Pacific Heart, Lung & Blood Institute http://www.phlbi.org A 501(c)(3) non-profit medical research institution. Mon, 26 Jun 2017 16:48:00 +0000 en-US hourly 1 https://wordpress.org/?v=4.8 The Alkaline Diet: A Natural Cancer Cure? http://www.phlbi.org/blog/2017/06/alkaline-diet-natural-cancer-cure/ http://www.phlbi.org/blog/2017/06/alkaline-diet-natural-cancer-cure/#respond Mon, 26 Jun 2017 16:46:37 +0000 http://www.phlbi.org/?p=8745 The cure for cancer. Famous doctors devote their lives to finding a cure. Endless experiments have been conducted to find it. Millions of people search for this miracle treatment. But what if there already is an existing cure? Inflammation of the body and the increasing intracellular pH are the main promoters of the growth of […]

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The cure for cancer. Famous doctors devote their lives to finding a cure. Endless experiments have been conducted to find it. Millions of people search for this miracle treatment.

But what if there already is an existing cure?

Inflammation of the body and the increasing intracellular pH are the main promoters of the growth of cancer. These factors provide a perfect setting for cancer cells to thrive and multiply. The verdict for this inflammation? Diet. While a diet full of carbohydrates, sugar, and dairy products serves as an invitation for cancer cells to grow in the body, a diet that limits protein and carb consumption and highlights the importance of vegetables can reduce and even eliminate cancer cells in the body. An alkaline diet fits the criteria for regulating the inflammation and pH in the body.

An alkaline diet consists of fresh vegetables, fruits, and unprocessed sources of protein that are highly alkaline. This in turn results in a more alkaline urine pH level that helps protect healthy cells from cancer cells and balance essential mineral levels. To vastly increase the chances of erasing cancer cells in the body, there are some critical foods that must be cut out in this diet.

Sugar is a food that is dangerous to cancer patients. Sugar metabolism creates acid, which is the opposite of what the alkaline diet aims for. In addition to raising body acidity, cancer cells are fueled by sugar at an enormous rate. A PET test revealed that cancer cells uptake sugar 10-12 times the rate of healthy cells. Furthermore, sugar is proven to suppress a key response in the immune system, which weakens the immunity of the body up to a shocking 44%. Instead, raw honey or fruit eaten in moderation can serve as sugar replacements.

Glasses with fresh vegetable juices isolated on white. Detox diet.

It is crucial to cut out glutinous grains in the alkaline diet for cancer patients. Like sugar, gluten causes inflammation and causes immune dysfunction. Gluten smothers the lining of the intestines which causes digestion and nutrient absorption to be hindered when it is consumed. Gluten is found in grains such as wheat, rye, and barley which are common ingredients found in many baked goods. In its place, gluten-free grains such as rice, buckwheat, and quinoa can be used as substitutes.

Drinks play an essential role in this alkaline diet. Processed drinks such as fruit juices and soda should be eliminated as they have high concentrations of sugar and are highly acid forming. Likewise, alcohol consumption should be cut out. As always, clean water or lightly brewed green tea is a healthy, anti-cancer option for drinks. Another recommended option is fresh vegetable juice made at home.

The research for the cure for cancer has been going on for 50 years now. “Magic” treatments claiming to cure cancer have been announced numerous times to the world, but the results of these magical cures have been disappointing. While managing nutrition and diet might not be magic, it is a definite, proven way to fight off cancer.

References 

About the Author 

Joshua Moon is an intern at PHLBI who is interested in participating in biomedical research and exploring the medical field. He will be a senior at Oxford Academy in the 2017-2018 school year. Previously, he has participated in the research of the West Nile Virus and has been part of a biomedical class for two years. Joshua is an Eagle Scout and loves to play volleyball.

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Pacific Meso Center’s “Greatest Escape” Motorcycle Ride Raises Funds and Awareness for Mesothelioma Research http://www.phlbi.org/blog/2017/06/pacific-meso-centers-greatest-escape-motorcycle-ride-raises-funds-awareness-mesothelioma-research/ http://www.phlbi.org/blog/2017/06/pacific-meso-centers-greatest-escape-motorcycle-ride-raises-funds-awareness-mesothelioma-research/#respond Fri, 16 Jun 2017 17:50:21 +0000 http://www.phlbi.org/?p=8699 LOS ANGELES , CA, U.S., June 16, 2017 /EINPresswire.com/ — The Pacific Mesothelioma Center (PMC) at the Pacific Heart, Lung & Blood Institute (PHLBI) held its 5th annual “Greatest Escape” Motorcycle Ride on Sunday, June 4. The ride, inspired by The Great Escape movie and starring actor, motorcycle enthusiast, and mesothelioma sufferer, Steve McQueen, is […]

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LOS ANGELES , CA, U.S., June 16, 2017 /EINPresswire.com/ — The Pacific Mesothelioma Center (PMC) at the Pacific Heart, Lung & Blood Institute (PHLBI) held its 5th annual “Greatest Escape” Motorcycle Ride on Sunday, June 4. The ride, inspired by The Great Escape movie and starring actor, motorcycle enthusiast, and mesothelioma sufferer, Steve McQueen, is a unique event which honors those who have lost the fight against mesothelioma and raises money for research.

This year’s event enjoyed its biggest turnout ever! Over 200 riders participated and $78,657 was raised for mesothelioma research. For the first time, the ride kicked off from two locations-Top Rocker Harley-Davidson in Canoga Park and Antelope Valley Harley-Davidson in Lancaster. Officers from All Cities Transportation Company escorted riders out of Los Angeles with zero stops—a true luxury for riders accustomed to LA gridlock. From there, all roads led to the “twisties” and breathtaking vistas of Angeles Crest Highway on the way to historic Newcomb’s Ranch.
Riders were joined by a cast of celebrity riders, including actor/model, Fabio, Shades of Blue actor Antonio Jaramillo, American Crime actor Clayton Cardenas, and CHiPS star Larry Wilcox. Fabio, who returned for the third year as Celebrity Grand Marshal, summed up the experience, “I had a great time, it’s such a beautiful ride, one of the most beautiful rides in California”.

Things heated up at Newcomb’s Ranch where riders were joined by supporters who drove up to be part of the event and make a difference for mesothelioma sufferers. “The Sidemen” kept the event rocking with a lively mix of classic rock and blues. Fred and his crew at Newcomb’s rolled out an amazing taco lunch which many enjoyed with cold craft beer donated by Bend, Oregon brewery, Worthy Brewing. An array of vendors were there with a unique mix of items ranging from motorcycle gear to Italian ices. Also on display were over 50 raffle items including gourmet dinners, a vacation getaway to the Glen Tavern Inn, motorcycle gear, and so much more generously donated by sponsors.
With the addition of the second starting location, riders from all over Southern California were able to participate in this worthwhile event. “Motorcycle riders love the freedom of being on their bikes and going to out of the way places like Newcomb’s Ranch,” said John Caron of presenting sponsor, Worthington & Caron Asbestos Law Firm, “so it’s no surprise that more and more riders show up every year to help those who have lost their freedom to mesothelioma.”
PMC thanks everyone who participated in this year’s Greatest Escape, along with all the volunteers and sponsors who make this unique event possible.

 

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The 5th Greatest Escape Motorcycle Ride for Mesothelioma Research http://www.phlbi.org/blog/2017/06/greatest-escape-motorcycle-ride-mesothelioma/ http://www.phlbi.org/blog/2017/06/greatest-escape-motorcycle-ride-mesothelioma/#respond Tue, 13 Jun 2017 23:24:58 +0000 http://www.phlbi.org/?p=8625 The Pacific Mesothelioma Center at the Pacific Heart, Lung & Blood Institute held its most successful “Greatest Escape” Motorcycle Ride thus far! This event welcomed people of all ages to ride up to Newcomb’s Ranch, or meet there and enjoy a day full of live music, food, and more importantly…fundraising! This year the motorcycle ride […]

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Greatest Escape Motorcycle Ride Mesothelioma

The Pacific Mesothelioma Center at the Pacific Heart, Lung & Blood Institute held its most successful “Greatest Escape” Motorcycle Ride thus far! This event welcomed people of all ages to ride up to Newcomb’s Ranch, or meet there and enjoy a day full of live music, food, and more importantly…fundraising! This year the motorcycle ride took off from two locations, including the Top Rocker Harley Davidson in Canoga Park and the Antelope Valley Harley Davidson.

