically useful in situ vaccination approaches to generate therapeutic anti-tumor immunity.

Story Source:

Materials provided by Dartmouth-Hitchcock Medical Center. Note: Content may be edited for style and length.

Clear icon

Local hospital explains revolutionary CAR T-cell immunotherapy for cancer patients

  • June 13, 2021

SAN ANTONIO – There’s a breakthrough therapy for treating patients with blood cancer called CAR T-cell immunotherapy.

Dr. Paul Shaughnessy, medical director of the Adult Blood and Marrow STEM Cell Transplant Program at Methodist Hospital explains the therapy and how exactly it works.


How does it differ from other forms of cancer therapy?

“This immune therapy is much more directed, as much more specific to attack just the cancer cell and direct our immune system to fight cancer and our immune systems recognize and fight cancer all the time,” said Shaughnessy. “But this gives that extra boost to our immune cells to recognize this cancer that’s growing in the body unchecked and can really direct the immune system to fight cancer even more powerfully than chemotherapy.”


CAR T-cell immunotherapy

CAR T-cell immunotherapy is a new therapy that programs a patient’s immune system to recognize and fight cancer. The immune system is responsible for ridding the body of abnormal cells that are foreign (like cancer) or infected.

Ad

T-lymphocytes (T-cells) are a type of cell responsible for killing abnormal cells. During the CAR T-cell treatment process, T-cells are drawn from a patient’s blood and genetically modified to recognize the patient’s cancer cells when reinfused.

Here’s how it works:

  • First, a patient’s white blood cells are collected through a process called apheresis.

  • Then, the T-cells are isolated from other blood cells.

  • T-cells are then modified in a special facility to program them to recognize the cancer cells, which can be thought of as “fighter” T-cells.

  • Lastly, the new “fighter” T-cells are re-infused into the patient to target and kill cancer.


Doris Franke, former educator and patient shared her experience receiving CAR T-cell immunotherapy after qualifying for the therapy after two unsuccessful cancer therapies.

“It meant the world to me gave me an opportunity to have a longer period of remission so that I can enjoy my family, my grandchildren, this beautiful world, all kinds of activities that I’m so grateful that I was chosen to be part of this trial,” said Franke. “It was like a miracle. After I received the treatment, I had a reaction when I was in the hospital for several weeks, I came out of that and I just started getting better. After that, I felt good. I gained back my energy.”

Ad

To learn more, click here.

Copyright 2021 by KSAT – All rights reserved.

Old antidepressants show promise as immuno-oncology treatments in melanoma and colon cancer

Old antidepressants show promise as immuno-oncology treatments in melanoma and colon cancer

  • June 12, 2021

A class of antidepressants known as monoamine oxidase inhibitors (MAOIs) first hit the market in the 1950s and has since been eclipsed by drugs that are less likely to cause unwanted side effects. Now, scientists at the University of California, Los Angeles (UCLA) have evidence that these drugs may be able to be repurposed in the treatment of cancer.

The UCLA researchers discovered MAOIs help the immune system fight cancer, slowing the growth of colon tumors and melanoma in mice. They reported their findings in two papers, one published Nature Communications and the other in Science Immunology, UCLA said in a statement.

By studying immune cells from melanoma tumors in mice, the UCLA team discovered that immune cells that had invaded the tumors showed high activity of the gene monoamine oxidase A. The protein that gene produces, MAO-A is the target of MAOI drugs.

Mice that didn’t produce MAO-A in tumors showed better control of melanoma and colon cancer. When the animals were treated with the MAOIs phenelzine, clorgyline or mocolobemide, tumor growth slowed. The treatment worked even better in combination with drugs that block the immune checkpoint PD-1, the researchers reported.

RELATED: Could immuno-oncology treatments get a boost from a 64-year-old antipsychotic?

So how to MAOIs fight cancer? The UCLA team discovered that by blocking MAO-A, the antidepressants boost the activity of the immune system’s T cells. The drugs also inhibit tumor-associated macrophages, which normally function to help tumors evade immune destruction.

