Posts

The 6th Annual 5K Walk/Hike for Meso Raises Over $160,000 for Mesothelioma Research

LOS ANGELES, CALIFORNIA, UNITED STATES, November 1, 2017 /EINPresswire.com/ — The Pacific Mesothelioma Center at the Pacific Heart, Lung & Blood Institute marked its 6th annual 5K Walk/Hike for Mesothelioma on Oct 22nd, 2017, at the Paramount Ranch. With over 350 walkers, the event raised $160,495 to find better treatments for malignant pleural mesothelioma, an asbestos-related form of cancer. Mesothelioma affects almost 3,000 people in the US each year, one-third of whom are veterans.

Presented by Worthington & Caron, P.C, the event brought together people who can personally relate to the cause. Thirty-two teams, consisting of family members and friends of those who have mesothelioma, as well as supporting organizations and individual walkers, gathered at the park at 9 a.m. for check-in and team photos. Each registrant received a complimentary T-shirt, fruit products generously donated by Dole, and sunscreen before leaving on the 5K or 1-mile hike.

After the walk, participants enjoyed a catered lunch by local Agoura Hills favorite Italia Deli. The event also offered David’s Tea, Duverger Macaroons, Monster energy drinks, Mustache Mike’s Italian Ice and a concert by The Six Billion Dollar Band. The live auction featured items such as a photo safari for two in South Africa and a Maui luxury package. The silent auction and opportunity drawing featured items such as gift baskets, dining and adventure certificates and weekend getaways.

Prior to the day of the event, participants were also encouraged to fundraise on their own and compete for an engraved “Top Fundraising Team” award. Besides asking for donations, some teams took a creative route in raising their funds and awareness for the cause, such as a Pasta Party by Team Jarvis, a bake sale at UCLA for Team Cameron’s Cruisers, and a Powerball at Captain’s Treasure Chest by Team Ganoe. The top fundraising team, Double Nickels, led by team captain Cubby Winkel raised over $19,000 for mesothelioma research. Cubby Winkel walks to support his wife, Judy Winkel, a brave mesothelioma warrior.

Many walk to honor those they have lost to this devastating disease. Returning walker Philip Prokop states “I’m glad that my team and I were able to participate again in this year’s walk. It shows support from everyone there, that they appreciate the efforts that The Pacific Mesothelioma Center and Dr. Cameron and his staff are doing. I will continue to support and help any way that I can.” PMC supporter Courtney Erhart added “The Meso walk is a tradition to celebrate and remember my Mom by walking with people that loved her. It’s also a way to support families who are going through or have gone through similar challenges. It’s a terrible disease and every step towards a cure is a step worth taking”.

Donations for the 5K Walk for Mesothelioma are still being accepted at www.phlbi.org/5k-walk-for-mesothelioma.

Latest Breakthroughs In Mesothelioma Research Are Discussed At the 7th Symposium on Malignant Mesothelioma at UCLA

The Symposium Draws a Distinguished Panel of Researchers and Clinicians to UCLA to Discuss the Latest Breakthroughs in Prevention, Detection, and Treatment.

LOS ANGELES, CA, UNITED STATES, October 4, 2017 /EINPresswire.com/ — The 7th International Symposium on Malignant Pleural Mesothelioma was held on Saturday, September 30th, at the UCLA Meyer & Renee Luskin Conference Center. The focal point of the symposium was on clinical therapies and research data to prevent, detect and treat malignant pleural mesothelioma. Healthcare professionals including physicians, nurses, and scientists joined students, mesothelioma patients, and their families to attend this informative and educational conference.The Symposium was co-hosted by UCLA and the Pacific Mesothelioma Center (PMC).

The morning session was opened by symposium chair, Dr. Robert B. Cameron, MD, FACS, who discussed The future of mesothelioma surgery.“Although surgery in mesothelioma has decreased due to a perceived lack of efficacy among oncologists and other physicians, there are therapies, such as preoperative radiation, cryoablation, and Betadine lavage, which are keeping surgical results ahead of other therapies,” said Dr. Cameron, Professor of Clinical Cardiothoracic Surgery and Surgical Oncology. The highlights of his presentation centered on how these therapies supplemented standard of care treatments through preoperative, intraoperative, and postoperative therapeutic modalities. Dr. Cameron is a pioneer in the field of mesothelioma, Director of the Comprehensive Mesothelioma Program at UCLA, Senior Professor of Surgery at UCLA, and Chief of Thoracic Surgery at the West Los Angeles Veterans Affairs Medical Center.

