Biology Is the end of cancer near?

Snake_Baker

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A cure for cancer? Israeli scientists say they think they found one

“We believe we will offer in a year's time a complete cure for cancer."

By Maayan Jaffe-Hoffman

January 28, 2019 23:14

A small team of Israeli scientists think they might have found the first complete cure for cancer.

“We believe we will offer in a year’s time a complete cure for cancer,” said Dan Aridor, of a new treatment being developed by his company, Accelerated Evolution Biotechnologies Ltd. (AEBi), which was founded in 2000 in the ITEK incubator in the Weizmann Science Park. AEBi developed the SoAP platform, which provides functional leads to very difficult targets.

“Our cancer cure will be effective from day one, will last a duration of a few weeks and will have no or minimal side-effects at a much lower cost than most other treatments on the market,” Aridor said. “Our solution will be both generic and personal.”

It sounds fantastical, especially considering that an estimated 18.1 million new cancer cases are diagnosed worldwide each year, according to reports by the International Agency for Research on Cancer. Further, every sixth death in the world is due to cancer, making it the second leading cause of death (second only to cardiovascular disease).

Aridor, chairman of the board of AEBi and CEO Dr. Ilan Morad, say their treatment, which they call MuTaTo (multi-target toxin) is essentially on the scale of a cancer antibiotic – a disruption technology of the highest order.

The potentially game-changing anti-cancer drug is based on SoAP technology, which belongs to the phage display group of technologies. It involves the introduction of DNA coding for a protein, such as an antibody, into a bacteriophage – a virus that infects bacteria. That protein is then displayed on the surface of the phage. Researchers can use these protein-displaying phages to screen for interactions with other proteins, DNA sequences and small molecules.

In 2018, a team of scientists won the Nobel Prize for their work on phage display in the directed evolution of new proteins – in particular, for the production of antibody therapeutics.

AEBi is doing something similar but with peptides, compounds of two or more amino acids linked in a chain. According to Morad, peptides have several advantages over antibodies, including that they are smaller, cheaper, and easier to produce and regulate.

When the company first started, Morad said, “We were doing what everyone else was doing, trying to discover individual novel peptides for specific cancers.” But shortly thereafter, Morad and his colleague, Dr. Hanan Itzhaki, decided they wanted to do something bigger.

To get started, Morad said they had to identify why other cancer-killing drugs and treatments don’t work or eventually fail. Then, they found a way to counter that effect.

For starters, most anti-cancer drugs attack a specific target on or in the cancer cell, he explained. Inhibiting the target usually affects a physiological pathway that promotes cancer. Mutations in the targets – or downstream in their physiological pathways – could make the targets not relevant to the cancer nature of the cell, and hence the drug attacking it is rendered ineffective.

In contrast, MuTaTo is using a combination of several cancer-targeting peptides for each cancer cell at the same time, combined with a strong peptide toxin that would kill cancer cells specifically. By using at least three targeting peptides on the same structure with a strong toxin, Morad said, “we made sure that the treatment will not be affected by mutations; cancer cells can mutate in such a way that targeted receptors are dropped by the cancer.”

“The probability of having multiple mutations that would modify all targeted receptors simultaneously decreases dramatically with the number of targets used,” Morad continued. “Instead of attacking receptors one at a time, we attack receptors three at a time – not even cancer can mutate three receptors at the same time.”

Furthermore, many cancer cells activate detoxification mechanisms when in stress from drugs. The cells pump out the drugs or modify them to be non-functional. But Morad said detoxification takes time. When the toxin is strong, it has a high probability of killing the cancer cell before detoxification occurs, which is what he is banking on.

https://www.jpost.com/HEALTH-SCIENCE/A-cure-for-cancer-Israeli-scientists-say-they-think-they-found-one-578939
 

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CD Xbow

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That article is incredibly premature, as it has only been used in mice and hasn't started human trials yet. It reads like a prospectus for a Biotech company and I suspect is an attempt to bump up the companies share price.. As we understand the biology of various cancers better then specific treatments will become available, indeed some already have. I expect most cancers will be 'cured' this century, but I am very sceptical of a single, magic bullet. It's like thinking you could treat all infections with one drug. You can't.
 