Presented by Asbestos Law Firm Worthington & Caron, P.C., this event helped raise money to find improved treatments for malignant pleural mesothelioma, which is an asbestos-related form of cancer. Unfortunately, this rare form of cancer affects around 3,000 people in the U.S. every year and has no known cure. Our goal for this event, and for every event, is to bring together families and friends in memory of the victims of mesothelioma and to raise money for new research and treatments.

Starting the day off…

_X9A3881The day began around 8:30, when registration began at the Top Rocker Harley Davidson and 9:30am for the Antelope Valley Harley Davidson location. While the riders started flowing into the locations, Jack FM set up in the background playing some pre-ride tunes to get the riders and volunteers excited for the day ahead of them! The wonderful staff at Top Rocker Harley Davidson cooked up some delicious pancakes and sausages and handed them out while the riders signed in, received their ride bandanas and pins, and even purchased the new “Greatest Escape” Motorcycle Ride T-Shirts. Once everyone had received their pancake breakfast and their “Greatest Escape” apparel, it was time to head out. The ACT ride escort, Mike Carrillo, then began explaining the rules of the road for the ride and other important information for the riders to have a safe and fun experience. Clare Cameron, the executive director of PHLBI, gave one final thanks before the riders departed. Finally, it was time for the ride! Our celebrity riders; Fabio, Antonio Jaramillo, Clayton Cardenas, & Larry Wilcox took the lead with the other participants right at their tail!

_X9A3992By the time the riders arrived at Newcomb’s ranch, owned by the wonderful and generous Fred Rundell, the volunteers had the location set and ready for the exciting day ahead of them! K-Earth 101 played some upbeat tunes while the riders rolled in and wandered around, the vendors set up around the ranch, such as Rick’s Knives and Commache Motors. The riders spent around an hour enjoying the weather and shopping around the vendors and purchasing raffle tickets for the afternoon raffle. Around 12pm, The Side Men began to play some live music while the riders lined up for their taco lunch.

Riders were able to sip on some delicious craft beer donated by Worthy Brewing and plenty of water donated by Sparkletts! We also had another one of our generous sponsors, Monster Energy, handing out free drinks to the attendees. These sponsors as well as Capital Group     and Russ Brown Motorcycle Attorneys were a joy to work with and we couldn’t have made the event happen without them.

_X9A4207Once lunch was served, Clare Cameron thanked everyone for coming, including the guest celebrities such as our Grand Marshal and heart throb Fabio, Shades of Blue Antonio Jaramillo, CHiPS star Larry Wilcox, and American Crime Clayton Cardenas. Finally, it was time for the live auction and raffle drawings! The riders and other attendees finished up their last minute raffle ticket placing and took a seat while the volunteers began calling out raffle winners. This year we had incredible prizes for the raffle and live auctions worth thousands of dollars, and a few that could even be considered priceless (such as a safari adventure!). The raffle and live auction was the closing event of the day, and once it was over the band started to play its final set and the volunteers and vendors began cleaning up.

Thank You!

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Lastly, the 5th Annual “Greatest Escape” Motorcycle Ride, wouldn’t have been nearly as successful without the help from our volunteers, riders, and families and friends. Another HUGE thanks to our Title Sponsor, Worthington & Caron, our Platinum Sponsor Capital Group, our Bronze Sponsor Russ Brown, our Media Sponsors including K-Earth 101, 94.7 The Wave, Jack FM, KNX, and last but not least our Product Sponsors, including Top Rocker HD, Antelope Valley HD, Worthy Brewing, Sparkletts, Tourmaster, and PDC! We couldn’t have done this ride without your time and hard work…We are so excited to see you again at the next ride!

 

About The Author

Emily
Emily Ozanian is a rising junior at Virginia Commonwealth University. She has been interning at PHLBI for the summer and is interested in pursuing more non-profit work once she graduates in 2019. She’s currently studying business marketing and plans on attending graduate school once she receives her undergraduate degree.

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Olympic Medalist Lloyd Eisler Shares His Motivation for Riding in The Greatest Escape Motorcycle Ride http://www.phlbi.org/blog/2017/05/olympic-medalist-lloyd-eisler-shares-motivation-riding-greatest-escape-motorcycle-ride/ Fri, 26 May 2017 00:00:17 +0000 http://www.phlbi.org/?p=8609 Lloyd Eisler is many things, an Olympic ice skating medalist, a father to his sons, husband to his wife actress Kristy Swanson, an avid motorcyclist, a philanthropist, and, consequently, someone who knows the pain of losing a loved one to mesothelioma. Lloyd started riding in The Greatest Escape Motorcycle Ride two years ago. His father, […]

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Lloyd EislerLloyd Eisler is many things, an Olympic ice skating medalist, a father to his sons, husband to his wife actress Kristy Swanson, an avid motorcyclist, a philanthropist, and, consequently, someone who knows the pain of losing a loved one to mesothelioma.

Lloyd started riding in The Greatest Escape Motorcycle Ride two years ago. His father, a member of the Canadian Navy for over twenty years and who he describes as his biggest supporter and a great influence on his life died of mesothelioma in 2011. Lloyd rides to not only honor his father but raise awareness for mesothelioma.

Q. How would you describe your father? How did he influence you? What was the greatest thing he taught you? 

A. My Father was a very strong silent man whom everybody loved. He was incredibly gentle. He gave me strength to do anything and to never give up. He taught me to always believe in my dreams. He was my biggest supporter

Q. What did you enjoy doing with him?

A. He and I did lots of “garage stuff” together. He could fix anything

Q.Describe your personal connection with mesothelioma and how it affected your family?

A. It was very short as my Father was diagnosed in November and died in January. Although the Doctors were not sure why he was in no pain (ne never complained) as it was all though his body when he went in the Hospital

Q.  How was your father exposed to asbestos?

A.He was in the Navy and was a Gunner on the Naval Ships.

Q. When was he diagnosed and how was he treated?

A. Diagnosed in November on a routine check cuz he was a little sore in his back. It was stage 4 so there was nothing but to wait. My Father wanted NO treatment

Q. What is one word you would use to describe your father’s mesothelioma journey?

A. It was short which was so incredibly hard on us but wonderful for him.

Q. Had you ever heard what mesothelioma was before your Dad was diagnosed? 

A. Yes

Q.  When did you start riding motorcycles?

A. I was 14 when I first rode a motorcycle.

Q.  Did your Dad ride motorcycles? 

A.  He did but not to the point that I do now.

Q.  What do you love about motorcycle riding?

A. It is my safe haven to remove myself from the chaos of the world we live in today that is so full of hate and anger.

Q.  What bike do you ride?

A. I have a HD Switchback (FLHD).

Q.  This will be your third year riding “The Greatest Escape” Motorcycle Ride, what does the ride represent to you?

A.  It is a way to give back to the cause most importantly but to meet new people, see old faces and simply enjoy riding my motorcycle.

Q.  How do you think people can help to raise awareness for mesothelioma? 
A. I think people need to go for more regular checks ups and be aware that it can affect all of us.

Q. What is something that you would say to children who have a parent diagnosed with mesothelioma? 

A. Be strong but more importantly be supportive and respect their wishes, it is not about you but about them

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PMC Clinical Research Study Uses Fitness Device to Monitor Patient’s Recovery After Surgery http://www.phlbi.org/blog/2017/05/pmc-clinical-research-study-uses-fitness-device-monitor-patients-recovery-surgery/ Fri, 12 May 2017 20:07:31 +0000 http://www.phlbi.org/?p=8585 Background The student intern program at PHLBI was established in 2016 to allow students to have on the site training at PHLBI’s in-house laboratory.  When students are not assisting Lead Researcher Ray Wong they are encouraged to engage in their own research projects.  One such project is clinical research centered on measuring a patient’s recovery […]

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Background

The student intern program at PHLBI was established in 2016 to allow students to have on the site training at PHLBI’s in-house laboratory.  When students are not assisting Lead Researcher Ray Wong they are encouraged to engage in their own research projects.  One such project is clinical research centered on measuring a patient’s recovery after surgery led by student intern Blair Kimble.  Kimble has worked closely with PHLBI staff to recruit patients and monitor their recovery by loaning them FitBit devices that in turn will monitor how much activity they are getting, how much they are sleeping, what their heart rate is, and other valuable health information items on the patient.  Below Kimble discusses her project at greater length including what she hopes the research will ultimately demonstrate.