“This year has been incredibly hopeful as there are new biological advances, such as immunotherapy, anti-angiogenic therapy, and others, that are likely to lead to improved treatments in the future,” said Dr. Cameron. Immunotherapy is advancing rapidly and many other therapies, such as thermal, chemical, gene and cell-based therapies are on the horizon”.

Additional presentation topics included Immune Checkpoint Blockade in MPM; Recent Findings of Mesothelioma and BAP1; Intracavitary Therapeutics for MPM; Disabling Mitochondrial Peroxide Metabolism as an Effective Therapeutic Approach to MPM; Targeting the Epigenome in MPM; Engineering Mesenchymal Stem Cells for Immunotherapy of MPM; Inflammasome Modulation by Chemotherapeutics in MPM; The Benefits of a Mesothelioma Caregiver Support Group and Resources for Research – the Student Internship Program.

The symposium’s other distinguished faculty included: Anna Nowak, PhD of the University of Western Australia; Luana Calabrò, MD, University Hospital of Sienna, Italy; David S. Schrump, MD, National Cancer Institute, Maryland; Jacques P. Fontaine, MD, Moffitt Cancer Center, Tampa; Brian Cunniff, PhD, University of Vermont; Haining Yang, MD, PhD, University of Hawaii; Arti Shukla, PhD, University of Vermont; Olga Olevsky, MD, UCLA; Lien Hua-Feng NP, UCLA/VA/PHLBI and Clare Cameron, Executive Director of the PHLBI.

The symposium was supported by: Worthington & Caron PC, The International Association of Heat & Frost Insulators, and Waters Kraus & Paul.

The Pacific Meso Center Receives $100,000 Towards the Anonymous $1 Million Challenge Pledge to Help Fight Mesothelioma

LOS ANGELES, CA, U.S., August 30, 2017 /EINPresswire.com/ — The Pacific Mesothelioma Center (PMC), a division of the Pacific Heart, Lung & Blood Institute (PHLBI), is pleased to announce a generous $100,000 gift from Roger G. Worthington, of the law office Worthington & Caron P.C. This donation, made in response to the anonymous $1 million challenge grant the PMC recently received, will be used to further the PMC’s groundbreaking research on malignant pleural mesothelioma, asbestos-related cancer affecting the lining of the chest.

The gift will be used in support of NHLBI’s two new scientists – Dr. Masahide Tone and Dr. Yukiko Tone. Both scientists have worked at Cambridge University, Oxford University, University of Pennsylvania and Cedars Sinai Medical Center. They will work on novel immunotherapies for mesothelioma. Immunotherapy is an exciting and promising cancer treatment that uses the body’s immune system to fight cancer. It is the PMC’s firm belief that the future of mesothelioma treatment will involve combination therapy, including surgery, radiation, chemotherapy, and immunotherapy. Further, rational combinations of various immunotherapies combined with traditional cancer therapies holds the greatest promise for real progress in the treatment of mesothelioma and other cancers.

Roger Worthington is a long-time advocate for mesothelioma research. In 2005, in honor of his father Punch Worthington, Ph.D., Roger helped establish the David “Punch” Worthington Lab at the David Geffen School of Medicine at the UCLA Medical Center in Los Angeles. The Punch Worthington Lab. is the home of innovative research on novel strategies for the treatment of mesothelioma, lung cancer, and other occupational cancers. Sadly, his father passed away in 2006 from lung-cancer caused by asbestosis.

“We certainly are pleased to provide PMC with additional funds towards the anonymous $1 million matching gift that the institute recently received and I encourage others to donate, no matter how small”, said Roger Worthington, a long-term supporter of the PMC and principal of the Law Office of Worthington and Caron PC. “These funds will enable the PMC to continue their great work on mesenchymal stem cells with their groundbreaking research which holds immense potential to lead to effective treatments not only for mesothelioma but perhaps for many other cancers as well.”