Snake_Baker

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That article is incredibly premature, as it has only been used in mice and hasn't started human trials yet. It reads like a prospectus for a Biotech company and I suspect is an attempt to bump up the companies share price.. As we understand the biology of various cancers better then specific treatments will become available, indeed some already have. I expect most cancers will be 'cured' this century, but I am very sceptical of a single, magic bullet. It's like thinking you could treat all infections with one drug. You can't.
Are you claiming that targeted peptides couldn't be synthesized for all cancers?

"MuTaTo (Multi-Target Toxin), is a family of molecules armed with peptides that have the ability to interact with a wide variety of proteins expressed by the cancer cells. Rather than just targeting one kind of protein, the molecules have the ability to target a number of proteins at the same time, said Morad. “We create a multiple attack on cancer,” he said.


“Think of the arms of an octopus,” he elaborated. “The octopus in this case is the molecule, and at the end of each arm there are peptides that interact with the proteins and inhibit their action.” This interaction allows “toxic peptides” attached to many arms of the octopus to penetrate the cancer cell and destroy it from within."


I have no problem at all in believing that claim, or the ability to insert target peptides in to a host virus.
 

Snake_Baker

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**** I hope they can back this up!
Naturally.

It's well established science that:

a) Cancers have unique receptors that regulate their metabolic processes.
b) These receptors cannot be recognised by typical antibodies in the immune system
c) Novel peptides can be synthesized that can block receptors and/or trigger antibody activity
d) Novel peptides can be inserted in to virus DNA
e) Viruses can insert themselves in to cancer cells (oncolysis).
 

CD Xbow

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Are you claiming that targeted peptides couldn't be synthesized for all cancers?

"MuTaTo (Multi-Target Toxin), is a family of molecules armed with peptides that have the ability to interact with a wide variety of proteins expressed by the cancer cells. Rather than just targeting one kind of protein, the molecules have the ability to target a number of proteins at the same time, said Morad. “We create a multiple attack on cancer,” he said.


“Think of the arms of an octopus,” he elaborated. “The octopus in this case is the molecule, and at the end of each arm there are peptides that interact with the proteins and inhibit their action.” This interaction allows “toxic peptides” attached to many arms of the octopus to penetrate the cancer cell and destroy it from within."

I have no problem at all in believing that claim, or the ability to insert target peptides in to a host virus.
Not claiming anything. Simply the article reads like a presser. There has not been one clinical trial. There have been many technologies that seemed promising in the lab that don't make it in the real world. Viral delivery systems have been plagued with a few minor problems like death. It would be wonderful if it worked but the odds are against it.
 

Howard Littlejohn

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Not claiming anything. Simply the article reads like a presser. There has not been one clinical trial. There have been many technologies that seemed promising in the lab that don't make it in the real world. Viral delivery systems have been plagued with a few minor problems like death. It would be wonderful if it worked but the odds are against it.
At which point cancer ceases to be an ongoing medical problem. Therefore, cured.
 

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Jason mp

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I know it hasn't been a year since the OP but any updates on this? Would be such a fantastic outcome for cancer victims and their families, from very recent experience I can now understand why many have said that the cure can feel like it is worse than the disease.

I just finished(Friday just gone) 8 weeks of Chemotherapy and Radiation treatment for a Metastatic Squamous Cell Carcinoma in the tonsils, throat and neck Lymph Nodes, hellish thing to go through, hopefully I'm on the narrow end of what the prognosis is for side affects to start dissipating ie. anywhere between 2 weeks and a year, in rare cases the side affects can last a lifetime.