About the Study

When a surgery is successful, its success is not determined as the incisions are closed up. A surgery is a success when the patient has a smooth recovery and can return back to their daily lives. The comfort and recovery of a patient is a top priority for physicians, but the amount of time available every day to evaluate that recovery is incredibly limited. In having such a small window in which to evaluate a patients progress, a physician may not be able to see everything relevant.

With PHLBI’s newest clinical research project, we have designed a way we hope to measure patient recovery. In giving patients a Fitbit® activity monitor, we are able to collect data about their walking, their heart rate, and their sleep both before and after surgery. Using their data from before surgery as a baseline for their activity, we are then able to track how quickly they return to that normal baseline after surgery.

This research investigates some of the first quantitative measures of surgical patient recovery ever collected. Until now, recovery has been evaluated subjectively, but with objective data, we may be able to correlate certain kinds of physiological factors with a faster discharge from the hospital and smooth recovery after going home from the hospital. We expect that constant monitoring of patients in a quantitative, objective manner will be a more reliable and complete representation of their recovery than anything that has been collected before.

We are currently in the pilot portion of the research, focusing on making sure the data collected is accurate. We plan to soon move on to running a randomized trial where some patients will get access to their activity data measured by the Fitbit® and some will not. This will allow us to compare the pace of recovery between those who get feedback and those who not and hopefully show that the quantitative data is motivating for patients. We hope to ultimately demonstrate that with an activity monitor, we can help patients recover to their own baseline of activity faster and return to their daily life.

About the Author

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Blair Kimble is a third year undergraduate student at UCLA. She has been working at PHLBI for two years and has spent one year developing this clinical research. She also does immunotherapy research and plans to apply to medical school this summer. Blair practices martial arts and loves to cook.

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Immune Checkpoint Blockade and Adaptive Immune Resistance in Cancer http://www.phlbi.org/blog/2017/04/immune-checkpoint-blockade-adaptive-immune-resistance-cancer/ Thu, 27 Apr 2017 20:23:49 +0000 http://www.phlbi.org/?p=8580 Raymond M. Wong1∗ and Robert B. Cameron2 Appearing in Immunology and Microbiology » “Immunotherapy – Myths, Reality, Ideas, Future”,  Published: April 26, 2017 under CC BY 3.0 license. © The Author(s). Abstract The clinical success of immune checkpoint blockers is a pivotal advancement for treating an increasing number of cancer types. However, immune checkpoint blockers still rarely induce […]

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Raymond M. Wong1 and Robert B. Cameron2
Appearing in Immunology and Microbiology » “Immunotherapy – Myths, Reality, Ideas, Future”,  Published: April 26, 2017 under CC BY 3.0 license. © The Author(s).

Abstract

The clinical success of immune checkpoint blockers is a pivotal advancement for treating an increasing number of cancer types. However, immune checkpoint blockers still rarely induce complete remission and show little to no therapeutic efficacy in a significant percentage of cancer patients. Efforts are now underway to identify biomarkers that accurately predict which patients benefit from immune checkpoint blockers. Moreover, adaptive immune resistance can develop in tumors during treatment with immune checkpoint blockers. These adaptive resistance mechanisms in tumors might be disrupted by combining adjunctive immunotherapies, which could potentially improve the therapeutic efficacy of immune checkpoint blockers. This chapter discusses the mechanism of action of cytotoxic T lymphocyte antigen-4 (CTLA-4) and programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) immune checkpoint blockers and biomarkers that might predict clinical responses to these drugs. Lastly, ongoing research on mechanisms of tumor adaptive resistance could facilitate rationale design of adjunctive immunotherapies that can be synergistically combined with immune checkpoint blockers to more effectively treat cancer.

Keywords: immunotherapy, T lymphocytes, immune checkpoints, CTLA-4, PD-1, PD-L1

1. Introduction

Immune checkpoints are inhibitory pathways that are critical for maintaining self-tolerance. Immune checkpoints also control the magnitude and duration of physiological immune responses in peripheral tissues in order to minimize collateral damage. Immune checkpoint receptors and their cognate ligands are naturally expressed on a variety of cell types, including antigen-presenting cells, T cells, B cells, tumor cells, tumor stroma, and also normal tissue. A number of immune checkpoint pathways have been identified, including cytotoxic T lymphocyte antigen-4 (CTLA-4), programmed death-1 (PD-1), programmed death ligand-1 (PD-L1), T cell immunoglobulin and mucin domain 1 (TIM-1), T cell immunoglobulin and mucin domain 3 (TIM-3), lymphocyte-activation gene 3 (LAG-3), T cell immunoreceptor with Ig and ITIM domains (TIGIT), V-domain Ig suppressor of T cell activation (VISTA), carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1), leukocyte-associated immunoglobulin-like receptor 1 (LAIR-1), herpesvirus entry mediator (HVEM), B- and T-lymphocyte attenuator (BTLA), CD160, CD200, CD200 receptor, and adenosine 2A receptor (A2Ar). For brevity, this chapter will focus on CTLA-4 and PD-1/PD-L1, as clinical drugs targeting these pathways have been successfully developed to treat an increasing variety of human cancer types.

2. Main body

2.1. CTLA-4

CTLA-4 is the first immune checkpoint receptor to be clinically targeted. CTLA-4 is expressed mainly on the surface of activated T cells. While certain subsets of T regulatory cells constitutively express CTLA-4, it is virtually undetectable on naïve, inactivated T cells. Upon activation, both CD4+ and CD8+ T cells upregulate CTLA-4 on the surface, reaching maximum level within 2–3 days. CD4+ T cells are reported to express more CTLA-4 mRNA and protein compared to CD8+ T cells, suggesting that CTLA-4 has a more significant regulatory effect on CD4+ T cells [1].

CTLA-4 downregulates T cell activation by sequestering CD80 and CD86 costimulatory molecules on antigen-presenting cells. This prevents CD80 and CD86 from delivering costimulatory activation signals to T cells through the CD28 receptor. CTLA-4 binds to CD80 and CD86 with ~10 times higher affinity than CD28 [2]. CTLA-4 expressed on T cells can also remove CD80 and CD86 molecules from neighboring antigen-presenting cells through a process called trans-endocytosis [3]. CTLA-4 also prevents CD28 recruitment to the immunological synapse, further impairing T cell activation [4].

CTLA-4 knockout mice die within 2–3 weeks of age due to massive lymphoproliferation, resulting in destruction of vital organs [5]. This lethal phenotype is associated primarily with hyperactivated CD4+T cells, which are skewed toward a T helper type-2 phenotype and have increased resistance to apoptosis. These hyperactivated CD4+ T cells abnormally infiltrate into peripheral tissues, resulting in organ failure. These observations led cancer immunology researchers to hypothesize that blockade of CTLA-4 signaling could potentially induce effective T cell-mediated immune responses against tumor tissue.

A pivotal laboratory study reported in 1996 by James Allison’s group showed that treatment of tumor-bearing mice with a CTLA-4-blocking antibody could effectively induce tumor regression [6]. Despite much subsequent investigation, the in vivo mechanism of action of CTLA-4 blockade immunotherapy has remained elusive. The prevailing hypothesis is that CTLA-4 blockade not only enhances T cell infiltration into tumors but also reduces the relative presence of immunosuppressive T regulatory cells in tumor tissue [7]. This alteration in the ratio of effector T cells versus T regulatory cells in tumors tilts the immunological balance in favor of T cell-mediated destruction of tumor cells.

These studies led to pharmaceutical development of the first immune checkpoint blocker, ipilimumab (Yervoy®). Ipilimumab is a fully human monoclonal antibody that blocks the CTLA-4 receptor, thereby preventing its ability to sequester CD80 and CD86 costimulatory molecules. It was initially tested in melanoma, and demonstrated extended overall survival in patients versus a comparator melanoma peptide-based immunotherapy vaccine called gp100. In a randomized phase III clinical trial, melanoma patients receiving ipilimumab had a median overall survival of 10.4 months versus 6.4 months in those receiving only the gp100 peptide vaccine (Hodi 2010). Objective response rates (measureable tumor regression) were 10.9% in the ipilimumab group versus 1.5% in the gp100 vaccine group. The responses to ipilimumab were durable, with the 1-year and 2-year survival rate being 46 and 24%, respectively. By comparison, the 1-year and 2-year survival rate in patients receiving only the gp100 peptide vaccine was only 25 and 14%, respectively [8]. These trial results led to US FDA approval of ipilimumab for melanoma in 2011.

