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The Pacific Mesothelioma Center Showcases It’s Mesothelioma Research at Holiday Open House

The nonprofit medical research institute is hosting its annual holiday open house on December 6th at its in-house research lab in Los Angeles

LOS ANGELES, CA, USA, November 30, 2017 /EINPresswire.com/ — Fresh off the heels of its successful 5K Walk for Mesothelioma, The Pacific Mesothelioma Center at the Pacific Heart, Lung & Blood Institute (PHLBI) is excited to celebrate the holidays at the annual PMC Holiday Open House on Wednesday, December 6th, 2017 from 12 p.m. to 7 p.m. at the PMC office in Los Angeles. The annual open house showcases the innovative research conducted at PMC at their in-house research laboratory. Attendees will be able to meet the PMC researchers, learn about the exciting research taking place in the lab, eat delicious food from French- Moroccan eatery Chez Marie, and watch student interns perform live demonstrations.

The Pacific Heart, Lung & Blood Institute (PHLBI) is a 501(c)(3) nonprofit medical research institute that is trying to find better treatment options for diseases of the heart, lung, and blood including mesothelioma- a devastatingly under-researched and underfunded cancer that is caused by exposure to asbestos. The PHLBI operates two laboratories, one at its office on Santa Monica Blvd and the other, The Punch Worthington lab. at UCLA. The PHLBI’s current focus is on engineering mesenchymal stem cells to be used in combination with immunotherapy to treat a variety of cancers including mesothelioma.

The open house is being held at the Pacific Heart, Lung & Blood Institute’s office in Los Angeles (10780 Santa Monica Blvd, Suite 101, Los Angeles, CA, 90025) and will start at 12 p.m. and end at 7 p.m. Individuals new to the PHLBI are encouraged to attend so they can learn more about the institute, it’s exciting research, meet the researchers, and learn about the events held throughout the year to raise awareness and funds for research, including the 5K Annual Walk/Hike and The Greatest Escape Motorcycle Ride.

For more information about the Holiday Open House, please contact Clare Cameron at (310)-478-4678, or email to info@phlbi.org.

Year End Appeal Letter 2017

 

 

December 2017

Dear Friend,

This has been a truly groundbreaking year for The Pacific Heart, Lung & Blood Institute (PHLBI), making major strides in our laboratory investigations.   We have accomplished so much in 2017 and the year is not over yet.  We filed a patent for our mesenchymal stem cells in June …we recruited two new scientists in August … upgraded the lab. … expanded the student internship program … bought new equipment … received some expensive donated equipment…extended our tissue bank and now we are well on our way to furthering our research on gene-modified stem cells.  We are hoping to get feedback from the FDA to launch a clinical trial next year, to determine how well our unique anti-cancer interventions work in humans.

Our new scientists have experience in immunology and molecular biology.  Dr. Masahide Tone is our Director of Research and Senior Research Scientist.  He received his PhD at Tohoku University in Japan.  His wife Dr. Yukiko Tone, PHLIB’s Senior Researcher, received her degree at Tokyo Metropolitan University in Japan.  Both scientists have worked at Cambridge University, Oxford University, the University of Pennsylvania and Cedars Sinai Medical Center.  We are honored that they chose to join our lab and we are all very excited for the potential we have with our cutting-edge research program that could significantly advance anti-cancer research.

This year we have had some amazing fundraisers where we have experienced so much more than a motorcycle ride or a 5K walk.  We never forget those who are struggling in their fight against mesothelioma as well as their families.  For PHLBI it’s about the incredible lives that have touched us, people from all parts of the world and all different professions, and life stories that we have shared.

We were fortunate to receive an anonymous matching grant of $250,000 for contributions we receive between now and December 31st.  So please make your gift today and it will be worth twice as much!  If you would like to contribute to our annual appeal, please make an online donation at: http://www.phlbi.org/about/get-involved/donate or mail a donation in the self-addressed envelope enclosed.  Please note that all donations are tax deductible.

With you by our side, we hope to fulfill our joint dream of finding a cure for mesothelioma and other life-threatening chest diseases. Your charitable contributions are most welcome and appreciated.