“We are very fortunate to have the continued support of Mr. Worthington,” Dr. Cameron said. “We are tremendously indebted to him and to all those who contribute to PHLBI. This money will allow us to accelerate our search for novel therapies to improve both the longevity and the quality of life of those battling mesothelioma, lung cancer and other diseases of the chest.”

Dr. Cameron is a pioneer in the field of mesothelioma, Director of the Comprehensive Mesothelioma Program at UCLA, Professor of Surgery at UCLA and Chief of Thoracic Surgery at the West LA Veterans Affairs Medical Center. He is also one of the PMC’s Scientific Advisors.

Matching gifts can be made either by mail or online, at http://www.phlbi.org/about/get-involved/donate/.

Cutting-edge Research to be Presented at 7th Annual International Symposium on Mesothelioma at UCLA

LOS ANGELES, CA, UNITED STATES, August 24, 2017 /EINPresswire.com/ — On September 30th global experts on malignant pleural mesothelioma will again convene at the Meyer & Renee Luskin Conference Center at UCLA for the 7th Annual International Symposium on Malignant Pleural Mesothelioma (MPM), a rare form of cancer that results from exposure to asbestos and commonly affects the lining of the chest– the pleura. The event is jointly hosted by UCLA and the Pacific Mesothelioma Center (PMC).

The Symposium is geared towards physicians and offers continuing medical education (CME) credit. It will also provide up-to-date information on mesothelioma for medical students, nurses and other healthcare professionals, as well as mesothelioma patients, their families and other interested parties. Topics will cover: Surgery for Mesothelioma; Immune Checkpoint Blockades; Combining Angiogenesis Inhibition with Chemotherapy; Disabling Mitochondrial Peroxide Metabolism as an Effective Therapeutic Approach; Targeting the Epigenome in MPM; Recent Findings on Mesothelioma and BAP1 and more.

The Symposium will be led by Robert B. Cameron, MD, FACS, Director of the UCLA Mesothelioma Comprehensive Research Program and Chief of Thoracic Surgery at the West Los Angeles VA Medical Center. The roster of distinguished international faculty at the Symposium will include Anna Nowak, PhD of the University of Western Australia; Luana Calabrò, MD, University Hospital of Sienna, Italy; David S. Schrump, MD, National Cancer Institute, Maryland; Jacques P. Fontaine, MD, Moffit Cancer Center, Tampa; Brian Cunniff, PhD, University of Vermont; Haining Yang, MD, PhD, University of Hawaii; Arti Shukla, PhD, University of Vermont as well as local experts from UCLA.

“This event highlights the most promising medical advances in the treatment of mesothelioma as well as promising new research,” said Dr. Cameron. “Over the past five years we’ve seen unprecedented advances in mesothelioma research that we never would have predicted a decade ago. Our intensive collaborations between laboratory and clinical scientists are yielding new insights into promising future treatments for mesothelioma such as immunotherapy, which is the most recent breakthrough for treating cancer. The symposium gives an unrivaled opportunity for both the medically savvy and general public, including mesothelioma patients, to not only learn first-hand about groundbreaking discoveries, but also to exchange ideas.”

The Symposium is supported by: Worthington & Caron, P.C., Waters, Kraus & Paul, Asbetos.com and the International Association of Heat & Frost Insulators.

Early Bird tickets can be purchased before September 6th online at http://www.cme.ucla.edu/courses/.

The Pacific Mesothelioma Center Receives $1 Million Anonymous Challenge Grant to Help Fight Mesothelioma

LOS ANGELES, CA, USA, August 15, 2017 /EINPresswire.com/ — The Pacific Mesothelioma Center (PMC), a division of The Pacific Heart, Lung & Blood Institute (PHLBI), is pleased to announce a generous $1 million grant from an anonymous donor. The challenge grant is committed over the next four years with the challenge for the PMC to raise matching funds for additional immunotherapy research.