#f..kcancer
 

FireKraquora

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I know it hasn't been a year since the OP but any updates on this? Would be such a fantastic outcome for cancer victims and their families, from very recent experience I can now understand why many have said that the cure can feel like it is worse than the disease.

I just finished(Friday just gone) 8 weeks of Chemotherapy and Radiation treatment for a Metastatic Squamous Cell Carcinoma in the tonsils, throat and neck Lymph Nodes, hellish thing to go through, hopefully I'm on the narrow end of what the prognosis is for side affects to start dissipating ie. anywhere between 2 weeks and a year, in rare cases the side affects can last a lifetime.

#f..kcancer
Can't comment on the science part, but wishing you all the best with your recovery mate.
 

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I know it hasn't been a year since the OP but any updates on this? Would be such a fantastic outcome for cancer victims and their families, from very recent experience I can now understand why many have said that the cure can feel like it is worse than the disease.

I just finished(Friday just gone) 8 weeks of Chemotherapy and Radiation treatment for a Metastatic Squamous Cell Carcinoma in the tonsils, throat and neck Lymph Nodes, hellish thing to go through, hopefully I'm on the narrow end of what the prognosis is for side affects to start dissipating ie. anywhere between 2 weeks and a year, in rare cases the side affects can last a lifetime.

#f..kcancer

Sorry to read about this mate, chin up and stay on course with your recovery.:thumbsu:

I assume this is a stage 3 issue, so the prognosis should be very good.
 

Jason mp

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Sorry to read about this mate, chin up and stay on course with your recovery.:thumbsu:

I assume this is a stage 3 issue, so the prognosis should be very good.
Thanks Snake.

Yes, the prognosis is positive, I was told at the start that this course of treatment had a 90% success rate.

I will say that the standard of treatment you get through the public health system is outstanding, from the initial diagnosis to treatment starting was only 3 weeks. Then the numbers and quality of professionals you have working on your case is such a comfort for you and your family and friends. Oncologists, Radiologists, Nurses, Nurse Clinician's, Welfare, Dental, Speech & Diet, Volunteers are all just amazing, they make you feel like you are their only patient and sole focus.

Thank you science.
 

Snake_Baker

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Thanks Snake.

Yes, the prognosis is positive, I was told at the start that this course of treatment had a 90% success rate.

I will say that the standard of treatment you get through the public health system is outstanding, from the initial diagnosis to treatment starting was only 3 weeks. Then the numbers and quality of professionals you have working on your case is such a comfort for you and your family and friends. Oncologists, Radiologists, Nurses, Nurse Clinician's, Welfare, Dental, Speech & Diet, Volunteers are all just amazing, they make you feel like you are their only patient and sole focus.
Very happy to read that mate, and I will extrapolate your diagnosis from that data. Yes, there's a high recovery rate for your treatment.;)

Keep us updated, if you like.

Thank you science.
The only thing that separates us from the beasts in the field. :thumbsu: :thumbsu:
 

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It would be wonderful news. Also read this pretty positive news last year:

Hope we get there and do so sooner rather than later.
 

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Light-activated metal catalyst destroys cancer cells' vital energy source

by University of Warwick
September 23, 2019

A space-age metal that formed part of the asteroid that destroyed the dinosaurs could provide a new method of treating cancer tumors selectively using light.

Scientists at the University of Warwick in collaboration with colleagues in China, France, Switzerland and Heriot-Watt University have developed a technique that uses light to activate a cancer-killing compound of Iridium that attacks, for the first time, a vital energy source in cancer cells even under hypoxia, significantly opening up the range of cancers that can be treated using the technique. The technique is detailed in a paper published today (23 September 2019) in Nature Chemistry and could lead to another tool for clinicians to use in the fight against cancer, and potentially even vaccinate patients against future cancers.