In essence, then, MAO-A could be considered another immune checkpoint, the researchers suggested.

To back up that theory, the UCLA researchers measured MAOA gene expression in several types of tumors from patients. They discovered a link between high MAOA expression and shorter survival times.

The UCLA researchers noted the longstanding belief in the scientific community that there is cross-talk between the immune system and the nervous system. And this is not the first team to propose repurposing a brain treatment in cancer. Last year, for example, Australian researchers published a study showing that when they combined the antipsychotic prochlorperazine with a PD-L1 inhibitor in mice, it outperformed either therapy alone at shrinking tumors.

Researchers at the University of Southern California are running a phase 2 clinical trial of the MAOI phenelzine in prostate cancer patients. In interim results reported last year, they said that 11 of 20 participants saw their PSA levels drop after being treated with the antidepressant.

The UCLA researchers said they have patented the combination therapy they tested in mouse models of melanoma and colon cancer but have yet to try it in people. Still, they believe it’s an idea worth pursuing, especially because cancer patients are four times as prone to depression as the general population is.

“We suspect that repurposing MAOIs for cancer immunotherapy may provide patients with dual antidepressant and antitumor benefits,” said senior author Lili Yang, Ph.D., associate professor of microbiology, immunology and molecular genetics, in the statement.

Freiburg researchers receive ERC funding to develop and test immunostimulatory drug candidates

Macrophages can aid tumor growth by distracting cancer-killing CD8+ T cells

  • June 11, 2021

A Ludwig Cancer Research study adds to growing evidence that immune cells known as macrophages inhabiting the body cavities that house our vital organs can aid tumor growth by distracting the immune system’s cancer-killing CD8+ T cells.

Reported in the current issue of Cancer Cell and led by Ludwig investigators Taha Merghoub and Jedd Wolchok at Memorial Sloan Kettering (MSK) and Charles Rudin of MSK, the study shows that cavity-resident macrophages express high levels of Tim-4, a receptor for phosphatidylserine (PS), a molecule that they surprisingly found on the surface of highly activated, cytotoxic and proliferative CD8+ T-cells.

“We believe T-cells that infiltrate the peritoneal cavity can be distracted by the interaction with Tim-4-expressing macrophages,” explained study first author Andrew Chow, an assistant attending physician at the Ludwig Collaborative Laboratory at MSK.

The researchers also show that blocking Tim-4 in mouse models of cancer can prevent this distractive interaction and enhance the effectiveness of immunotherapies.

“I think in patients who have these serous cavity macrophages expressing high levels of Tim-4, blocking Tim-4 will make immune based therapies more effective,” Merghoub, co-director of the Ludwig Collaborative Laboratory at MSK, said.

Just as people living in different cities might have distinct customs or accents, the macrophages in our bodies can adopt specialized functions and respond to disease differently depending on which tissue they inhabit. Scientists are increasingly interested in such localized responses because macrophage activities can influence recovery from illness or injury and responses to therapy.

Merghoub, Wolchok, Rudin, Chow and colleagues began exploring the role of macrophages in tumor immunosuppression after noticing that cancer patients with lesions in their pleural and peritoneal cavities-;which house the lungs and organs of the gastrointestinal tract, respectively-;were substantially less responsive to immune checkpoint blockade therapy, which stimulates a CD8+ T cell attack on tumors.

“That told us there was something immunosuppressive in these cavities, so we went hunting for what that could be,” Chow said.

Previous studies have shown that other immunosuppressed sites in the body, such as the liver and bone, harbor macrophages expressing high levels of Tim-4. Others have shown that macrophages living in the pleural and peritoneal cavities of mice also exhibit a strong Tim-4 signal.

The researchers therefore suspected that cavity-resident macrophages might impair the anti-tumor activity of CD8+ T cells through the actions of Tim-4.

These suspicions were partly vindicated when the researchers analyzed the cavity macrophages of human lung cancer patients and found that while Tim-4 levels varied between individuals, those with higher levels of the receptor tended to have a reduced presence of CD8+ T cells that had features of responding to the tumor.