The grant will be used to support a molecular biologist and an immunologist working on novel immunotherapies for mesothelioma. Malignant pleural mesothelioma is an asbestos-related cancer that affects the lining of the chest – the pleura. Immunotherapy is an exciting and promising cancer treatment that uses the body’s immune system to fight cancer. It is the PMC’s firm belief that the future of mesothelioma treatment will involve combination therapy, including surgery, radiation, chemotherapy and immunotherapy. Further, rational combinations of various immunotherapies combined with traditional cancer therapies, holds the greatest promise for real progress in the treatment of mesothelioma and other cancers. The donation will help propel this initiative forward.

Upon an annual review by the anonymous donor, a grant of up to $250,000 will be awarded each year until 2021. Gifts can be made by mail (10780 Santa Monica Blvd, Suite 101, Los Angeles, CA 90025) or online, at http://www.phlbi.org/about/get-involved/donate/.

As a result of this generous grant, the PMC are pleased to announce the appointment of two new Molecular Immunologists who have worked at the Universities of Cambridge and Oxford, the University of Pennsylvania and Cedars Sinai Medical Center. Masahide Tone, Ph.D will bring his immense knowledge, vast skills and leadership capabilities to the PMC lab as Senior Researcher and Director of Research. Yukiko Tone, DSc will be a senior research scientist. Their positions commence on August 21st, 2017.

“This pledge comes at a really exciting time in immunotherapy research,” said Dr. Robert B. Cameron. “For the first time ever, we are seeing real benefit of immunotherapy for malignant pleural mesothelioma. Combining different immunotherapies with more traditional cancer treatments, like surgery, in rational ways holds great promise for finally improving the survival of patients with this formerly fatal disease.”

Dr. Cameron is a pioneer in the field of mesothelioma, Director of the Comprehensive Mesothelioma Program at UCLA, Professor of Surgery at UCLA and Chief of Thoracic Surgery at the West LA Veterans Affairs Medical Center. He is also one of the PMC’s Scientific Advisors.

Immune Checkpoint Blockade and Adaptive Immune Resistance in Cancer

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.

Researchers Offer New Hope to Meso Sufferers at the 6th International Symposium on Malignant Pleural Mesothelioma

 6th International Symposium on Malignant Pleural Mesothelioma

The Symposium on MPM Draws a Distinguished Panel of Scholars, Researchers, and Clinicians to UCLA to Discuss the Latest Breakthroughs in Detection & Treatment

LOS ANGELES, CALIFORNIA, UNITED STATES, September 30, 2016 /EINPresswire.com/ — The 6th International Symposium on Malignant Pleural Mesothelioma was held on Saturday, September 24, at the UCLA Meyer & Renee Luskin Conference Center. The focal point of the symposium was on clinical therapies and research data to prevent, detect and treat malignant pleural mesothelioma. Health care professionals including physicians, nurses, and scientists joined students, mesothelioma patients and their families to attend this informative and educational conference. The Symposium was co-hosted by The David Geffen School of Medicine at UCLA and the Pacific Mesothelioma Center (PMC).
The morning session was opened by symposium chair, Dr. Robert B. Cameron, MD, FACS, who discussed options for intraoperative adjuvant therapies. “Adjuvant therapy enhances primary therapy,” said Dr. Cameron, Professor of Clinical Cardiothoracic Surgery and Surgical Oncology. The highlights of his presentation centered on how these therapies supplemented standard of care treatments through preoperative, intraoperative, and postoperative therapeutic modalities. Dr. Cameron is a pioneer in the field of mesothelioma, Director of the Comprehensive Mesothelioma Program at UCLA, Senior Professor of Surgery at UCLA, and Chief of Thoracic Surgery at the West Los Angeles Veterans Affairs Medical Center.

“This year was incredibly hopeful as there are new biological advances likely to lead to new treatments in the future” said Dr. Cameron. “Immunotherapy is advancing rapidly and many other therapies, including thermal, chemical, gene and cell-based therapies are on the horizon”.
Additional presentation topics included an update on mesothelioma clinical trials, treatment options such as Cryoablation, Immunotherapy, Mesenchymal Stem Cells, HOX Genes, Targeting Dendritic Cells in Vivo, and East-West approaches to cancer. Other subjects such as the benefits of nurse navigators and tissue-banking resources for researchers were also presented during the symposium.