Thank you for your commitment to PHLBI over the years and for your renewed generosity. On behalf of our patients and their families, may we wish you a Happy Holiday Season.  We are honored to have you on our team.

Sincerely,

Clare Cameron

Clare Cameron

Executive Director

ccameron@phlbi.org

310-478-4678

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.

Immunotherapy 101

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 

Inquiries with the Investigator: CAR-T Cell Therapy

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.

Inquires with the Investigator : Using MSC’s in Placenta’s for Mesothelioma Research

placenta

What is a placenta?

A placenta is a flattened circular organ that develops in a woman’s uterus during pregnancy. The placenta attaches to the uterine wall and develops an umbilical cord which is then used to provide oxygen and nutrients to the growing baby while simultaneously removing waste products from the baby’s blood. The day of delivery the expectant mother delivers her baby and her placenta. Placentas are usually thrown out by hospitals after delivery, some mothers elect to keep it and have it made into a pill or shake and eat it, while others decide to donate the placenta for research.

 

Placenta Donations to The Pacific Mesothelioma Center

Over the last two years The Pacific Mesothelioma Center has received six placenta donations from families. The placentas biological makeup is rich in mesenchymal stem cells which are ideal for advancing the PMC’s research agenda. This past week Lead Research Investigator Raymond Wong received another placenta donation and took the time to share his process harvesting placentas and explaining their intrinsic value to research.

 

What are you getting out of the placenta and how does it help our research?

Placenta contains mesenchymal stem cells (MSCs), a type of cell that normally serves as a reservoir to replenish tissue – primarily fat, cartilage, and bone.  MSCs can be isolated from placenta and expanded to large numbers for laboratory research and also for medical treatment.  MSCs are of interest to medical researchers as they might be useful for treating certain degenerative conditions such as arthritis, diabetes, heart maladies, and even nervous system injuries.  Due to their natural anti-inflammatory properties, MSCs might also be useful for treating inflammatory conditions such as graft-vs-host disease and Crohn’s disease.  For cancer, MSCs are believed to preferentially migrate to malignant tumors.  This opens the possibility that MSCs can be engineered to deliver anti-cancer drugs preferentially to tumors, thereby increasing the potency of anti-cancer drugs while also limiting toxic side effects.  PHLBI is working on engineering MSCs to deliver immune-boosting proteins as a form of immunotherapy.

 

Explain the significance, if any, of the sex or ethnicity of the baby’s whose placenta is donated?

MSCs harvested and grown from placentas can originate from the mother, the baby, or a mixture of both.  The composition of each batch of MSCs is unpredictable with regard to the exact mixture.  The ethnicity of the mother or baby is unlikely to have significance.  The sex of the baby may influence the level of anti-inflammatory properties of the resulting batch of harvested MSCs.  This might impact the ability of a particular MSC batch to be universally compatible with genetically diverse recipients who are infused with donated MSCs.For reference, the immune system of males vs. females is generally known to be different.  For reference, females have higher incidences of inflammatory disorders, which might suggest that MSCs from a female baby have lower anti-inflammatory properties.  The lower anti-inflammatory properties of female-derived MSCs could possibly make them more prone to being rejected when infused into a genetically unrelated recipient.

newPNG *Pictured above is Lead Investigator Raymond Wong  working on a placenta donation last week in the lab.

 

Describe the process for getting mesenchymal stem cells out of a placenta? How long does it take?      

 Placentas are first cut into small pieces, and then digested for ~2 hours with an enzyme called collagenase to loosen MSCs.  The resulting mixture of digested placental cells contains a very small percentage of MSCs.  By growing the digested placental cell mixture in specialized nutrients, the small number of MSCs is expanded exponentially to large numbers.  This process results in nearly 100% purified MSCs within 3-4 weeks.

 

What is the difference between a placenta from a c-section and placenta from natural birth?

Biologically, there is no difference.  The main impact of c-section vs. natural birth is the amount of microbial contaminants on the placenta when it is obtained.  C-section is a sterile surgery, resulting in lower microbial contaminants.  Natural birth passes the placenta through the virginal canal, resulting in a much larger amount of microbial contaminates (yeast, bacteria, fungus, etc).  Nonetheless, our laboratory protocol for harvesting MSCs utilizes anti-fungal and antibiotic drugs to eliminate microbial contaminants.