Photodynamic therapy (PDT) uses light to kill cancer tumors in the body by activating a chemical compound called a photosensitizer, which creates species that can attack cancer cells in the presence of light. Using this method, clinicians can direct the light to specific regions of the cancer tumor and spare normal tissue from damage. Current methods mainly rely on the presence of oxygen and many tumors are 'hypoxic," which means that they are deficient in normal oxygen often due to poor blood supplies. The international team of scientists have now developed a compound of the metal Iridium that will kill cancer cells in culture even when oxygen concentration is low. The technique can treat any tumors where light can be administered, and would be particularly suited to treat bladder, lung, esophageal, brain and skin cancers. There are around 10,000 bladder cancer cases in the UK per year, of which about 5,000 might potentially benefit from this kind of treatment.

Professor Peter Sadler from the University of Warwick's Department of Chemistry said: "All the time in cancer treatment, clinicians are trying to fight resistance. Drugs can kill the cancer cells initially, but with repeated treatment the cells become resistant, they learn how to chemically modify the drug or counteract its mechanism of action. Researchers are looking for novel ways in which the cancer cell will die. If they have become resistant to other cancer drugs, they may not be resistant to this treatment because the way it kills the cancer cells is different. "There is an increasing interest in reducing the side effects of cancer treatment as much as possible and anything that can be selective in what it targets will help with that. The compound that we have developed would not be very toxic at all, we would give it to the cancer cells, allow a little time for it to be taken up, then we would irradiate it with light and activate it in those cells. We would expect killing of those cancer cells to occur very quickly compared with current methods."

Once light-activated, the Iridium compound attacks the energy producing machinery in the cancer cells—a vital co-enzyme called nicotinamide adenine dinucleotide (NADH) - and catalytically destroys that co-enzyme or changes it into its oxidized form. This upsets the energy-producing machinery in a cancer cell and effectively cuts off the tumor's power source. Our bodies need coenzyme nicotinamide adenine dinucleotide (NADH) to generate energy. Cancer cells have a very high requirement for NADH, because they need a lot of energy to divide and multiple rapidly. The researchers even found that the compound still works in the presence of oxygen, by converting it into a 'toxic' type of oxygen that will kill the cancer cells.

The team of scientists also noted that as the cancer cells die, they change their chemistry in such a way that they will generate an immune reaction in the body, what is known as an immunotherapeutic response. This suggests that those treated by this technique might be immunized against attack by that cancer, and will be investigated further in future research.

- Professor Vas Stavros (University of Warwick) commented: "The power of light to change the reactivity of chemical molecules dramatically within a thousandth of a millionth of a second can now be harnessed to treat resistant cancers."

- Professor Martin Paterson (Heriot-Watt University) commented: "This breakthrough illustrates the power of modern computation to understand the effects of light on chemical molecules to provide drugs of the future with truly unique mechanisms of action."

- Professor Hui Chao (Sun Yat-Sen University) commented: "Now we have a potential new drug which can not only selectively kill cancer cells with normal oxygen supplies, but also hypoxic cancer cells which often resist treatment by photodynamic therapy."

- Professor Peter Sadler added: "The ability of metal compounds to induce an immunogenic response in the body that may effectively vaccinate a person against future attack by cancer is an exciting development. It is very speculative, but we are looking further into the hallmarks of that. Importantly we were fortunate to have had 3 highly talented young Royal Society Newton International Fellows in our team working on this challenging interdisciplinary project, who will undeniably contribute towards the future of this crucially important research."

Iridium was first discovered in 1803, and its name comes from the Latin for "rainbow." From the same family as platinum, it is hard, brittle, and is the world's most corrosion-resistant metal. Yellow in color, its melting point is more than 2400° Celsius. It is used in satellites and spacecraft due to its resistance to extreme environments, and is commonly believed to have been enriched in the earth's crust by a meteorite that wiped out the dinosaurs 66 million years ago.

 

Jason mp

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jason pm you haven't posted for a while, hope all is ok with you?
I'm good TP, just decided to have a break for a few weeks from Big Footy. I'll hang around for the trade period and then have some more time off over the off season, I don't want too much of a good thing.