2.2. PD-1

PD-1 is another major immune checkpoint receptor that regulates T cell activity against tumor tissue. PD-1 is a cell surface receptor originally identified in a murine T cell hybridoma undergoing programmed cell death [9]. PD-1 is absent on naïve inactivated immune cells but is significantly upregulated on activated T cells, B cells, natural killer cells and myeloid-derived cells [10]. In T cells, PD-1 expression is induced by T cell receptor signaling [11] and also by certain pro-inflammatory cytokines including interleukin-2, interleukin-7, interleukin-15, and interleukin-21 [12].

PD-1 signaling downregulates T cell activity primarily via interaction with its two natural ligands: Programmed Death Ligand-1 (PD-L1) and Programmed Death Ligand-2 (PD-L2). PD-L1 is expressed on a wide variety of cell types including hematopoietic cells, T cells, B cells, myeloid cells, and dendritic cells [10]. It is also expressed on a wide variety of peripheral tissues such as skeletal muscle, lung, heart, and placenta [10]. Notably, PD-L1 is also expressed on a wide variety of cancer cells and generally is associated with poorer patient prognosis [13]. PD-L2 expression is generally more restricted, being found primarily on dendritic cells, macrophages, and occasionally cancer cells [14]. PD-L2 binds to PD-1 with two- to sixfold higher relative affinity than PD-L1 [15]. However, PD-L2 is generally expressed at lower relative levels [16]. Thus, it is believed that PD-L1 is the predominant ligand for PD-1.

Signaling through the PD-1 receptor on T cells results in downstream inhibition of PI3K/AKT activation [17]. The net effect is downregulation of a number of effector functions including cytokine secretion and cytolytic activity. PD-1 knockout mice have various autoimmune pathologies, including autoantibody-induced cardiomyopathy [18], arthritis and lupus-like disease [19], and diabetes [20]. In peripheral tissues, the immunosuppressive activity of PD-1 is mediated primarily by interaction with PD-L1 [21]. PD-L1 expressed in tumor tissue also impairs host antitumor immune responses [22]. PD-L1 and/or PD-L2 in tumor tissue facilitates evasion from host immune responses via multiple mechanisms including induction of T cell anergy and exhaustion [23], promoting T cell apoptosis [24], and also by enhancing the expansion and activity of immunosuppressive T regulatory cells [25]. Moreover, PD-1 can transmit an antiapoptotic signal to PD-L1-expressing tumor cells, which renders them resistant to lysis by cytotoxic T lymphocytes [26].

This fundamental understanding of the PD-1/PD-L1 axis in suppressing host antitumor immune responses led to development of the first clinical PD-1 blockers, nivolumab (Opdivo®) and pembrolizumab (Keytruda®). Both nivolumab and pembrolizumab are fully human monoclonal antibodies that block the PD-1 receptor, thereby preventing its ability to bind its natural ligands PD-L1 and PD-L2. In large phase I clinical trials, nivolumab and pembrolizumab each demonstrated durable clinical response rates with acceptable safety profiles in patients with advanced melanoma, non-small cell lung cancer, renal cell carcinoma or Hodgkin’s lymphoma [2730]. Nivolumab and pembrolizumab are now both FDA approved for treating melanoma and non-small cell lung cancer. Nivolumab is additionally approved for treating renal cell carcinoma, Hodgkin’s lymphoma, and also for use in combination with the CTLA-4 blocker, ipilimumab, for treating melanoma. Remarkably, in two separate melanoma clinical trials, the combination of nivolumab and ipilimumab induced objective responses in ~60% of patients, with complete responses seen in ~11.5–22% of patients [3132].

Pembrolizumab and nivolumab (and a third investigational PD-1 blocker, pidilizumab) are now collectively continuing in 500+ clinical trials. Virtually all cancer types are now being targeted with PD-1/PD-L1 blockers in some capacity. Notably, there is a significant effort to test nivolumab or pembrolizumab with other adjunctive therapies to determine synergistic combinatorial regimens. Conventional treatments like chemotherapy and radiation have shown in animal tumor models to potentially synergize with PD-1/PD-L1 blockers [3335]. In addition, PD-1 blockers are now also being tested in combination with small molecule drugs (investigational and Food and Drug Administration (FDA) approved) and also experimental immunotherapies such as vaccines and chimeric antigen receptor T cells.

All clinical PD-1 blockers have the same mechanism of action. Slight variances in the protein structure among different PD-1 blockers could potentially confer differences in binding affinity for the PD-1 receptor and also differences in half-life (i.e. persistence in the body). The physiological significance and clinical effectiveness of such variances remain undetermined.

2.3. PD-L1

Expression of PD-L1 is found on diverse cell types, including normal and malignant tissue, antigen presenting cells, myeloid cells, B cells, and T cells. PD-L1 downregulates T cells via multiple mechanisms. PD-L1 expressed on various cells primarily interacts with PD-1 expressed on T cells, delivering an inhibitory signal that downregulates T cell activity. PD-L1 also binds to CD80 expressed on both antigen-presenting cells and activated T cells [36]. Interaction of PD-L1 with CD80 on antigen-presenting cells prevents CD80 from delivering costimulatory activating signals to T cells. When PD-L1 binds to CD80 expressed on activated T cells, an inhibitory signal is delivered to T cells. Currently, it is unknown exactly what intracellular signaling pathways are altered when PD-L1 binds to CD80 on T cells. Nonetheless, it is now generally understood that blocking PD-L1 results in enhanced T cell activation.

Atezolizumab (Tecentriq®) was the first PD-L1 blocker to enter clinical trials. Atezolizumab is a fully human monoclonal antibody that prevents PD-L1 from binding to PD-1 and CD80. It was initially tested in patients with PD-L1-positive metastatic bladder cancer [37]. Bladder cancer patients with PD-L1-negative tumors were subsequently included for treatment. Clinical response rates were ~15% of PD-L1-negative patients and ~25% of PD-L1-positive patients [37]. Because of the higher clinical activity of atezolizumab in PD-L1-positive bladder cancer, a companion diagnostic called the Ventana PD-L1 (SP142) assay is offered to provide tumor PD-L1 expression status of patients considering atezolizumab treatment. In 2016, atezolizumab was FDA approved for urothelial carcinoma, the most common form of bladder cancer. Like nivolumab and pembrolizumab PD-1 blockers, atezolizumab is now continuing in clinical trials for a wide variety cancer types and also being tested in combination with conventional cancer treatments, small molecule drugs and other investigational immunotherapies. Alternative PD-L1 blockers, such as avelumab and durvalumab, are also now in clinical trials.

2.4. PREDICTIVE BIOMARKERS FOR CTLA-4 AND PD-1/PD-L1 BLOCKERS

CTLA-4 and PD-1/PD-L1 immune checkpoint blockers have proven to be pivotal advancements in cancer treatment. However, a significant proportion of cancer patients still experience little to no clinical benefit from treatment. Even among responding patients, only a small minority achieve complete remission. Studies using clinical tumor specimens from patients treated with immune checkpoint blockers have revealed some potentially important differences between responders versus nonresponders.

During early clinical development of PD-1 blockers, it was hypothesized that differential expression levels of PD-L1 in tumor tissue would correlate with clinical responses. It was anticipated that PD-L1 expression in tumor tissue could therefore be a predictive biomarker to accurately identify patients likely to respond to PD-1 or PD-L1 blockers. However, a definitive correlation has thus far not been established. Both PD-L1-positive and PD-L1-negative tumors can respond to PD-1 or PD-L1 blockers. Further confounding factors include variability of PD-L1 expression in different anatomical areas of tumor tissue. In addition, PD-L1 expression in tumor tissue may be transient—appearing and disappearing due to treatments or other poorly understood influences. Lastly, assays measuring PD-L1 in tumors have yet to establish a clear threshold of expression that defines what is considered “PD-L1-positive.” For instance, the FDA-approved Ventana PD-L1 assay defines ≥5% PD-L1-positive cells in bladder cancer tissue to be associated with higher clinical response rates to atezolizumab [38]. However, alternative PD-L1 assays used in various other clinical trials of nivolumab or pembrolizumab have wide variability in PD-L1 expression analysis methodologies. Overall, it is generally agreed upon that low or absent PD-L1 expression in tumors is not sufficient to preclude a patient from treatment with PD-1/PD-L1 blockers [39].