The symposium’s other distinguished faculty included: Edgar G. Engleman, MD, Professor of Pathology and Medicine Stanford University School of Medicine Palo Alto; Thierry M. Jahan, MD, Professor of Medicine, UCSF; Edward K. Moon, MD, Assistant Professor of Medicine at the University of Pennsylvania; Richard Morgan, PhD Director of The Institute of Cancer Therapeutics University of Bradford, England; Daniel H. Sterman, MD, Director of Division of Pulmonary, Critical Care and Sleep Medicine NYU; Haining Yang, MD, PhD Professor Cancer Biology Program University of Hawaii; Olga Olevsky, MD, oncologist UCLA Medical Center in Santa Monica and assistant clinical professor at UCLA; Fereidoun Abtin, MD, Associate Professor, Department of Radiology, UCLA; Raymond Wong, PhD research scientist at PMC and PHLBI; Ka-Kit Hui, MD, UCLA Center for East-West Medicine, UCLA; Graciela Hoal, R.N., N.P, nurse practitioner at the Mesothelioma Center for Excellence at the VA West Los Angeles Medical Center; and Clare Cameron, PHLBI executive director; PHLBI.

The symposium was supported by: Worthington & Caron, P.C., Eli Lilly and Company, The International Association of Heat & Frost Insulators, and Waters & Kraus.

“International Mesothelioma Conference Will Kick Off at UCLA”

By: Tim Povtak

 

Thoracic surgeon and renowned mesothelioma specialist Dr. Robert Cameron will be hosting the 6th International Symposium on Malignant Pleural Mesothelioma on Saturday, Sept. 24, at the UCLA School of Medicine.

Cameron, director of the UCLA Comprehensive Mesothelioma Program, is a global leader in the development of the lung-sparing pleurectomy/decortication surgery and a vocal advocate for military veterans who develop the asbestos-related disease.

The conference will cover the latest in mesothelioma therapeutics, including novel immunotherapies, gene therapy, upcoming clinical trials and surgical advancements. The purpose is to improve the understanding of multidisciplinary treatment, learn about adjuvant therapy possibilities, raise awareness to various types of immunological therapies, and emphasize the need to treat mesothelioma as a chronic disease.

Oncologists, pulmonologists, surgeons, nurses, medical students, mesothelioma advocates, patients and families across the nation will attend to exchange thoughts and ideas.

The Mesothelioma Center’s Patient Advocates Karen Selby and Vanessa Blanco will participate, ensuring patients and loved ones who reach out to the organization in the coming months will receive the latest information on mesothelioma treatments.

Selby, a registered nurse with a surgical and oncological background, joined The Mesothelioma Center in 2009.

“It’s important for us to be there, hearing about the cutting-edge research and learning about it even before it is published,” Selby said. “We go there to learn what’s working for patients, and what isn’t. It really helps us help our patients.”

The recently opened UCLA Luskin Conference Center will host the symposium. Each speaker will allow a question and answer session following the presentation. Patients, families and speakers can network during the intermissions.

International Panel of Mesothelioma Specialists

A panel of international specialists, including Cameron, will discuss a variety of important topics at the mesothelioma conference. These include:

  • Options for Intraoperative Adjuvant Therapies, Cameron
  • Genetic Immunotherapy for Pleural Mesothelioma, Dr. Daniel Sterman, New York University School of Medicine
  • Targeting Dendritic Cells in Vivo for Tumor Immunotherapy, Dr. Edgar Engleman, Stanford University School of Medicine
  • HOX Genes as Targets and Markers in Mesothelioma, Dr. Richard Morgan, Institute of Cancer Therapeutics, University of Bradford, England
  • Mesothelioma Prevention and Early Detection, Dr. Haining Yang, University of Hawaii Cancer Center

Pacific Heart, Lung & Blood Institute Executive Director Clare Cameron (no relation to Dr. Robert Cameron) will speak on mesothelioma tissue-banking resources for researchers.