Still a few side affects hanging around from the treatment but I'm a hell of a lot better than I was a month ago. I just have to wait now till late November to find out if it worked for me.
 

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The Promise of CRISPR

Biochemist Samuel H. Sternberg describes the limitations, realities and potential of gene-editing technology.

by Marci A. Landsmann

The CRISPR gene-editing system takes advantage of a natural defense found within the chromosomes of bacterial cells that includes repeating strands of DNA separated by so-called spacers. This region, referred to as clustered regularly interspaced short palindromic repeats (CRISPR), encodes RNA to seek out that specific DNA sequence in viruses. Once the sequence has been found, a protein called Cas9 cuts both strands of the DNA. Thus, by harnessing the same technique that helps bacteria protect themselves from pathogens, scientists can engineer a sort of “global positioning system” that locates and resects malfunctioning DNA or inserts new sequences at specific locations.

As part of his graduate and postgraduate work, Samuel H. Sternberg studied this technology in the lab of biochemist Jennifer A. Doudna at the University of California, Berkeley. Doudna was part of an international group of scientists who described the technology’s ability to cut targeted DNA sequences in Science in June 2012. After receiving his doctorate in chemistry in 2014, Sternberg teamed with Doudna to write A Crack in Creation: Gene Editing and the Unthinkable Power to Control Evolution, which details the lab’s research with the technology and outlines its prospects, limitations and key ethical considerations.

Today, Sternberg runs his own research lab at Columbia University in New York City, where he is working to develop more precise gene-editing techniques. He spoke with Cancer Today about recent developments in gene editing.

Q: In its simplest form, I’ve heard CRISPR-Cas9 described as a cutting tool, but is there more to the process of inserting a gene in a precise spot after the cut?

A: Yes, the technology cuts, but it’s getting more complicated. CRISPR is really becoming this umbrella term that focuses on different enzymes, different genes, different RNA protein molecules, and many of them have slightly different functions. The idea is we’ll have a toolbox to use the most functional tools depending on what we want to achieve.

Q: The technology you’re working on in your lab doesn’t make a cut. What is the benefit of that?

A: An adverse effect of using a cut for gene editing is there has been a lot of work showing that these cuts can introduce wrong deletions, even the fusion of different chromosomes with something called a translocation. And that is why, in some cases, it is somewhat undesirable because the cell goes into a red-alert mode and sometimes it can do things you really don’t want.

Q: Let’s talk a little bit about the controversy with gene editing. What are some of the challenges?

A: One of the inherent challenges here is that there is no one person who controls technology, and there’s no real likelihood that everyone is going to think the same about it. People have different attitudes about where we should and should not intervene. I think it is unrealistic to assume that there will be some outcome where everyone just agrees. Nevertheless, I think we need to have those difficult conversations.

Q: Is there any person or organization taking the lead?

A: The National Academy of Sciences and the National Academy of Medicine, along with international organizations, took a leadership role. These organizations held the first conference that really tackled these issues in D.C. in 2015. They then published a lengthy report that came out in 2017. The report can be quite technical, but it is encouraging to have the leading scholars, scientists and ethicists coming together and doing a deep dive on the technologies, and not just on the scientific side of it, but on the downstream implications. I think that report really does a good job of laying the groundwork for these conversations.

Q: What are some realistic applications of CRISPR technology?

A: Even before gene-editing tools became developed, cancer immunotherapy had such rapid movement. I think I see the most immediate excitement in using a combination of CRISPR and immunotherapy when using CAR-T cells, which has already been in trials in China and is now in clinical trials at the University of Pennsylvania in Philadelphia.

Q: CAR-T cell therapy, which is currently approved by the U.S. Food and Drug Administration for some blood-related cancers, involves a process where T cells are taken from the patient’s blood. They are then engineered with a special receptor to help bolster an immune response and infused back in the patient. Does being able to have these cells modified in the lab make it easier to do gene editing?