Alternative predictive biomarkers for clinical response to PD-1/PD-L1 blockers are currently being explored. CD8+ T cell infiltration into tumors might be predictive of clinical response to PD-1 blockers. Specifically, the density of pretreatment CD8+ T cells at both the tumor invasive margin and tumor center may be correlated with clinical response to pembrolizumab. In serially biopsied tumors from melanoma patients undergoing pembrolizumab treatment, it was shown that responding patients generally had higher densities of CD8+/PD-1+ cells in close proximity to PD-L1-expressing tumor cells [40]. Furthermore, serial analysis of tumor biopsies showed that intratumoral CD8+/PD-1+ T cells actively proliferate during pembrolizumab treatment [40]. These data offer insights on a potential mechanism of PD-1 blockade efficacy, whereby presence of pretreatment CD8+ T cells in tumors is a prerequisite for clinical response. However, like tumor PD-L1 expression assays, establishing a standard cut-off threshold value for CD8+ T cell levels in tumors that accurately predicts clinical response to PD-1/PD-L1 blockade will be challenging. Tumors of various tissue origins often contain infiltrating T cells that can vary greatly in absolute number, density, and also anatomical location within the intratumoral space. Nonetheless, establishing a “scoring system” based on pretreatment CD8+ T cell infiltration warrants further investigation as a potential predictive biomarker.

Another intriguing biomarker with predictive potential may be intratumoral expression of indoleamine-2,3-dioxygenase (IDO). IDO is a tryptophan catabolizing enzyme that is occasionally expressed in various tumor types. Depletion of tryptophan within tumors by IDO may be a rate-limiting step for effective antitumor T cell activity. Studies in melanoma patients treated with ipilimumab suggest a correlation between pretreatment IDO expression and clinical response. In one study, intratumoral IDO was detected in 37.5% of responding melanoma patients and only 11.1% in nonresponders [41]. It remains to be seen if similar patterns are seen in other cancer types and also patients treated with PD-1/PD-L1 blockers.

Genetic signatures of tumors are yet another parameter with potential for yielding predictive biomarkers for clinical response to immune checkpoint blockers. Certain tumors, such as colorectal cancer, are highly refractory to treatment with PD-1 blockers. In early clinical trials of nivolumab, it was found that only 1 in 33 colorectal cancer patients responded to treatment [2728]. Subsequently, it was hypothesized that the single responding colorectal cancer patient harbored a defect in DNA mismatch repair in tumor tissue, resulting in a significantly high load of somatic mutations [42]. Defects in tumor tissue mismatch repair can result in thousands of somatic mutations, providing a larger pool of neo-antigens for immune recognition. Immune checkpoint blockade therapy could therefore amplify the natural adaptive immune response to mutated neo-antigens. Hence, mutational load in pretreatment tumor tissue might be predictive of clinical response to immune checkpoint blockers. To test this hypothesis, a small clinical trial focusing primarily on colorectal cancer showed that patients with defects in tumor tissue mismatch repair harbored significantly higher loads of somatic mutations versus those with mismatch repair-proficient tumors. Upon treatment with pembrolizumab, higher response rates and longer survival times were seen in patients with mismatch repair defects versus those with proficient mismatch repair [42]. This pivotal study has catalyzed further investigation of tumor mutational profiles to determine if a correlation with clinical responses can be established in large studies of diverse cancer types.

2.5. ADAPTIVE IMMUNE RESISTANCE

Mechanisms of inherent and acquired resistance to immune checkpoint blockade are poorly understood. Clinical responses to CTLA-4 and PD-1/PD-L1 blockers are often durable, sometimes lasting years. However, complete regressions are still relatively rare and eventual disease relapse among responding patients is frequent. Recent studies have offered insights that immunological parameters of tumor tissue adapt in response to T cell-mediated attack induced by immune checkpoint blockers. Enhanced T cell activity within tumors involves local production of inflammatory mediators, such as interferon (IFN)-γ, which is known to upregulate PD-L1 on peripheral tissues [43]. Upregulation of PD-L1 on various cell types within tumor tissue might result in heightened CD80-mediated inhibition of proximal effector T cells.

Furthermore, augmentation of effector T cell activity in tumor tissue via PD-1 blockade may subsequently induce compensatory upregulation of alternative immune checkpoint receptors, TIM-3. TIM-3 is a receptor expressed primarily on IFN-γ-secreting CD4+ and CD8+ T cells [44]. TIM-3 is bound by multiple ligands, including galectin-9, CEACAM-1, and high-mobility group box 1 (HMGB-1). Signaling through TIM-3 in activated T cells triggers the release of human leukocyte antigen B-associated transcript 3 (BAT3) from the TIM-3 cytoplasmic domain. This results in defective production of IL-2, IFN-γ, and likely other pro-inflammatory cytokines [44]. Although the TIM-3 signaling pathway has yet to be fully elucidated, it seems clear that TIM-3 affects T cell receptor downstream signaling via a mechanism distinct from PD-1 and CTLA-4.

TIM-3 appears to be co-expressed with PD-1 in tumor-infiltrating lymphocytes of cancer patients and is upregulated on T cells upon therapeutic PD-1 blockade [45]. This may provide a mechanism of immunological escape and a possible reason for incomplete clinical responses upon PD-1 blockade immunotherapy. It might also be a contributing factor toward acquired resistance to PD-1 blockade clinically, whereby patients initially respond to treatment but eventually relapse despite continuous therapy. Preclinical studies in animal tumor models show that PD-1 blockade immunotherapy results in upregulation of TIM-3 on T cells. Co-blockade of both TIM3 and PD-1 can prevent resistance to PD-1 blockade immunotherapy [45]. As such, TIM-3 blocking antibodies are now in early phase clinical trials to evaluate their safety, tolerability, and dosing ranges. Figure 1 illustrates how PD-1/PD-L1 blockade may result in compensatory upregulation of TIM-3 and/or PD-L1 on T cells and tumor cells.

media/F1.png

FIGURE  1.

PD-1/PD-L1 blockade promotes T cell-mediated inflammation in tumors. In turn, this can trigger upregulation of PD-L1 on various cells within tumor tissue. This can also trigger compensatory upregulation of TIM-3 on effector T cells. Upregulation of PD-L1 and TIM-3, even during continuous treatment with PD-1 blockers, can impair T cell activity and result in clinical resistance.

Downregulation of major histocompatibility (MHC) receptor expression in tumors might also contribute to acquired resistance to PD-1 blockers. Loss-of-function mutations in the MHC beta-2 microglobulin antigen-presenting protein have been noted in selected melanoma patients who initially responded to pembrolizumab therapy but subsequently relapsed [46]. Further studies in larger patient populations are necessary to confirm the association of MHC-related mutations and acquired resistance to PD-1 blockers.

2.6. STRATEGIES TO COUNTERACT ADAPTIVE RESISTANCE TO IMMUNE CHECKPOINT BLOCKADE

The mechanism of inherent and acquired/adaptive resistance to CTLA-4 and PD-1/PD-L1 immune checkpoint blockers is not fully understood and could possibly vary between individual patients and different tumor types. However, research on predictive biomarkers and mechanisms of adaptive resistance to PD-1 blockers have yielded insight that might be extrapolated to rationally design combination immunotherapies that synergistically enhance the efficacy of immune checkpoint blockers. For instance, it is now generally understood that PD-1 blockers augment T cell-mediated inflammation in tumor tissue. In turn, this can promote upregulation of PD-L1 on various cells in tumors, likely due to IFN-γ signaling [43]. Upregulation of PD-L1 expression in tumor tissue can promote enhanced CD80 signaling in T cells, which impairs T cell activity [36]. PD-1 blockade may also induce compensatory upregulation of alternative immune checkpoint receptors, such as TIM-3, on T cells within tumor tissue [45]. TIM-3 signaling results in downregulation of T cell activity. Next-generation immunotherapeutic regimens might combine PD-1 blockers such as nivolumab/pembrolizumab with PD-L1 blockers like atezolizumab, to counteract PD-L1 upregulation induced by T cell-mediated inflammation in tumor tissue. Other rational combinations might include PD-1/PD-L1 blockers combined with investigational TIM-3 blockers, to counteract the effects of TIM-3 upregulation on activated T cells.