“I think patients and families especially will get a lot out of the symposium this year,” Clare Cameron said. “This could be our best symposium yet.”

Mesothelioma Conference Is a Learning Experience for All

Mesothelioma is the rare and aggressive cancer caused by exposure to asbestos fibers. It is diagnosed in an estimated 3,000 people annually in the U.S. And while researchers made many advances in recent years, these breakthroughs reach the oncology community slowly, accentuating the need for the symposium.

Other clinical titles that will be discussed include:

  • Cryoablation in the Management of Recurrent Mesothelioma, Dr. Fereidoun Abtin, UCLA School of Medicine
  • Role of Immunotherapy in Advanced Pleural Mesothelioma, Dr. Thierry Jahan, University of California-San Francisco Comprehensive Cancer Center
  • East-West Medicine Approaches to Cancer Therapy, Dr. Ka-Kit Hui, Centers for Integrative Medicine, UCLA School of Medicine
  • Harnessing the Full Potential of Immunotherapy by Targeting the Tumor Microenvironment, Dr. Raymond Wong, Pacific Heart, Lung & Blood Institute

“The symposium is important because it’s a learning experience for everyone who comes,” Clare Cameron said. “There is still so much we can learn about this disease.”

6th International Symposium on Malignant Pleural Mesothelioma Schedule

 

6th International Symposium on Malignant Pleural Mesothelioma Program 

Jointly Hosted by the David Geffen School of Medicine at UCLA and the Pacific Mesothelioma Center 

Saturday, September 24th, 2016 at the UCLA Luskin Conference Center 

Mesothelioma_2016 Brochure Cover (1)      Luskin Center      hollywood

7:30                           Registration and Breakfast

                                                                                                                                                                                                    

8:00                           Welcome  Robert B. Cameron, MD, FACS

 

Morning Session I:

Moderator: Robert B. Cameron, MD, FACS

 

8:15                           Options for Intraoperative Adjuvant Therapies Robert B. Cameron, MD, FACS

                                     

8:45                           Update from Recent Mesothelioma Clinical Trials  Olga Olevsky, MD

                                     

9:15                           Cryoablation in Management of Recurrent Mesothelioma Fereidoun Abtin, MD

                                     

9:45                           Discussion

 

10:00                        Break

 

Morning Session II:

Moderator:  Olga Olevsky

 

10:15                        The Role of Immunotherapy in Advanced Pleural Mesothelioma Thierry Jahan, MD

                                     

10:45                       Genetic Immunotherapy for Malignant Pleural Mesothelioma  Daniel Sterman, MD

                                     

11:15                        Targeting Dendritic Cells in Vivo for Tumor Immunotherapy  Professor Edgar Engleman

 

11:45                        Discussion

 

12:00                       Lunch

 

Afternoon Session I:

Moderators: Robert B. Cameron, MD, FACS and Raymond Wong, PhD

 

1:00                           HOX genes as targets and markers in mesothelioma   Professor Richard Morgan

                                     

1:30                           Adoptive Immunotherapy Utilizing Chimeric Antigen Receptor  Edmund K. Moon, MD

                                     

2:00                          Harnessing the Full Potential of Immunotherapy by Targeting the Tumor Microenvironment.  Raymond Wong, PhD

                                     

2:30                          Mesothelioma Prevention and Early Detection  – Are we there yet?  Haining Yang, MD, PhD

     

3:00                          Discussion

 

3:15                           Break

 

Afternoon Session II:

Moderator: Robert B. Cameron, MD and Clare Cameron

 

3:30                           East-West Medicine Approaches to Cancer Therapy  Ka-Kit Hui, MD

 

4:00                          The Benefits of Nurse Navigators in Mesothelioma  Lien Hua-Feng, NP and Graciela Hoal, NP

 

4:20                           Tissue-Banking Resources for Researchers  Clare Cameron

 

4:40                           Discussion

 

4:55                           Concluding Remarks   Robert B. Cameron, MD, FACS

 

5:00                           Adjourn

Luskin Center