A: Yes, that’s ex vivo therapy, which is another reason why it’s attractive in terms of being a more low-hanging fruit. For genetic diseases, it’s quite straightforward to repair a disease-causing mutation in cell lines in the laboratory. But how do you do this effectively in a patient? When you engineer T-cells in a lab, you have all the control over how the cells are cultured and the ways of delivering CRISPR into those cells. CAR-T cell therapy allows you to access gene editing in a context where it is easiest.

Q: What are your hopes for CRISPR technology when you think of cancer?

A: We share one story in the book about a 1-year-old girl who was dying of leukemia. She received an infusion of gene-edited T cells on a compassionate use basis because essentially that was the last resort. And that was able to bring her back to health long enough for her to receive a bone marrow transplant that was successful in sending the cancer into remission. The real dream is that we can deliver this kind of precision medicine—designer therapy for a particular cancer—by engineering the T cells or the immune cells to specifically hunt down those cancer cells in the body. That’s where I see a lot of excitement, where I see some commercial therapies being developed.

 

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First-In-US trial of CRISPR-edited immune cells for cancer appears safe

Abramson Cancer Center researchers to present initial safety data after treating three patients

University of Pennsylvania School of Medicine

PHILADELPHIA - Genetically editing a cancer patient's immune cells using CRISPR/Cas9 technology, then infusing those cells back into the patient appears safe and feasible based on early data from the first-ever clinical trial to test the approach in humans in the United States. Researchers from the Abramson Cancer Center of the University of Pennsylvania have infused three participants in the trial thus far - two with multiple myeloma and one with sarcoma - and have observed the edited T cells expand and bind to their tumor target with no serious side effects related to the investigational approach. Penn is conducting the ongoing study in cooperation with the Parker Institute for Cancer Immunotherapy (PICI) and Tmunity Therapeutics.

"This trial is primarily concerned with three questions: can we edit T cells in this specific way? Are the resulting T cells functional? And are these cells safe to infuse into a patient? This early data suggests that the answer to all three questions may be yes," said the study's principal investigator Edward A. Stadtmauer, MD, section chief of Hematologic Malignancies at Penn. Stadtmauer will present the findings next month at the 61st American Society of Hematology Annual Meeting and Exposition in Orlando (Abstract #49).

The approach in this study is closely related to CAR T cell therapy, which engineers patients' own immune cells to fight their cancer, but it has some key differences. Just like CAR T, researchers begin by collecting a patient's T cells through a blood draw. However, instead of arming these cells with a receptor like CD19, the team first uses CRISPR/Cas9 editing to remove three genes. The first two edits remove a T cell's natural receptors to make sure the immune cells bind to the right part of the cancer cells. The third edit removes PD-1, a natural checkpoint that sometimes blocks T cells from doing their job. At that point, a lentivirus is used to insert an affinity-enhanced T cell receptor (TCR), which tells the edited T cells to target an antigen called NY-ESO-1.

"Our use of CRISPR editing is geared toward improving the effectiveness of gene therapies, not editing a patient's DNA," said the study's senior author Carl June, MD, the Richard W. Vague Professor in Immunotherapy and director of the Center for Cellular Immunotherapies in the Abramson Cancer Center. "We leaned heavily on our experience as pioneers of the earliest trials for modified T-cell therapies and gene therapies, as well as the strength of Penn's research infrastructure, to make this study a reality."

Even with that experience, moving this work into the clinic while ensuring appropriate patient safeguards meant the research team had to move through a comprehensive series of institutional and federal regulatory approval steps. This included approval by the National Institutes of Health's Recombinant DNA Research Advisory Committee, which was charged with providing advice on safety and ethical issues associated with emerging biotechnologies. After that, plans for the trial were reviewed by the U.S. Food and Drug Administration, as well as Penn's institutional review board and institutional biosafety committee. The whole process took more than two years.