Another strategy to enhance the efficacy of immune checkpoint blockers might involve improving T cell trafficking to tumor tissue. The extent of T cell infiltration into tumor tissue may be a predictive biomarker and a prerequisite for efficacy of both CTLA-4 and PD-1/PD-L1 blockers. As such, therapies that promote T cell trafficking to tumors could potentially improve tumor sensitivity to immune checkpoint blockers. Studies of human melanoma tumors have identified a set of chemokines that are associated with enhanced recruitment of T cells toward tumor tissue. These chemokines, including CCL2, CCL3, CCL4, CCL5, CXCL9, and CXCL10, might have utility as clinical therapies to improve T cell trafficking to tumors [47]. However, such chemokines or other T cell recruitment factors must be targeted specifically to tumor tissue in order to effectively recruit T cells. T cell recruitment factors might be coupled to antibodies that bind to tumor cell receptors, thus providing a vehicle for tumor targeting. In animal tumor studies, a T cell recruitment factor called LIGHT (also called tumor necrosis factor superfamily member 14) was fused to an anti-epidermal growth factor receptor (EGFR) antibody. This LIGHT-anti-EGFR fusion molecule was able to promote more extensive T cell infiltration into EGFR-expressing tumors. In turn, this prevented resistance to PD-L1 blockade immunotherapy [48]. Similar strategies that target other T cell recruitment factors toward tumors might be feasible.

Our group at the Pacific Heart, Lung & Blood Institute (Los Angeles, CA) is conducting research on gene-modified human mesenchymal stem cells (MSCs) as a strategy to alter the tumor microenvironment and prevent resistance to immune checkpoint blockers. MSCs can be isolated and expanded from various adult tissues including bone marrow, fat, umbilical cord blood, and term placentas. MSCs are known to preferentially migrate to tumor tissue, making them potentially useful drug delivery vectors to alter the immunological microenvironment of tumors [49]. In animal tumor models, MSCs have been genetically modified in diverse ways to effectively treat tumors. These include modification to produce immunostimulatory cytokines (e.g. IFN-α, IFN-β, IL-12) and T cell trafficking molecules such as LIGHT [5053].

Both autologous and allogeneic MSCs have been used extensively in clinical trials for treating severe inflammatory disorders and certain degenerative conditions, and generally have an acceptable safety profile [54]. Autologous gene-modified MSCs have recently entered clinical trials for cancer [55]. It remains to be seen if MSCs and other tumor-targeting systems can effectively deliver pro-inflammatory agents to tumor tissue and improve sensitivity to clinical immune checkpoint blockers.

3. Acknowledgements

Research funding at the Pacific Heart, Lung & Blood Institute is provided in part by grants from the Richard M. Schulze Family Foundation, the H.N. & Frances C. Berger Foundation, and the Kazan McClain Partners’ Foundation.

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Two New Board Members Join The Pacific Mesothelioma Center to Help Fight Mesothelioma http://www.phlbi.org/blog/2017/04/two-new-board-members-join-pacific-mesothelioma-center-help-fight-mesothelioma/ Thu, 13 Apr 2017 00:25:59 +0000 http://www.phlbi.org/?p=8519 LOS ANGELES, April 10th 2017 – The Pacific Heart, Lung & Blood Institute (PHLBI), a division of which is the Pacific Mesothelioma Center (PMC), has announced the appointment of Kellie Sutherland and Joseph Garland to its board of directors. Kellie, an engineer who has worked with Northrop-Grumman for the past nine years, received her Masters […]

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Kellie Sutherland (2)

LOS ANGELES, April 10th 2017 – The Pacific Heart, Lung & Blood Institute (PHLBI), a division of which is the Pacific Mesothelioma Center (PMC), has announced the appointment of Kellie Sutherland and Joseph Garland to its board of directors.

Kellie, an engineer who has worked with Northrop-Grumman for the past nine years, received her Masters of Arts in Organization Management and a Bachelors of Science in Business Management at the University of Phoenix. Kellie has volunteered for the Institute for the last 2 years, arranging health fairs and lunch meetings to raise awareness for mesothelioma and has headed up a Northrop- Grumman walk team each year. She is appointed to the role of Secretary of the Board.

“I was impressed with this organization from the very beginning and that is why I have carried a banner for them. Now I am more than excited about being part of this board at this important time for the Institute as they make big strides in their mesenchymal stem cell research” said Kellie. I am honored to be working with such an amazing and dedicated team”.

Joseph Garland (21)The second appointment to the board is Joseph Garland, who is the Managing Partner and CEO at Centennial Harvest Group. Joseph has over 20 years in healthcare. He is board certified in Healthcare management and holds the distinction of Fellow, American College of Healthcare Executives.

He received an MBA in Health Services Management at Keller Graduate School of Management and a Masters in Health Administration from USC. Joseph is committed to advancing public health while improving Healthcare organization’s outcomes and sustainability.

“What interests me most about committing my time and energy to PHLBI is their mission and commitment to health advancements through research and innovation, and as such I feel the PMC’s mission is a good fit for me” Joseph stated.

“We are delighted with the appointment of both these dedicated and passionate individuals to the board of directors at a crucial time as we move forward in our fight to defeat mesothelioma”, said Rhonda Ozanian, chair of the board of directors at the PMC.

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Immunotherapy 101 http://www.phlbi.org/blog/2017/04/immunotherapy-101/ Thu, 06 Apr 2017 23:10:32 +0000 http://www.phlbi.org/?p=8478 What is Immunotherapy?   Photo Credit: The Cleveland Clinic Immunotherapy is a treatment that utilizes the body’s own immune system to recognize and fight cancer.   It boosts the body’s natural defenses by either using substances made by the body or by using man-made components that make the immune system work better in attacking cancer.  Immunotherapy […]

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What is Immunotherapy?

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Photo Credit: The Cleveland Clinic

Immunotherapy is a treatment that utilizes the body’s own immune system to recognize and fight cancer.   It boosts the body’s natural defenses by either using substances made by the body or by using man-made components that make the immune system work better in attacking cancer.  Immunotherapy is also called biologic or biotherapy, since it uses substances made from living organisms to treat cancer.  Immunotherapy is not yet as widely used as surgery, chemotherapy and radiation therapy, but it has been approved to treat people with many types of cancer.  Clinical trials are ongoing to expand the use of immunotherapies for the treatment of many more kinds of cancer.  Currently, immunotherapies for mesothelioma are being researched and tested and are showing some promise.  However, they are not currently available for regular treatment.

 

How does Immunotherapy work?

The body’s immune system is designed to detect foreign invaders, such as bacteria or viruses, which could harm the body, and then target and destroy these invaders.  However, cancer cells typically avoid detection by the immune system because they evolve from the body’s normal cells.  This is because cancer cells are regular body cells that have mutated, or changed, to grow out of control.  Since they have some of the same protein markers as normal cells, the immune system does not recognize them as foreign invaders and leaves them alone, allowing the cancer to grow unchecked.  Immunotherapy is designed to alert the body’s immune system to the cancer cells so it will attack and destroy them.

Immunotherapy is a variety of treatments that work in different ways to improve or restore immune system function in fighting cancer, and can work in the following ways: 1) By stopping or slowing the growth of cancer cells, 2) By stopping cancer from spreading to other parts of the body, or 3) Helping the immune system work better at destroying cancer cells.  The specific types of immunotherapies used in cancer treatment are:

  • Monoclonal Antibodies
  • Adoptive T cell Transfer
  • Cytokines
  • Immune Checkpoint Inhibitors
  • Cancer Vaccines

Monoclonal Antibodies

Monoclonal antibodies are man-made versions of immune system proteins.  They are also known as “targeted therapies,” because these man-made antibodies target cancer cells, while leaving healthy cells unharmed.  Monoclonal antibodies mimic the immune system’s antibody response to pathogens in the body.  When the immune system detects a foreign substance in the body, it makes a large number of antibodies against the foreign invader.  The antibody is designed to stick to a protein on the invading substance called an antigen.  Once it finds the antigen on the foreign substance, it then alerts the immune system to attack the substance it has attached to.  Monoclonal antibodies are manufactured antibodies that are designed to stick to an antigen in a specific cancer. The manufactured antibodies are injected into patients and then attach themselves to a particular antigen on the cancer.  This then alerts the body’s immune system to find and attack the cancer cells.  The challenge for researchers has been in indentifying the specific antigen on a certain cancer.   So far, the FDA has approved monoclonal antibodies for use in the treatment of a dozen different cancers.