Based on these observations, the researchers explored whether blocking Tim-4 would enhance the efficacy of PD-1 blockade therapies in a pre-clinical mouse model of colon and lung cancer in the peritoneal cavity.

“We showed that you get the best tumor protection when you block both molecules,” Chow said.

While blocking Tim-4 alone didn’t reduce the number of tumors or improve survival in the mice, it did enhance the tumor protection afforded by PD-1 blockade and boost the numbers of CD8+ T cells in the peritoneal cavity. The researchers also showed that Tim-4 blockade reduces immunosuppression in adoptive T-cell therapy, in which tumor-targeting T-cells are isolated and selectively grown in a lab before they’re reinfused into the patient.

“Together, these results suggest that Tim-4 blockade is a strategy to improve immunotherapy, regardless of whether you’re trying to boost your immune response through immune checkpoint blockade therapy or via adoptive T-cell therapy,” said Chow.

For Merghoub, the new findings demonstrate the need to better understand the diversity of immune landscapes in and around tumors. “In the same way we profile tumor genomes to guide the use of small molecule inhibitors for targeted therapies, we need to profile the immune landscapes of tumors and personalize immune-based therapies on the basis of such studies,” he said.

UCLA: Antidepressant Drug May Help Fight Cancer

UCLA: Antidepressant Drug May Help Fight Cancer

  • June 11, 2021

LOS ANGELES (CNS) – Results of a new study released today by UCLA suggests that a class of drug commonly prescribed to treat depression might have another health benefit by helping the immune system attack cancer.

The class of drug called monoamine oxidase inhibitors work by boosting levels of serotonin, the brain’s “happiness hormone,” according to researchers.

“MAOIs had not been linked to the immune system’s response to cancer before,” said Lili Yang, senior author of the study and a member of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA.

“What’s especially exciting is that this is a very well-studied and safe class of drug, so repurposing it for cancer isn’t as challenging as developing a completely new drug would be.”

The findings are reported in two papers, which are published in the journals Science Immunology and Nature Communications.

Recent advances in understanding how the human immune system naturally seeks out and destroys cancer cells, as well as how tumors try to evade that response, has led to new cancer immunotherapies — drugs that boost the immune system’s activity to try to fight cancer.

In an effort to develop new cancer immunotherapies, Yang and her colleagues compared immune cells from melanoma tumors in mice to immune cells from cancer-free animals. Immune cells that had infiltrated tumors had much higher activity of a gene called monoamine oxidase A, or MAOA. MAOA’s corresponding protein, called MAO-A, controls levels of serotonin and is targeted by MAOI drugs.

“For a long time, people have theorized about the cross-talk between the nervous system and the immune system and the similarities between the two,” said Yang, who is also a UCLA associate professor of microbiology, immunology and molecular genetics and a member of the UCLA Jonsson Comprehensive Cancer Center.

“So it was exciting to find that MAOA was so active in these tumor-infiltrating immune cells.”

Copyright 2021, City News Service, Inc.

Common Antidepressent Might Help Immune System Attack Cancer - Cerritos Community News

Common Antidepressent Might Help Immune System Attack Cancer – Cerritos Community News

  • June 10, 2021

 

June 10, 2021

(UCLA) ~ A class of drug called monoamine oxidase inhibitors is commonly prescribed to treat depression; the medications work by boosting levels of serotonin, the brain’s “happiness hormone.”

A new study by UCLA researchers suggests that those drugs, commonly known as MAOIs, might have another health benefit: helping the immune system attack cancer.

Their findings are reported in two papers, which are published in the journals Science Immunology and Nature Communications. “MAOIs had not been linked to the immune system’s response to cancer before,” said , senior author of the study and a member of the “What’s especially exciting is that this is a very well-studied and safe class of drug, so repurposing it for cancer isn’t as challenging as developing a completely new drug would be.”