 

 How many placenta donations are we looking to have donated each year?                                                              

We have averaged around 2-3 placenta donations each year.

 

 Are any embryonic stem cells cultivated from the placenta?                                                                                                  

MSCs are not embryonic stem cells.  They are considered “adult” stem cells, meaning they are derived from organs that have already developed (bone marrow, placenta, etc).

For questions, additional information, or inquires about how one can donate their placenta to research contact Lead Investigator Raymond Wong at (310)-474-1113 or by email at : rwong@phlbi.org .

Immunotherapy Inquiries

Inquiries with Investigator Raymond Wong : Immunotherapy Immunotherapy Inquiries with Raymond Wong

  1. What is immunotherapy and how does it differ from more common types of cancer treatments such as chemotherapy, radiation, and surgery?

Immunotherapy comprises a class of treatments that activate patients’ immune systems to fight cancer.  In general, immunotherapy is better tolerated by patients and has fewer side effects than chemotherapy, radiation, and other molecular-targeted cancer drugs.  Furthermore, unlike chemotherapy, radiation, and surgery, the beneficial effects of immunotherapy often continue even after stopping treatment.  This is due to establishment of immunologic memory, similar to how preventive vaccines can protect an individual for years/decades after initial immunization.

 

  1. Why doesn’t the immune system naturally fight cancer?

Under normal circumstances, the immune system routinely detects and destroys cancer cells (even pre-cancerous cells).   Some cancer cells evade detection by the immune system and progress to form tumors.  This process of immune evasion can be rapid (weeks/months), or prolonged (years/decades).  Multiple mechanisms can allow cancer cells to evade the immune system, such as random mutations in cancer cells, and the overall health of the patient.  Scientists are still trying to fully understand how cancer cells evade the immune system.  Improved understanding of cancer immune evasion will help guide the development of new immunotherapies that effectively reverse these mechanisms.

 

  1. Describe the different types of immunotherapy? Which are the most successful?

Different forms of immunotherapy exist, including vaccines, cytokines, engineered antibodies, and engineered immune cells.  Most immunotherapies are administered intravenously, while some are injected subcutaneously.  The most successfully immunotherapies are immune checkpoint blockers, which are now FDA-approved for multiple cancer types.  Immune checkpoint blockers are engineered antibodies that target specific proteins that impair immune responses against tumors.  The patient’s immune system then becomes more active, sometimes resulting in complete destruction of existing tumors.

Other promising immunotherapies in clinical trials include chimeric antigen receptor (CAR) T cell treatment.  CAR T cells are created by removing T cells from a cancer patient’s circulating blood, engineering them with cancer-targeting receptors, and then re-infusing them back into the patient.  CAR T cells are showing a high cure rate for certain treatment-refractory blood cancers.  However, CAR T cells have limited potency against solid tumors, and side effects can sometimes be severe.  It will likely be years before CAR T cell technology is fully optimized to reduce side effects to acceptable levels.

 

  1. Which cancers are currently FDA-approved for immunotherapy treatment?

Melanoma, prostate cancer, lung cancer, kidney cancer, bladder cancer, and Hodgkin’s lymphoma.  Immunotherapy for other cancer types, like mesothelioma, are typically accessible only through clinical trials.

 

  1. What is the future of immunotherapy? How do you see it changing cancer treatment in the next five years? 

Currently, there is serious discussion of immune checkpoint blocker immunotherapy moving towards first-line treatment for melanoma and lung cancer.  As clinical trials progress, it is possible that these treatments may also become a first-line treatment option for other cancer types.  Combination immunotherapy, whereby different immunotherapy drugs are used together, is now being actively studied in clinical trials.  In fact, the first combination immunotherapy regimen (nivolumab + ipilimumab) was FDA-approved for melanoma in 2015.  This particular combination, and other combination immunotherapy regimens in development, is likely key to improving patient response rates.

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.