There are three different ways that monoclonal antibodies are used in the treatment of cancer:

  1. Naked Monoclonal Antibodies. These are monoclonal antibodies that work by themselves without a drug or radioactive material attached to them.  This is the most common way monoclonal antibodies are used.  They function by either attaching themselves onto cancer cell antigens and marking them for destruction by the immune system, or by blocking antigens on cancer cells that help them grow.
  2. Conjugated Monoclonal Antibodies. These are Monoclonal Antibodies that are joined to a chemotherapy drug or a radioactive particle.  The monoclonal antibody is used as a targeting mechanism, taking these substances directly to cancer cells, thereby lessening the damage to normal cells.  Conjugated monoclonal antibodies are also known as tagged, labeled or loaded antibodies.  They can be radiolabeled, meaning they have radioactive substances attached to them, or chemolabeled, meaning they have a chemotherapy drug attached to them.
  3. Bispecific Monoclonal Antibodies. These are two monoclonal antibodies that are joined together, which allows them to attach to two different antigens at the same time.  The purpose is for the monoclonal antibodies to bind to a cancer cell and an immune cell at the same time, thereby brining them together, and causing a more targeted immune response.

Monoclonal Antibodies are given intravenously (through a needle in the vein).  The side effects are similar to an allergic reaction and can include fever, chills, weakness, headache, nausea, vomiting, diarrhea, low blood pressure and rashes.  These side effects are typically the result of stimulating the immune system into an immune response.  They tend to be most common when first given, and can diminish over time.

 

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Adoptive T Cell Transfer

T cells are a type of white blood cell designed to hunt down and destroy foreign invaders within body.  Adoptive T Cell Transfer consists of taking T cells from a person’s cancerous tumor, isolating and/or modifying them, and then giving them back to the same person to fight their cancer.  After the T cells are removed from a tumor, they are then isolated to find out which ones are most active against the tumor or they are modified to make them more effective in destroying specific cancer cells.  Once they are identified or modified, the T cells are then grown in large batches, a process which can last from 2 to 8 weeks, depending on how fast a person’s T cells grow.  Once enough T cells are grown, they are injected back into the person.  Another name for this therapy is chimeric antigen receptor (CAR) T cell therapy.  Researchers are looking for other ways to use T cells in the treatment of cancer.

 

Cytokines

Cytokines are proteins made by immune system cells.  They play a vital role in regulating the communication and activity of the immune system and its ability to respond to cancer.  There are two groups of cytokines that are especially important in the treatment of cancer:

  1. These are a group of cytokines that help white blood cells communicate and grow more quickly to respond to a threat to the body.  There are more than a dozen kinds of interleukins, but one of them, Interleukin-2 (IL-2), has been shown to be especially helpful in the treatment of cancer.  IL-2 has been used both by itself to boost the immune system in response to cancer, or combined with chemotherapy drugs or other cytokines to boost its effect.  IL-2 can have very strong side effects, such as low blood pressure, abnormal heartbeat, chest pain and other heart problems, especially if combined with other treatments.   When IL-2 is administered in large doses, it requires a patient to be hospitalized.  Several other interleukins (IL-7, IL-12 and IL-21) are also being studied for use in cancer treatment.
  2. These are cytokines that help the body resist infections.  They are three proteins, released by T cells in reaction to foreign invaders in the body.  Interferons are named for the first three letters of the Greek alphabet:  interferon-alpha (IFN-alpha), interferon-beta (IFN-beta), and interferon-gamma (IFN-gamma).  Only IFN-alpha is used in the treatment of cancer.  It works by enhancing the ability of immune cells to attack cancer cells, and may also slow the growth of cancer cells or shrink the blood vessels that allow tumors to grow.  The side effects of IFN-alpha are flu-like symptoms, thinning hair, low white blood cell counts and skin rashes.

There are also drugs that have been developed that mimic cytokines in the body.  Three drugs that are currently in use are thalidomide (Thalomid), lenalidomide (Revlimid), and pmalidomide (Pomalyst).  These are known as immunomodulating drugs (IMiDs), and they work by enhancing the immune system’s response to cancer.  The side effects of these drugs include drowsiness, fatigue, low blood cell counts, and neuropathy (painful nerve damage).

 

Immune Checkpoint Inhibitors

The immune system has natural “brakes” or “checkpoints” that keep it from destroying healthy, normal cells.  Basically proteins on T cells, which are white blood cells that attack foreign invaders in the body, recognize and bind to a protein on a normal cell, telling the T cell not to attack it.  However, cancer cells, which are mutated normal body cells, can also use these checkpoints to avoid being detected by the immune system.  Immune Checkpoint Inhibitors are drugs that prevent the binding of T cell proteins to cancer cell proteins, allowing the immune system to be activated and attack the cancer.  There are two sets of proteins that are affected by Immune Checkpoint Inhibitors:

  1. PD-1 and PD-L1. PD-1 is a checkpoint on T cells that binds to PD-L1, which is a protein found on other cells.  When PD-1 and PD-L1 bind together, it communicates it works as an “off-switch” to the T cell, telling it to leave the other cell alone.  However, some cancer cells can have large amounts of PD-L1, causing them to escape being attacked by the immune system.  Immune Checkpoint Inhibitors, block either PD-1 or PD-L1, stopping the binding of T cells to cancer cells, then allowing the T cell to attack the cancer.  One of the main concerns with Immune Checkpoint Inhibitors is that they can also allow the immune system to attack normal, healthy cells in the body.  This can lead to serious side effects such as:  skin rash, fatigue, cough, nausea, loss of appetite and itching.  They can also cause organ damage, such as serious problems of in the lungs, intestines, liver, kidneys, hormone-making glands or other organs.
  2. CTLA-4. CTLA-4 is another protein that works to stop T cells from attacking other cells.  Like normal cells, cancerous cells can send signals to CTLA-4 receptors on T cells to prevent them from being attacked by the immune system.  Drugs that block the cancer cell’s ability to send signals to the CTLA-4 receptor then expose the cancer as an invader and allow the body’s immune system to respond.  An example of this is the drug, tremelimumab, which is being researched to help treat patients with mesothelioma.  Tremlimumab binds to the CTLA-4 receptor on the surface of T-cells, allowing T cells to recognize the cancer and potentially attack mesotheiloma cells.

 

Cancer Vaccines

Cancer vaccines come in two forms:  those that prevent cancer, and those that are used to treat cancer.  There are some forms of cancer that can be caused by viruses.  Cancer prevention vaccines work by preventing the virus that can cause the cancer.  In this way, they work the same as regular vaccines by exposing individuals to low-dose or killed viruses, which triggers an immune response.  Currently, cancer prevention vaccines are being used to prevent Human papillomavirus (HPV), which can lead to cervical cancer, anal cancer, vaginal, vulvar, penile and other cancers; and Hepatits B (HBV), which can lead to liver cancer.  Cancer prevention vaccines protect against cancer by targeting a virus that might lead to cancer, but they do not target the cancer cells directly.

Cancer treatment vaccines work by activating the immune system to target cancer cells in someone who has already developed cancer.  Cancer treatment vaccines can be made from cancer cells taken from patients, parts of cancer cells or even just the antigen on the cancer cell.  Vaccines are often combined with other substances, called adjuvants, to boost the immune system response further.   The vaccine introduces a special antigen from the cancer cell into the body, causing the immune system to respond by attacking the cancer cells.  The advantage of cancer treatment vaccines is that the immune system has memory for antigens to which it has been exposed, opening the possibility that the vaccine might work long after it is given. As of now, the most promising cancer treatment vaccine is Provenge, which is used in the treatment of prostate cancer.

About the Author

unnamed-5 Sri Ramakumar is a freelance writer with a Master of Science (MS) in Family Studies & Human Development and a Master of Social Work (MSW) from the University of Arizona and the University of Minnesota respectively.  She also has a Bachelor of Arts  in English Composition from the University of Washington.  She was also a research assistant at the University of Arizona studying the role of parenting in the social and emotional development of children. Currently, Ms. Ramakumar works as a freelance writer focusing on medical and behavioral health issues for various nonprofits. Ms. Ramakumar resides in Tucson, Arizona with her husband and four children.