Recent advances in understanding how the human immune system naturally seeks out and destroys cancer cells, as well as how tumors try to evade that response, has led to new cancer immunotherapies — drugs that boost the immune system’s activity to try to fight cancer. In an effort to develop new cancer immunotherapies, Yang and her colleagues compared immune cells from melanoma tumors in mice to immune cells from cancer-free animals.

Immune cells that had infiltrated tumors had much higher activity of a gene called monoamine oxidase A, or MAOA. MAOA’s corresponding protein, called MAO-A, controls levels of serotonin and is targeted by MAOI drugs.

“For a long time, people have theorized about the cross-talk between the nervous system and the immune system and the similarities between the two,” said Yang, who is also a UCLA associate professor of and a member of the “So it was exciting to find that MAOA was so active in these tumor-infiltrating immune cells.”

Next, the researchers studied mice that didn’t produce MAO-A protein in immune cells. The scientists found that those mice were better at controlling the growth of melanoma and colon tumors. They also found that normal mice became more capable of fighting those cancers when treated with MAOIs.

Digging in to the effects of MAO-A on the immune system, the researchers discovered that T cells — the immune cells that target cancer cells for destruction — produce MAO-A when they recognize tumors, which diminishes their ability to fight cancer.

That discovery places MAO-A among a growing list of molecules known as immune checkpoints, which are molecules produced as part of a normal immune response to prevent T cells from overreacting or attacking healthy tissue in the body.

Cancer has been known to exploit the activity of other previously identified immune checkpoints to evade attack by the immune system. In the the scientists report that MAOIs help block the function of MAO-A, which helps T cells overcome the immune checkpoint and more effectively fight the cancer. But the drugs also have a second role in the immune system, Yang found.

Rogue immune cells known as tumor-associated macrophages often help tumors evade the immune system by preventing anti-tumor cells including T cells from mounting an effective attack. High levels of those immunosuppressive tumor-associated macrophages in a tumor have been associated with poorer prognoses for people with some types of cancer.

But the researchers discovered that MAOIs block immunosuppressive tumor-associated macrophages, effectively breaking down one line of defense that tumors have against the human immune system. That finding is reported in the Nature Communications paper.

“It turns out that MAOIs seem to both directly help T cells do their job, and stop tumor-associated macrophages from putting the brakes on T cells,” Yang said. Combining MAOIs with existing immunotherapies Yang said she suspects that MAOIs may work well in concert with a type of cancer immunotherapies called immune checkpoint blockade therapies, most of which work by targeting immune checkpoint molecules on the surface of immune cells.

That’s because MAOIs work on MAO-A proteins, which are inside cells and function differently from other known immune checkpoint molecules. Studies in mice showed that any of three existing MAOIs — phenelzine, clorgyline or mocolobemide — either on their own or in combination with a form of immune checkpoint blockade therapy known as PD-1 blockers, could stop or slow the growth of colon cancer and melanoma.

Although they haven’t tested the drugs in humans, the researchers analyzed clinical data from people with melanoma, colon, lung, cervical and pancreatic cancer; they found that people with higher levels of MAOA gene expression in their tumors had, on average, shorter survival times.

That suggests that targeting MAOA with MAOIs could potentially help treat a broad range of cancers. Yang and her collaborators are already planning additional studies to test the effectiveness of MAOIs in boosting human immune cells’ response to various cancers. Yang said MAOIs could potentially act on both the brain and immune cells in patients with cancer, who are up to four times as likely as the general population to experience depression.

“We suspect that repurposing MAOIs for cancer immunotherapy may provide patients with dual antidepressant and antitumor benefits,” she said.

The experimental combination therapy in the study was used in preclinical tests only and has not been studied in humans or approved by the Food and Drug Administration as safe and effective for use in humans.

The newly identified therapeutic strategy is covered by a patent application filed by the UCLA Technology Development Group on behalf of the Regents of the University of California, with Yang, Xi Wang and Yu-Chen Wang as co-inventors. a Ruth L. Kirschstein National Research Service Award.

Comments

comments

Powered by Facebook Comments

capsimmunesystem.org