The CRISPR-edited T cells are not active on their own like CAR T cells. Instead, they require the presence of an antigen known as HLA-A201, which is only expressed in a subset of patients. This means that patients had to be screened ahead of time to make sure their tumors are a match for the approach. Participants who met the requirements received other clinically-indicated therapy as needed while they waited for their cells to be manufactured. Once that process was completed, all three received the gene-edited cells in a single infusion after a short course of chemotherapy. Analysis of blood samples revealed that all three participants had the CRISPR-edited T cells expand and survive. While none have yet responded to the therapy, there were no treatment-related serious adverse events. Researchers say the number of edits made to each T cell means there are multiple possible cells produced and the optimal and most active cell product remains to be determined. They are continuing to analyze patient samples and say they need longer clinical follow-up to more definitively study this emerging approach.

"Tmunity is proud to be a part of the first U.S. trial in humans with a CRISPR-edited cell therapy," said Usman "Oz" Azam, MD, President and Chief Executive Officer of Tmunity. "These data establish a beachhead in the continued evolution of Tmunity's innovative portfolio and provides key insights into the development of allogeneic cell therapies."

While this phase 1 safety study continues and genetic analysis is ongoing, researchers say the feasibility and safety they've demonstrated so far provides optimism that the approach may be applicable across multiple areas of gene therapy research.

"Our purpose is to make sure PICI investigators have the support they need to bring bold ideas like this to life. These early findings are the first step as we determine if this new, breakthrough technology can help rewrite how we treat patients with cancer and perhaps other deadly diseases," said Sean Parker, Founder and Chairman of PICI. "CRISPR editing could be the next generation of T cell therapy, and we are proud to be a part of the first human trial in the United States."

Stadtmauer will present the findings Saturday, December 7 at 7:30 a.m. in Room W414AB at the Orange County Convention Center. Additional Penn authors include Adam D. Cohen, Kristy Weber, Simon F. Lacey, Vanessa E. Gonzalez, J. Joseph Melenhorst, Joseph A. Fraietta, Gabriela Plesa, Joanne Shea, Tina Matlawski, Amanda Cervini, Avery L. Gaymon, Stephanie Desjardins, Patricia Mangan, Eric Lancaster, Bruce L. Levine, Don L. Siegel, Yangbing Zhao, Wei-Ting Huang, Elizabeth Hexner.


 

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Researchers block metastasis-promoting enzyme, halt spread of breast cancer

by University of California, San Francisco

In a breakthrough with important implications for the future of immunotherapy for breast cancer, UC San Francisco scientists have found that blocking the activity of a single enzyme can prevent a common type of breast cancer from spreading to distant organs.

While studying a mouse model that replicates key features of early-stage human breast cancer, the researchers discovered that a ubiquitous enzyme called MMP9 is an essential component of the cancer's metastasis-promoting machinery, helping to create a hospitable environment for itinerant cancer cells to form new metastatic tumors.

"Metastasis is the biggest hurdle when it comes to successfully treating breast cancer, and solid tumors in general," said Vicki Plaks, Ph.D., now an assistant adjunct professor in the Department of Orofacial Sciences at UCSF. "Once a cancer becomes metastatic, there's really no cure, and the only option is to manage it as a chronic disease." Plaks co-led the team that made the discovery when still a postdoctoral fellow in the laboratory of Zena Werb, Ph.D., a professor of anatomy and associate director for basic science at the UCSF Helen Diller Family Comprehensive Cancer Center.

When they examined lung tissue in their mouse model, the researchers found that MMP9 is involved in remodeling healthy tissue and transforming it into a kind of safe haven for migrating breast cancer cells. When the cancer cells colonize these sites with the help of MMP9, they're able to start growing into new tumors.

The new study, published Nov. 14 in the journal Life Science Alliance, shows that these metastases can be stopped before they are able to lay the foundations for tumor growth. By administering an antibody that specifically targets and disrupts MMP9 activity, the scientists were able to prevent cancer from colonizing the lungs of mice. But interestingly, interfering with MMP9 had no effect on the primary tumor, which suggests that the enzyme's primary role in this scenario is helping existing malignancies metastasize and colonize other organs rather than promoting the growth of established primary tumors.