References 

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Fabio Returns as Celebrity Grand Marshal for the 5th Annual “The Greatest Escape” Motorcycle Ride http://www.phlbi.org/blog/2017/04/fabio-returns-celebrity-grand-marshal-5th-annual-greatest-escape-motorcycle-ride/ Thu, 06 Apr 2017 20:13:35 +0000 http://www.phlbi.org/?p=8494 Model Fabio Returns as Celebrity Grand Marshal for the 5th Annual “The Greatest Escape” Motorcycle Ride for Mesothelioma Research in Los Angeles LOS ANGELES, CALIFONIA , USA, April 4, 2017 /EINPresswire.com/ — The Pacific Mesothelioma Center (PMC) at the Pacific Heart, Lung & Blood Institute (PHLBI) is thrilled to announce the fifth annual “The Greatest […]

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Model Fabio Returns as Celebrity Grand Marshal for the 5th Annual “The Greatest Escape” Motorcycle Ride for Mesothelioma Research in Los Angeles

LOS ANGELES, CALIFONIA , USA, April 4, 2017 /EINPresswire.com/ — The Pacific Mesothelioma Center (PMC) at the Pacific Heart, Lung & Blood Institute (PHLBI) is thrilled to announce the fifth annual “The Greatest Escape” Motorcycle Ride, proudly presented by Asbestos Injury Law Firm Worthington & Caron, P.C. The ride will be on Sunday June 4, 2017 and, for the first time ever, will start at two locations: Top Rocker Harley Davidson in Canoga Park and Antelope Valley Harley Davidson in Lancaster. The escorted ride will follow routes through beautiful Angeles National Forrest, concluding at historic Newcomb’s Ranch on Angeles Crest Highway. The event benefits victims of mesothelioma, a devastating cancer caused by asbestos that disproportionally affects veterans who were exposed to asbestos while serving their country.

Both starting locations will open for check-in, registration, and refreshments at 8:30 a.m. At 10 a.m. it’s “kickstands up” as riders are escorted on their way to the twisting and scenic roads of Angeles National Forrest. Riders will be joined by Celebrity Grand Marshal Fabio, along with a host of celebrities including Larry Wilcox of CHiP’s, Sons of Anarchy actor Rusty Coones, Mayans M.C. actor Antonio Jaramillo, Buffy the Vampire actress Kristy Swanson, and Olympic medalist Lloyd Eisler. All roads lead to Newcomb’s Ranch where riders will enjoy a BBQ lunch, refreshing Worthy Brewing craft beers, live music, raffle, and prizes valued at thousands of dollars. K-Earth 101 Morning Show DJ, Gary Bryan, will serve as emcee for the festivities at the Ranch.

Inspired by “The Great Escape” movie and its star, motorcycle enthusiast Steve McQueen who lost his own battle with mesothelioma in 1980, the ride brings hundreds of riders and non-riders together to honor those who fought valiantly against mesothelioma, support those currently fighting the disease, and raise money for research into a cure.

Celebrity model Fabio states “I am honored to once again serve as Grand Marshal for the Greatest Escape Motorcycle Ride to benefit the Pacific Mesothelioma Center. It is a great event for an important cause and I look forward to seeing everyone out there on June 4th”.

The event is open to all–riders as well as non-riders who simply want to join the fun. The registration fee is $35 for riders and $15 for passengers who register online by June 3, 2017. On-site registration is an additional $5. The fee includes a ride pin, bandanna, lunch, entertainment, and parking. For non-riders tickets are $20 for lunch, entertainment, and parking. To register, visit www.TheGreatestEscape.org. To sponsor this event, contact Clare Cameron at (310) 478-4678 or email ccameron@phlbi.org. All proceeds will go towards mesothelioma research and improving the quality of life for victims of mesothelioma.

About Us: Established in 2002, PHLBI is a 501(c)(3) non-profit institution. The PMC, a division of the PHLBI, is focused on the treatment and prevention of malignant pleural mesothelioma. The PMC serves a growing number of mesothelioma victims by supporting the nation’s first-of-its-kind research lab which provides laboratory-to-the bedside research that improves mesothelioma victims’ lives and longevity. www.PacificMesotheliomaCenter.org

 

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Inquiries with the Investigator: CAR-T Cell Therapy http://www.phlbi.org/blog/2017/03/inquiries-investigator-car-t-cell-therapy/ Sat, 04 Mar 2017 00:49:25 +0000 http://www.phlbi.org/?p=8423 Immunotherapy – a class of treatments that uses the body’s own immune system to fight cancer – has increasingly gained widespread acceptance from leading biomedical scientists. There are various types of immunotherapeutic agents. Recently one approach to immunotherapy called “Chimeric Antigen Receptor T-Cell Therapy (CAR-T-Cell Therapy) has received a great deal of attention and is […]

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Immunotherapy – a class of treatments that uses the body’s own immune system to fight cancer – has increasingly gained widespread acceptance from leading biomedical scientists. There are various types of immunotherapeutic agents. Recently one approach to immunotherapy called “Chimeric Antigen Receptor T-Cell Therapy (CAR-T-Cell Therapy) has received a great deal of attention and is finding success in current clinical trials.  CAR-T Cell Therapy entails engineering a patient’s own immune cells to recognize and attack their tumors.  Investigator Ray Wong explains in greater detail below what CAR-T Cell therapy is, what the risks are, and what the future of this form of immunotherapy might look like.

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  • How does Chimeric Antigen Receptor T-Cell therapy (CAR-T Cell therapy) work?

The current generation of CAR T cell therapies being tested in clinical trials involves a complex manufacturing process.  A patient’s immune cells are first removed from their bloodstream through a process called leukapheresis.  Leukapheresis typically takes 2-4 hours, where a patient is connected to a machine that separates immune cells from the blood, and the remaining components are returned to circulation.  The immune cells are shipped to specialized manufacturing facilities where the T cells in the leukapheresis specimens are genetically engineered to insert specific anti-tumor receptors called chimeric antigen receptors (CAR).  The T cells are simultaneously grown to large numbers over 7-10 days, then shipped back to the patient for intravenous infusion by their oncologist.  CAR T cell therapy is currently combined with chemotherapy, which appears necessary to achieve full effectiveness of CAR T cells.

CAR-T Cell Diagram PNG

Photo Credit: UNC Lineberger

  • What are some of the limitations of CAR-T Cell therapy? Which cancers have the best response rate so far?

Other than the two week manufacturing time and high financial cost of treatment, the main limitation is that it thus far only works well in blood cancers like certain leukemias and lymphomas.  There does appear to be a high cure rate in certain blood cancers, with some clinical trials reporting well over 50% complete response rates (disappearance of all disease).  However, solid tumors like mesothelioma have been much more difficult to treat with CAR T cells.  The current prevailing hypothesis is that CAR T cells do not efficiently penetrate solid tumors and/or are shut down by immune suppressive factors often present in solid tumors.

 

  • What are your thoughts on the future of CAR-T-Cell therapy?

Patient safety is still the top concern of CAR T cell therapy.  The FDA has halted some clinic trials as recently as 2016 due to patient deaths.  CAR T cells are very powerful, and can causes excessive immune reactivity resulting in a condition called “cytokine release syndrome,” which can be fatal.  The interaction of CAR T cells combined with chemotherapy is still not fully understood.   The FDA may want several more years of extensive clinical trials to further study safety improvements of CAR T cell therapy.

 

Next-generation CAR T cells may not need to be custom manufactured for each patient.  Researchers are now exploring the use of a gene deletion technology called “clustered regularly interspaced short palindromic repeats” (CRISPR) in the laboratory.  CRISPR might be used to convert T cells from healthy donors into universally compatible CAR T cells.  In laboratory studies, CRISPR can be used to delete proteins on the surface of T cells that normally would cause them to be rejected in genetically unrelated recipients.  If successful, this would allow for bulk manufacturing of “off-the-shelf” CAR T cells ready for immediate use, analogous to universally compatible Type O-negative blood.  CRISPR is also being studied to delete other genes in CAR T cells that would make them more resistant to immune suppression.  This might improve their effectiveness in solid cancers.

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