Prior to this study, Werb and others had found that MMP9 plays an important role in remodeling the extracellular matrix (ECM)—a patchwork of biomolecules found outside of cells that provides structure and shape to organs, helps cells communicate with one another, and establishes a microenvironment that promotes cell health, among its many other functions. Although MMP9 was known to be involved in cancer, specifically in remodeling the ECM to build tumor niches that are hospitable to malignancies, its role in the earliest stages of metastasis had not been fully explored.

"Lots of studies that examined metastatic niche formation in breast cancer have focused on late-stage cancers, when the tumors are fairly progressed. What sets our study apart is that we chose to focus on processes that alter the tumor and metastatic microenvironment early on. This approach enabled us to show that MMP9 really matters in the early stages," said Mark Owyong, co-lead author of the new study with Jonathan Chou, MD, Ph.D., a clinical fellow in the UCSF School of Medicine. Owyong, Chou and Plaks conducted the research as members of the Werb lab.

The first hint that MMP9 might be involved in early-stage metastasis came from publicly available gene expression data from clinical breast cancer biopsies. While sifting through this data, the researchers noticed that MMP9 levels were elevated in metastatic disease.

To further investigate MMP9's role in metastasis, the researchers turned to a unique mouse model of "luminal B" breast cancer, which is among the most frequently diagnosed forms of the disease. "We selected the model because it's one of the few that captures the natural progression of breast cancer, closely mimicking the progression of the disease experienced by patients," Owyong said.

In a key set of experiments, the researchers injected tumor cells into mice that had early stage breast cancer but no discernible metastases. They found that the cells colonized the lungs and formed new tumor growth sites. But when these cells were injected into genetically identical mice without breast cancer, no metastases formed.

When the experiment was repeated in mice with early stage breast cancer whose MMP9 gene had been knocked out, there was a significant reduction in the size of metastatic lung tumors, though there was no effect on the primary breast tissue tumor. These findings suggest that MMP9 is required to promote metastasis, but not essential for continued growth of the primary tumor.

Similar results were seen when the researchers disrupted the activity of MMP9 with a unique antibody that specifically targets the activated form of the enzyme. The researchers injected tumor cells into these mice, followed by injections of the antibody every two days. At the end of the treatment regimen, the researchers inspected the mice and saw a significant reduction in the number and size of lung metastases in mice who received the antibody compared with those that didn't.

"This was a very promising result and suggests that a therapeutic paradigm focused on intercepting metastasis early might offer a new route for treating certain kinds of breast cancer," said Plaks.

The researchers also discovered that interfering with MMP9 activity helped recruit and activate cancer-fighting immune cells to metastatic sites, a result with important implications for treating certain types of metastatic breast cancer with immunotherapy.

Immunotherapies work by enlisting the body's immune system to find and kill cancer cells. But certain cancers—including luminal B breast cancer, the main focus of the new study—don't succumb to immunotherapy. According to Plaks, this is because, beyond their direct effects on metastatic growth, enzymes like MMP9 also play an important role in remodeling the ECM and building mesh-like barriers around metastatic sites that help to exclude immune cells. This may explain why some metastatic cancer cells are able to evade the immune onslaught triggered by immunotherapies.

But the new study shows that when MMP9 is incapacitated, metastatic sites may no longer be able to keep immune cells at bay. Plaks thinks that this represents an important step towards making breast cancer more susceptible to immunotherapies that have proven effective against other forms of cancer.

"These findings come at an exciting time in cancer immunology, with antibodies targeting MMP9 being actively explored for clinical use within the biotech industry," Plaks said. "There's been great interest in trying to use immunotherapy to treat metastatic breast cancers of the luminal B type, but so far, success has been limited. Our work indicates that a combination approach of immunotherapy with antibodies targeting MMP9 activity might actually succeed."


 

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